ETHICAL ISSUES IN INTERNATIONAL HEALTH
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- ETHICAL ISSUES IN INTERNATIONAL HEALTH
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Ethical Issues in International Health
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June 14 -18,1999
Center for Continuing Professional Education
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Future Challenges to the Ethics
of Human Experimentation
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HAROLD EDGAR and
DAVID J. ROTHMAN
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Columbia University
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POLITICAL AND
GOVERNANCE
INSTITUTION,
nothing in the regulatory domain resembles the institutional re
view board (IRB). To invert the classic story about God del
egating authority to a committee to perfect His creations and getting a
giraffe in return, the IRB is the giraffe, so odd is it when compared to
other creatures in the jungle.
Despite its many idiosyncrasies, over the past two decades IRBs have
transformed the conduct of research projects involving human subjects.
Unquestionably, their very existence has tempered the inevitable pro
pensity of researchers to pursue investigations without dispassionately
weighing the risks they are asking others to assume or fully informing
their subjects of them. Indeed, IRBs have been so successful as to set an
international standard for monitoring clinical research.
Nevertheless, in the American context, the very proliferation of these
committees, to the point where they arc to be found in every type of in
stitution conducting research, raises critical questions about uniform
standards and performance. Is it truly the case that a "one size fits all”
approach works well? Arc the same general procedures for appointing
members and defining their obligations appropriate for reviewing re-
The Milbank Quarterly, Vol. 73, No. 4, 1995
© 1995 Milbank Memorial Fund. Published by Blackwell Publishers,
238 Main Street, Cambridge, M?t 02142, USA, and 108 Cowley Road.
Oxford 0X4 1JF, UK.
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search conducted pot only at the Central Intelligence Agency (CIA), the
Burcau/of Prisons, and. the National Institutes of Health (NIH), but also
at for-profit hospitals, local community hospitals, and university-affiliated,
tertiary-care centers? Docs it make sense to give the leadership of an institu
tion, which by its very nature cannot survive without the funds and fame
brought in by clinical research, the responsibility for appointing the mem
bership of a monitoring committee? Or, more broadly framed, is the local
and institutional basis of IRB organization still appropriate? Are the as
sumptions that initially underlay that choice still valid? The goal of this
essay is to suggest that the answers to these questions may well be no,
and to provide some modest, but potentially important, recommenda
tions for change. IRBs can take credit for remarkable accomplishments,
but it may be time to revise the framework governing human experi
mentation.
The IRB Structure
The IRB system rests on two sets of federal regulations. The first com
mits various agencies of the U.S. government to securing IRB approval
before research is conducted on human subjects, cither in house or through
the grants they fund for outside projects. Government-supported biomedi
cal research is the paradigm case.’ Before any federal money can be ex
pended on research involving human subjects, the regulations require that
a protocol must be approved by this institutionally based committee, with a
membership of no less than five persons, at least one of whom must not be
affiliated with the institution. The IRB’s central charges are, first, to review
whether the benefits of the proposed research outweigh the risks, and sec
ond, to make certain that the investigators have explained all the relevant is
sues so as to secure the subject’s informed consent. Although the federal
regulations that establish the IRB system apply only to federal activities and
federally funded grants, many states require IRB review for all research per
formed within their jurisdiction, no matter how it is funded. Moreover, the
vast majority of academic institutions choose to review all their research pro
tocols through an IRB, rather than reviewing some, but not others, on the
basis of who is providing the funding.
1 45 Code of Federal Regulations | 46.101 et seq.
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Thus, the power to approve or disapprove research on ethical grounds
is granted to a local institutional committee, composed pf members of
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Contrary to what many people presume, IRB regulations do not require
the review of all innovations in medical practice, let alone all instances of
physicians following their preferred treatment strategies without ascer
taining whether their approach works better than someone else’s. The
IRB focuses exclusively on activities intended to gain generalizable
knowledge, and to the extent that someone, a surgeon for example, for
swears an interest in general knowledge and presumes that the best way
to treat Parkinson’s disease is to burn the brain’s pallidum —to take an
illustration from the Wall Street Journal's headline story of February 22,
1995 —that surgeon need not bring his new technique before an IRB.2
Independent of federal funding regulations, the Food and Drug Ad
ministration (FDA) requires that protocols involving human subjects and
new drugs or medical devices must be approved by IRBs. For example,
were a surgeon to use a new commercial medical device in order to ac
complish a proposed intervention, FDA procedures would be triggered.
Insofar as testing new drugs on human subjects is concerned, FDA regu
lations are in important respects the same as those imposed by the De
partment of Health and Human Services (DHHS) on research institutions
seeking grants. Yet FDA oversight differs in several important respects.
FDA reviewers themselves examine the merits of the protocol and do not
leave all decision-making to the IRB. Thus, in ways that overlap or su
persede an IRB finding, FDA reviewers may reject research that they
consider too risky or may compel investigators to carry out more animal
studies before beginning clinical trials. At the same time, the FDA may
impose strict regulations on the manufacture of drugs and biologies before
they are tested, again going well beyond the IRB’s usual safety concerns.
The FDA procedures do provide a degree of national oversight for
clinical research. In addition, some funding agencies may conduct their
own reviews of a protocol’s research ethics; NIH study groups, for exam
ple, have been known to do this on occasion, rejecting a proposal on eth
ical grounds that a local IRB has already approved. But many human
experiments do not come under either FDA or NIH study group pur
view, leaving decisions about the ethics of research solely in the hands of
the IRB.
2 On the IRB and FDA regulatory process see, in general: 39 Federal Register
18917 (May 30, 1974); National Research Act of 1974, P.L. 93-348, 88 Stat. 342
(Title II), U.S. Cong;ress and Administrative News, 95rd Cong., vol. 1, p. 379;
. i .nd 46
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the IRB Icve room for diM«i.f«tlo^D«pl« rhe .mourn of ume th«
IRBs devote to examining the Irmgu.ge of the consent form, they .re not
reauired to investigate whether the consent language they haxntnet^out
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so onerous, causing innumerable delays, that the investigator left the in
stitution within months.
Nevertheless, the IRB s autonomy and isolation are largely theoretical,
in that no federal controls or regulations exist on how the institution de
cides who gets appointed to the committee, how long those persons stay,
or on what grounds a member may be dismissed or not reappointed.
Indeed, powerful people within an institution have a myriad of largely
untraceable ways for punishing an obstructionist IRB member: from with
holding or delaying promotion to blocking his or her access to other grants a fact that no IRB member can fail to recognize. Similarly, there are no
formal controls on the selection of the outside and unaffiliated members,
of these outsiders may understand and appreciate the scientific or ethical di
mensions of research, there is no way to ensure that they arc anything other
than a friend of a trustee, looking for an opportunity to participate in an in
stitutional activity.
finally, not only the formal structure but also the actual workings of
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Thus, the power to approve or disapprove research on ethicaf grounds
is granted to a local institutional committee, composed pf members of
the same institution'•(with the one necessary exception) that is seeking
the funding. Moreover, by all reports, the members who dominate the
IRB discussions are these insiders, not the outsiders (who arc everywhere
a distinct minority). So, in effect, the key decision-makers on thc IRB
arc colleagues who must live with any disappointed applicants whose
protocols they have rejected. Furthermore, most IRB committee mem
bers arc themselves researchers and the standards they set for others will
come back to bite them too.
To be sure, the IRB is uniquely well protected from formal institu
tional domination. Unlike most committees, which arc structured to ex
ercise power delegated by a parent and arc ultimately responsible to that
parent, an IRB decision to disapprove research may not legally be over
turned by the institution. For example, if it believes it has grounds to do
so, an IRB can effectively terminate a researcher’s career at a particular
institution by rejecting his protocols or by insisting on such close super
vision that it becomes impossible for him to carry out investigations. At
one institution, a researcher, whose casual attitude toward consent was
notorious, was required by the IRB to have one of its members present
whenever he obtained consent from a subject. The requirement proved
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the IRB Icave room for dissatLsfaction. Despkc the amount of time that
IRBs devote to examining the language of the consent fotm, they are not
required to investigate whether the consent language they hammer out
either is actually used on the floor or serves to educate the patient about
the nature of the research he or she has consented to. It is rare for an IRB
to leave the confines of its committee room and examine what actually
occurs in the consent process.
In effect, then, the regulations governing the IRB arc, to say the least,
a permeable shield, with no strong framework to ensure that subjects’
interests take precedence over institutional, ones. The judgments that
will be made on this basis need mot be so flagrant as to eventually pro
voke a scandal. Balancing research risks against benefits is complicated,
and a committee that consistently makes the calculus in favor of the re
search will hardly ever be identified. On occasion, a glaring miscalcula
tion will command headlines; the decision of the UCLA IRB to allow
investigators to withdraw medication from schizophrenic patients in the
course of a trial may be one such instance. But the overriding point is
not how typical the UCLA actions arc, but how the IRB system provides
so few bulwarks against this tilt in decision making (Office for the Pro
tection from Research Risks 1994).
To put the case bluntly, if one were to look at the IRB exclusively in
terms of formal structure and organizing principles, it would seem to be
a paper tiger. An individual serving on the body and an institution orga
nizing it may fulfill the highest ethical standards; any one participant
may claim, with full justice, that his or her IRB is exemplary in its func
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tioning. Nevertheless, there arc very few provisions in the regulations
that protect against bodies that might be sloppy, venal, or subservient to
the institution. Put another way, the quality of an IRB s work depends
to an inordinate degree on the conscience and commitment of its volun
teer members. The fact that the NIH has created an Office for the Pro
tection from Research Risks (OPRR) in no way mitigates this point. OPRR
is empowered to review the membership roster on local IRBs, but because
the formal requirements arc so minimal, such review is of limited effect.
Nor docs OPRR have the funds or personnel to conduct regular and ongo
ing examinations of how individual IRBs normally function. If OPRR docs
learn about a particular ease (either through the institution, the press, or
the grapevine), it will investigate ihc incident. In 1994, however, the office
made only 10 site visits (Burd 19 )5).
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Experimentation
this, of course, was precisely the basis on which America fought the
ideological contest in the difficult years of the late 1940s and early
1950s, when the communist movement threatened to win elections in Italy
and France and indeed throughout Western Europe (Annas and Grodin
When and why did the IRBs assume this peculiar structure? Why were
SXr in the first p,acc'and why was their
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1992; McNeil 1993).
From an American perspective, a maximization of collective welfare
was not a legitimate basis for imposing harms of whatever magnitude
upon individuals. Theories of individual rights set a limit on govern
ment authority, even if the community was then less well off, a position
that was taken seriously at a time when the rate of Soviet economic growth
allegedly surpassed our own. Although it took some 20 years for Nurem
berg to become synonymous with the horrors of human experimentation —
what caused the initial period of silence and why it came to an end is still
not well understood —by the mid-1960s, and even more prominently in
the 1970s and 1980s, the lessons to be drawn from the Nazi experience be
came widely recognized and shared.
These events represent a fascinating twist in the history of political
theory in America. The intellectual leadership of the United States be
fore World War 11 was profoundly committed to general utilitarian val
ues. For example, one way to characterize the fight over the New Deal
was as an argument by opponents that the proposed reforms violated tra
ditional property and contract rights, which was countered by propo
nents with the claim that such rights should be limited by public needs.
In effect, conservatives were defending individual rights and liberals were
ready to restrict them in the name of collective well-being. Similarly, such
seminal legal thinkers as Oliver Wendell Holmes and Felix Frankfurter
were forever extolling the need for general legal standards and for impos
ing such requirements on people whether or not they could measure up to
them. Holmes wrote that he would tell a person about to be executed, who
might have had no power to avoid his wrongful deed, that he should regard
himself as a soldier in the cause of general deterrence of crime.
This persistent and powerful strain of ideological positivism in the
United States was brought into disrepute in the postwar era because it
provided no sure stopping point whenever those in power believed a
course of action to be absolutely necessary for collective well-being. In
deed, recall Justice Holmes’s decision in Buck v, Bell, justifying the ster
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the sacrifice wnwws
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StOry ?rnSln tt,C Car'y 1960S' Whc" ,hose ctlar8cd with adminis
tering research fundmg. particularly at the NIH, took note of the public
uror generated by exposes of gross abuses in medical research. These in
cluded the uncontrolled promotional distribution of thalidomide throughout t e Umted States labeled as an experimental drug; the administration
of cancer cells to senile and debilitated patients at the Brooklyn Jewish
ironic isease Hospital; and the uncontrolled distribution of LSD to chil
dren of several prominent families at Harvard through Professors Alpert and
eary^Most important, of course, was Henry Beecher’s 1966 article in the
EnglandJournal ofMed.cme, detailing 22 protocols of dubious ethicaluy and declanng that the roster had been winnowed down from a longer list
culled more or less from periodicals crossing his desk (Beecher 1966; Roth-n 198 , 1991). nih officials. as administrator of government funds.
deeply concerned about the impact of these scandals and moved in pre
emptive ways to ensure that Congress would not curtail research ffinding
What accounts for the extraordinary capacity of medical experimenta
tion abuse to be perceived as a major scandal, even when the provable
physical harms that resulted from it were small, certainly when compared
to the harms done by impaired physicians (an issue that has never sparked
pubhc furor)? The answer lies in the unique combination of events that
made human experimentation a symbol for the two great nightmares of
twentieth-century life. The first is the frightening power of some political
'deolog'es to demand that no private interest impede the accomplishment
of the public good. The second is the acute fear that man must adapt to
whatever science produces, and that science is ultimately beyond social
control.
In imprinting the first nightmare, the significance of the crimes commuted by the Nazi doctors cannot be overstated. The U.S. government
used the war crimes trials to teach that there must be limits to government power. One could not justify maiming and killing by claiming that
the state required answers to pressing medical questions. Even an institu
tion once as prestigious as German medicine was corrupted by succumbldeotogv
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community. The case of Buck v. Bell, not surprisingly, was frequently
invqkcd by German defense lawyers at Nuremberg?
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The experience of convicting Nazis has had the ironic result that the
victors’ earlier confidence in general utilitarian theories was largely su
perseded by the victors’ intelligentsia, in favor of ultimately deontolpgical
theories such as John Rawls’s Theory ofJustice. These theories trace their
intellectual provenance to Kant, and to the German tradition, which was
itself a nineteenth-century rejection of English utilitarian writers like John
Stuart Mill and Jeremy Bentham. The result of this change was that medi
cal experiments and social policy toward them became, in our society, the
symbol of our acknowledgment of absolute limits on the claims the collec
tive can make on the individual, and the rejection of a principle that any
thing goes so long as we are persuaded that more will gain than some will
lose.
These arc not, of course, the only alternatives by which experiments
may he judged, but so powerful is the symbol of clinical research with
out consent that we approach them with extreme reluctance. The contro
versy over whether to permit experiments in emergency situations, where
no consent is feasible, illustrates the attitude. And the recent fervor over
the radiation experiments that government agencies conducted during
the 1940s and 1950s on unknowing subjects suggests that medical exper
imentation has lost none of its symbolic power (Burd 1994).
If Nuremberg was one critical underpinning for public attitudes to
ward human experimentation, the second was the social awareness that
new medical breakthroughs affected not simply the individual patient,
but also human life more generally, and, given the dimensions of the
potential transformations, the innovations had to be reviewed and au
thorized by someone other than the particular investigator. The rapid
growth in transplant procedures was one dramatic instance: do we as a
society want to promote a medical technology that makes the body into
a collection of spare and reusable parts? Moreover, physicians themselves
were often eager to share responsibilities in decision making, not only so
as to alert the public to what was going on, but also to share the respon
sibility for allocating the novel resources. The most noteworthy case was
that of the Seattle doctors’ move to establish a lay kidney dialysis com
mittee for the purpose of deciding who received the life-saving benefits.
The negative reference point, of course, was the fate of physics and physv. Bell (274 U.S. 200, 47 S. Ct. 584, 71 L. Ed. 1000).
icists who thought about Sanskrit poems as they watched the mushroom
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altered the: course of history without securing a
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of nuclear weapons that encouraged biologists to convene the
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broader consensus about its safety could be secured (Rothman 1991).
The Local Character of the IRBs
Although the scandals in human experimentation drove the decision to
regulate research, they hardly explain why the results placed such heavy
reliance on local, institution-based procedures. One major reason was
that the research community was ahead of the curve of public deman ,
regulating itself before otheis did so. Local, institutional review was the
least intrusive means of allaying public fears. Ask anyone in the pharma
ceutical industry whether they fear more their review by an IRB or their
fate with an investigational new drug (IND) at the FDA, and you will
than the
FDA. An IRB is far
• learn that the IRB is vastly more flexible
1-—---- ------communicate quickly what troubles it and how those troumore apt to ca
The public interest, it should be noted, often
bles may be overcome.
gains significantly from this flexibility, but it comes, as we shall see,
with a price.
The preference for localism drew as well on a whole set of assumptions
about the research enterprise and those who conduct it. First, when the
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IRB mechanisms were put into place over the -----1970s, everyone,
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research. The
the NIH, assumed that funds were readily available
inevitable result of IRB review was to delay things, but the costs of delay
could be absorbed in a generous overhead allotment; moreover, the re
searcher who had to move more slowly on project A could always find
support for project B. In other words, by making review local, the penaltics of regulation were minimized.
Second, regulators presumed that IRBs would almost always operate
within a university teaching hospital where a shared commitment to the
ideals of good science would far outweigh any tendency for persons to
trade favors or elevate concerns for the financial viability of the institu
tion above their loyalty to the integrity of science or the well-being of
subjects. The accepted premise was Robert Merton’s persuasive argument
that the universal principles of science override narrow academic alle
giances. Thus, once science incorporated ethical principles in human ex-
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sucimsts would effectively enforce
them, offsettmg any dangers in localism. Moreover, the forces motivating
0 researchers were promottons, prizes, and grants, all of which depended
upon the respect of peers. No one wouid, therefore, risk imperiling the
prestige of his or her mstitution by letting sloppy or unethical research slide
by. Thus, it seemed as though the local character of IRB review secured all
die advantages that came with being close to or part of the action, without
very scarce, and researchers have no confidence that there will always be
another grant if this one is delayed.
Even more important, many potential subjects no longer regard par
ticipation in experiments as a dangerous activity. The line between experi
ment and therapy has blurred, and human subjects do not necessarily greet
departures from accepted procedures, even exceptionally risky ones, with
suspicion. Accordingly, the IRB presumption that a well-crafted consent
form was a meaningful protection has weakened: subjects may well be sim
ply too eager to obtain what they see as the most advanced and potentially
therapeutic intervention. The shock troops leading the assault on the tradi
tional perspective of risk were persons with AIDS. Their perspective is now
being shared by advocates for those with Alzheimer’s disease, advanced
breast cancer, and indeed, for all those with a deadly illness (Edgar and
Rothman 1990; Rothman and Edgar 1992).
All the while, new medical technologies continue to move society in
totally new directions, with no systemic review of their desirability.
Take, for example, the recent announcement from George Washington
University that its investigators have begun experiments that may lay the
groundwork for human cloning. The research received the approval of
the institution’s IRB. (It turns out that the IRB approved the protocol
without knowing that the investigators had already conducted the re
search. VC^hcn it learned of this breach, the IRB penalized the investiga
tors, compelling them to withdraw an ahitract of their findings for our
purposes, the critical point is that the local IRB did ratify the protocol
and would have allowed the research to go forward [Schwartz 1994).
Those interested in giraffes may note, however, that a committee estab
lished pursuant to federal law directed academics not to publish their re
search, and no widespread discussion of First Amendment implications
has ensued.) But precisely who vested George Washington University
with the responsibility for deciding whether human material should be
so used? Indeed, by what processes were the men and women chosen
who made the ultimate determination to approve it? And what did they
hear by way of opposition to the researchers’ request to go ahead?
Surely, some alternative or supplement to such local decision-making
seems in order (Fackelman 1994).
So too, the proportion of research that is industry funded, rather than
government supported, has increased dramatically, which carries several
critical implications for IRB reviews (National Institute of Health 1993).
Researchers may have entrepreneurial interests in products being tested
funmng the risk of havtng regulators captured by the regulated
Ih.rd, the designers of the IRB system expected that the subjects
themselves were likely to be suspicious about human experimentation,
adopting a cautious, self-protective stand against involvement. Participation
was perceived as both burdensome and risky; experiments were dangerous
and subjects were folly alert to the implications of being a guinea pig. Dis'
cussion of research ethics spoke of the need to distribute fairly the burden of
participation, not relying on and exploiting the poor. All the while, the
attention devoted to the specific wording of consent forms was a way to
guarantee that subjects would be able to act so as to promote their own
self-interest. Well-informed subjects would never put themselves at Undue risk. Where subjects were for one or another reason not capable of
giving consent (owing to the debilitating effects of illness, mental disabd.ty youth, or confinement to a prison), it seemed right to bar them
rom being used as subjects. The one exception was in the event that
they had a spec.al stake in the research mission; research on retardation
for example, might well require that persons with retardation be the
subjects-even then, additional protections had to be employed Research carried such danger that, although the policy was rarely made expilot, women, particularly women of child-bearing age. also seemed to
requtre special protection. The fair sex should be protected, and even
more, the fetus should be protected, lest some experiment adversely affeet embryonic development.
The Limits of Localism
Each one of these three premises has now been substantially undercut
w.th the end result that the localism of the IRB appears to generate more
problems than it solves. The confidence that IRB delay or disapproval
carried no penalties because a surfeit of research opportunities was avail
able has weakened-really disappeared. Money for research has become
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at their home universities. Indeed, the academic institutions face major
issues of conflict of interest because medical entrepreneurialism has be
come a goal of the university itself. For example, whereas Harvard Uni
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versity used to prohibit patenting of medical innovations as contrary to
the public interest, it now has established an in-house investment com
pany to provide seed capital for ideas worthy of commercialization, and
the proceeds of such commercialization are to be returned to the univer
sity and distributed to the inventor, to his or her laboratory, and to re
search more generally (Gupta 1994). Increasingly, universities take
equity positions in faculty-created start-up companies. Although no data
arc available to ascertain the frequency with which medical institutions
hold equity in companies whose products arc tested in their facilities, or
how often researchers have a substantial financial stake in the products
they arc investigating, both phenomena now occur, and arc all the more
likely to occur in the future.4
Indeed, some institutions now function economically as packagers of
patients with rule diseases, rhe concentration of patients at the institu
tion makes feasible corporate-sponsored research protocols that could not
otherwise be done; the institution profits handsomely by providing ex
perimental options to those sponsors, in effect matching sponsors and
volunteers who would not otherwise efficiently find one another. To
these ends, a pharmaceutical company recently purchased an advanced
cancer treatment center, with the hope, we presume, that along with
whatever other benefits the center might bring, it would provide a site
for clinical trials. While the results of these trials may well contribute to
improving medical treatment, the concern is whether the institution’s fi
nancial stake in research has grown so great as to jeopardize the indepen
dence of locally based IRBs.
In fact, for these reasons, and others as well, the academic center,
which served as a paradigm for the IRB, is likely in the future to lose
what was once a near monopoly over research. Its role is being usurped
from at least two sides. One the one hand, huge multistate and inter
national trials have been, and will be, organized, bringing thousands of
patients into a single trial, run by a coordinating group. With research
becoming more national, ethics review on the local level makes still less
sense. Second, the managed care plan provides a perfect site for many
trials. To the extent that health maintenance organizations and other
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prepared to insist as part of the managed care
brings. Indeed, if we are [
rcvolution that cost-containment measures be researched rather than .mpost;; (which we may not be), then an in-house IRB mo^l .s hard.y
equipped to serve as guardian of patrent interests (Freedman 1994).
One final point about the locus of research activity has recently as
sumed exceptional importance. I^e original 1960s assumpt.on that he
university was the site of most human experimentatron mimmrzed th
importance of the fact that a number of government agencies including
the Department of Energy (DOE) and rhe CIA, were already heavdy mvested in such activities. Although there were discussmns and hear g
on whether so local and internal a system made sense in this context a
these agencies in time did agree to come under the regulations and es
tablish their own IRBs, not until the 1994 expose of cold war radiation
research did the disadvantages of this arrangement become the cento o
public attention and policy analysis. I. it truly mcanmgful for the DO
or the CIA to run its own IRB? In light of what we now know about their
activities, the local basis for the regulation of their human expenmenta-
tion seems less satisfactory.
Taking the "I” out of the IRB
If the old paradigms no lenger hold, what revisions should be made m
public policy? Where do we go from here?
The IRB system has worked reasonably well, and to lsrn“"' c 1
would be a mistake. Nonetheless. IRBs were a ’’one sue firs all solu
tion. Obviously, no single reform or institutional structure will be ab
to provide adequate oversight of all biomedical innovations. Accord
ingly, public policy innovations should move forward s.multaneously on
a number of fronts. We mention three.
IRB procedures are completely inadequate to protect the public interest from the ends of resci rch. or to assure sufficient lead time to perrmt
political focus on the lim.ts, if any, that should accompany the develop
ment of new technologies. Mechanisms must he found to assure ha.
proposed research that crosses frontiers achieves pubhc v.s.bthty and pr vides opportunity for poUtical choice before it .s unplememed. In con-
4 35 United States Code, §§ 200-12 (annotated).
;
•••
npl:
how
coni " ‘ this
one ‘ " iwn
tabh
ic
establishment of a super committee or committees,i charged at the
minimum with a monitoring function, at /the maximum with the right
to veto research deemed unacceptable.
How can this be done? Throughout the world, various countries have
established national ethics committees to serve as ongoing advisors on
difficult ethical issues associated with research, and medical practice more
generally. Numerous bills have been put forward to establish such a com
mittee in the United States, and the Clinton Administration has expressed
interest in such a proposal. But, in the past, initiatives have floundered on
the question of who gets to appoint whom to do what, particularly when
everyone knows that the issue of abortion may lie in the background (Of
fice of Technology Assessment 1993).
Three principal and interrelated issues must be addressed in the de
sign of an overarching monitoring mechanism:
First, whether to constitute one committee, endowing it with visibility
and prestige because of its singularity, or several committees, distribut
ing responsibility among members selected for their particular expertise.
The NIH’s recombinant DNA advisory group is; the prototype of the spe
cial committee. And it has worked. Researchers complain about its de
lays, but it has had a profound impact on securing public consensus that
gene research is an appropriate end, and one that can be safely pursued.
Such committees should not, however, be appointed ad hoc, as the re
cent experience with the special committee established to advise the N1H
on embryo research demonstrates. The President rejected out of hand a
key recommendation —to permit the occasional creation of embryos for
limited research purposes—before it was even considered by the NIH.
Had procedures been in place that had earned credibility over time, it
might not have been possible to dismiss a proposed policy in such politi
cally expedient fashion.
Second, to determine how expansive a committee’s jurisdiction should
be: whether it will be limited to reviewing funded grant proposals and issu
ing advisory opinions, leaving the ultimate decisions to local IRBs and re
searchers, or whether its approval will be required before research is
undertaken.
Third, to decide who should appoint such a committee, and what
kind of staff it should have, questions that obviously become more or
less sensitive depending on what powers the committee is granted.
l
wn |
encc
see’
*tipk
nitv
f spc<ap
pointed by DHHS-NIH officials, whose responsibilities woulu extend io
their particular fields of research-neurobiology, genetic therapy, repro
duction-without regard to the sources of the research funding, govern
mental or private.
After considerable hesitation (and an initial difference of opinion be
tween us), we would not grant the committee formal power to halt re
search. Adding another layer to the review of human investigation
would incur too much expense and delay. Instead, we prefer to have
such committees stay abreast of research methods and issues, making
public the significant questions and providing general guidance to local
IRBs about particular protocols. Yes, investigators who can persuade
their own IRBs of the propriety of their work will be able to take the first
research steps in advance of such review (the George Washington Univer
sity cloning research is a case in point). But two considerations seem to
us to reduce the potential risks. For one, frontier research is usually in
cremental. in the sense that the relevant professional community knows
who is involved with research near the boundary and what the likely
pace of advance will be. The presence of professional leaders on a com
mittee with high visibility will encourage people in the field who have
doubts about their own or their colleagues’ agendas to ask whether and
to what extent the issues that concern them have already been analyzed
and considered. For another, expert committees will have ready access to
the media and to policy makert, for biomedical research is (and will iontinue to be) in the public spotlight. Accordingly, expert committees will
have time to foster debate about the research and ultimately provide the
opportunity for an informed political decision on its desirability. In
short, controversies about the stopping points in particular lines of
research-whether they involve cloning, genetic enhancement, or other
novel procedures-will have to be decided ultimately in the political
arena, and administrative mechanisms cannot avoid thA fact.
The second broad area of reform involves improving the present IRB
system to take account of the newly entrepreneurial character of biomed
ical science that we have described.
Many of the concerns we raised are the appropriate object for formal
legal rules. For example, conflict-of-interest guidelines can, and should,
specify the limits on researchers and institutions that are simultaneously
financially invested in the development of products and the testing of
'- ■’V-i -
iHffi
tv/-. t»z/>iiIz4
frtr
mnlr or^cludc investigators from re-
______
^_J_ ..r«.^n’t^c ffc>t
exttiinsututionaA review ■Umade,
°* art.
were a commitment to <
rhr mbiects’ well-being could
1 ■
»
r/»«-r -an/
i
i
:
I
.
g
-dHHK,'
u<
^^#*-«aSS«»MSMS
H
those products. Wc wouldF for example, preclude investigators from re-
4
1
•1
-i;
1
J
/
1
cruiung patients and conducting clinical evaluations where the product
being tested is one in which they hold a commercial stake? So too, pa
tients should be told of any financial commitments that would motivate
the investigator to select this treatment for the patient rather than the
others on hand (Rodwin 1993).
The third direction that reform must take is to strengthen the “out
side” elements of the IRBs, while leaving review based in the institution
itself. Localism has the advantage of accomplishing review not only more
quickly but also with the knowledge, informal as it is, of the character of
the investigators. Most important, it greatly facilitates learning that
something is going wrong: nurses, residents, physicians do not have to
cross institutional lines to inform someone of their concern that a proto
col is not being followed.
IRBs processing a substantial number of protocols should, however,
include experts drawn from scientific groups outside the institution’
Moreover, there must be more focus on the appointment and renewal
process. Wc should also seek to quasi-professionalizc the role of outside
members, linking them in groups that could come together to study
common issues, so that there might be greater uniformity given to con
cepts like minimum risk. (The programs for IRB members run by such
organizations as Public Responsibility in Medicine and by the Office for
the Protection from Research Risks itself provide the beginnings of a
model for such an effon.) The proposition that outside members can
represent a relevant “community’’ has always seemed suspect to us; and
we would prefer to see on each IRB a member who felt loyalty to a newly
constituted community of research ethics advisors.
These stipulations about strengthening the outside role in IRB review
take on special importance when the research is being conducted by the
government itself. To make certain that such bodies as the DOE and the
CIA remain well within the bounds of ethical research, it is vital that
outsiders play an even more important role in their reviews than else
where. To accomplish this change would not be easy, not only because
these bodies arc very insular, but because outsiders also might well re
quire security clearances and have to assume burdens of confidentiality
that would hamper their effectiveness in bringing abuses to light. But
5 A final Public Health Service rule has just been announced. Sec 60 Federal
Register, 35810, issuedjuly 11, 1995.
.. :>..*:J . _ Ytevlew ’mide; litiitgftS Cot'it ‘'
were a commKmcnVto ottralns'dtutionid
once iprotecting
? _ the
1 national
"
‘ !interest and
J the subjects’ well-being could
be designed.
Finally, and almost certainly, we should have far more effective over
sight mechanisms. It would be entirely feasible, for example, for an NIH
office to sample (in the technical sense) protocols from research settings
(not only universities, but also companies and government agencies),
and to include in this effort interviews with the subjects of the research
(reviewing the process by which they gave consent, what they understood
the experiment to be, and how the research itself was conducted). The
very existence of such a procedure might help improve IRB performance.
In sum, it is time to take the superintendence of human research to a
different, and more national, level. Whether this change can be accom
plished within the current political climate is debatable. The necessity
for such a shift is not.
References
Annas, G., and M. Grodin. (Eds.). 1992. The Nazi Doctors and the
Nuremberg Code: Human Rights in Human Experimentation. New
York: Oxford University Press.
Beecher. H.K. 1966. Ethics and Clinical Research. New EnglandJournal
of Medicine 74:1354-60.
Burd, S. 1994. U.S. Will Coordinate Rules on Obtaining Research Sub
jects’Informed Consent. Chronicle ofHigher Education (July 13):A22.
----------- . 1995. Research by the Rules. Chronicle of Higher Education
(April 14):A32.
Edgar, H., and D. Rothman. 1990. New Rules for New Drugs: The
Challenge of AIDS to the Regulatory Process. Milbank Quarterly 68
(suppl. 1): 111-42.
Fackclman, K.A. 1994. Cloning Human Embryos. Science News (Feb. 5):
92- 5.
Freedman, B. 1994. Multicenter Trials and Subject Eligibility: Should Lo
cal IRBs Play a Role? IRB 16 (Jan.-April): 1-6.
Gupta, U. 1994. Hungry for Funds, Universities Embrace Technology
Transfer. Wall Street Journal (July 1):A1, A5.
McNeil, P.M. 1993. The Ethics and Politics of Human Experimentation.
Cambridge: Harvard University Press.
National Institutes of Health. 1993. NIH Data Book (DHHS pub. no.
93- 1261). Bethesda, Md.
Office for the Protection from Research Risks. 1994. Evaluation of Hu
man Subject Protections m Schizophrenia Research Conducted bv
^BeecheXisited. He^EngHnd^al
A Strategic Framework for Infant Mortality
Reduction: Implications for “Healthy Start”
19,-7
DONNA STROBING, PATRICIA O’CAMPO,
KENNETH C. SCHOENDORF, ET AL.*
Books'"1' Strangen at the Bedside (ch»PS- 1-5). New York: Basic
ROtht^n£JeboanTriH| Edgr ' 1992' S.Cientifit Ri8of and Medical R«l<“'$• Placebo Trials in Cancer and AIDS Research. In AIDS' The
Johns Hopkins University
I
£b"h F“ ,"d D“i" P»-
"‘"zzZdSzlZ'"'"” v"'“'d g™
v"'-
HE UNITED STATES RANKED 21ST AMONG DEVELoped countries in infant mortality in 1992 (Wegman 1994), de
spite the fact that it spends 12.2 percent of its gross domestic
product on health care (Levit et al. 1991), more than any other nation.
Although the provisional U.S. infant mortality rate (IMR) of 8.3 infant
deaths per 1,000 live births in 1993 represents a progressive downward
trend (Wegman 1994), the health care system has not been successful in
closing the gap in IMRs with other developed countries (Liu et al. 1992).
Moreover, infant mortality (IM) rates remain persistently high among
minority populations and in large urban areas in the United States
(Hogue and Hargraves 1993).
The poor international ranking of the United States, coupled with the
high IMRs among populations in urban areas, led to the initiation of
“Healthy Start” by the federal government in 1991. Healthy Start (HS)
is a national program to reduce infant mortality (IM) in 15 selected com
munities with the nation’s highest IMRs (Chu and Reilly 1992). It repre
sents the most recent national effort to reduce IM, following a history
I
1
I
* Coauthors arc listed at the end of the article.
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■
The Milbank Quarterly, Vol. 73, No. 4, 1995
© 1995 Milbank Memorial Fund. Published by Blackwell Publishers,
238 Main Street, Cambridge, MA 02142, USA, and 108 Cowley Road,
0X4 UF' UK'
r
. ...
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guidelines for ERB Review of
[ntemational Collaborative
Medical Research: A
proposal
I
ary Terrell White
2 ssl
p"i
* i!
he increase in the scope of international collabora|
five medical research involving human subjects is
JL raising the problem of whether and how to mainKain Western ethical standards when research is conducted
■Mpn countries with very different social and ethical values.
* ^Existing international ethical guidelines for research largely
HBjFretlect Western concepts of human rights, focusing on the
I ^■Kioethical principles of respect for persons, beneficence, and
J^Kjustice. However, in countries and societies where these
A iW^ues arc understood differently or are not expressed in
local cultures and institutions, it may be impossible or of
SjWno practical value to insert them into the research setting.
0 A
In the United States, individual informed consent is
■f.l
considered ethically imperative for research involving human subjects. However, this imperative may be difficult to
instill in societies that define persons by their relations to
? others, and important decisions are commonly made by
y
heads of households or group leaders rather than by individuals.1 The baseline economic and health care conditions
r
^orei6n communities may also create ethical conflicts. In
a study acquired immune deficiency syndrome (AIDS)
r
conducted in Tanzania, Western researchers were required
Kg;’ <7 their institutions to include in their protocol that subp|E'Iccts be informed whether they had the human immunodeI E^a'ency v*rus (bHV). But because the country lacked reK;"sources even for palliative care, local Tanzanian officials
HE Prohibited disclosure of subjects’ HIV status out of concern for the distress that the information would cause.2More
recently, studies of maternal-infant transmission of HIV
1 resulted in a dispute over whether it is acceptable to use
J® pkcebo controls in drug trials when effective treatments
|are known but are too expensive to be used as the standard
R
of care in the host country.3
In the United States, all federally funded research pro
tocols involving human subjects must by law be approved
by an institutional review board (IRB). The IRB, a commit
tee composed of researchers, physicians, and other institu
tional and lay affiliates, represents the primary investigator’s
home institution. Its purpose is to screen research proto
cols to ensure that the rights and welfare of human subjects
are protected as required by law. A minimum set of ethical
expectations for research involving human subjects is out
lined in the Federal Register.4 These include the require
ment that subjects’ voluntary and informed consent be ob
tained prior to paniciparion, that risks to subjects be mini
mized and reasonable relative to the anticipated benefits of
research, and that the selection of subjects not unduly ben
efit or burden particular groups. Individual institutions may
develop additional requirements corresponding to the val
ues of the institution and the types of research conducted.
The ethical principles governing Western medical re
search reflect the historical and anticipated risks for human
subjects participating in medical research conducted in the
United States. Historical harms include research performed
on subjects without their consent, studies that endangered
the health of uninformed study subjects, and studies per
formed on vulnerable populations.5 Even though contem
porary research is designed to minimize the likelihood of
these or similar harms, risks of manipulation or exploita
tion persist. These risks are due to the disparity in social
power between physician researchers and subjects, the com
plexity of medical information that may inhibit subjects’
understanding of the research, and subjects’ sometimes des
perate need for medical care when all previous treatments
have been ineffective. These risks are magnified in interna
tional collaborative research when subjects’ social and cul
tural norms differ significantly from those of the sponsor-
J x
W-i
J
1
i
1
1 J"
;
Journal ofLaw, Medicme & Ethics^ U (1999): 87-94.
© 1999
1 9QQ by
biv the
rliA American
A m^nnn Society
Crv~i6»fv of
nF Law,
I ow Medicine & Ethics.
’
©
■ ’J
■
87
I
s -'-7-'7^3
7^5"
=
^4.
Volume 27:lt Spring 1999
ing researchers, or when health care is otherwise minimal
or nonexistent. Additional risks may arise due to politS
countries, m which case foreign procedures for human se
lects protection may be substituted for the U.S requirernents but only .f the substituted procedures offer prorel
tions at least equivalent” to those provided by U.S poli
ces Beyond this vague provision, the regulations offer no
further comment on how to assess risks accurately in for-
International codes of ethics similarly fail to address
cross-cultural research, because they are based primar ly
on Western ethical standards. Among the most wdl known
are the Nuremberg Code,7 the Declaration of Helsinki»
and the gmdehnes developed jointly bv the Council for InWldH I °7nizations of
Sciences with rhe
World Health Organization (CIOMS guidelines).’ Each of
these codes of ethics delineates principles of conduct that
essentially reflect values of respect for persons, beneficence
and justice. The CIOMS guidelines are the most compre
hensive, giving significant attention to cross-cultural con
flicts in research and making a number of recommenda
tions for IRB revew. These guidelines are an important first
step, but the recommendations made are nor specific enough
be used by IRBs evaluating cross-cultural research. Morl
over to date, they lack any means of enforcement.
In summary, neither the U.S. federal regulations nor
any of the established international codes of ethics provide
guidelines for IRB review of cross-cultural collaborative
research. Absent clear criteria, some approved research may
ualivT 7^ tlClpat7for Sub'ero whi|e other potenially valuable research might be prohibited. In this Lcle
LnP Orhthe
weakness« °f two contrasring
approaches to IRB review of cross-cultural research pjposing a compromise between the two as a culturally sens!
J-.';.; IB'
iiP4
the Chinese would return to their home univerJ W
questionnaire developed during rheir training
of testing, the Chinese planned to conduct ovl^S
face interviews with patients attending a clink
The interviews contained questions about the
sexual practices, history of STDs and HIV hSkW
sexual orientation, and current sex risk behavi^* 3
well a
l^&therc
Hjnteed,
»^pons;
In the accompanying consent form, the
promised to maintain confidentiality by not releaZ^M
without written permission, omitting personaK^B
m published reports, and storing data in a secure
Subjects were assured of their right to refuse to
without penalty. The American consent form
lared into Chinese and back into English to en^^B
weTJrlT5 tPPr°Ved
insritution'slS
well as the ethics review committee at the Chinece —^l
ers home institution. The Chinese committee also DmSiP
a statement declaring that subjects’ confidentiaEtr3
not be violated and that subjects would not be pimJSS
gftyproc
Ujwhethe
^Kption
IfeKencei
H^derec
■ft. In 1
Bncala
Kold.l1'
Ift^uire
Sftandar
HKards
Rrasubie0
Wand pi
Klexan
any way or participating or refusing to participate.«
Ihis protocol raises numerous questions berondS
routine scope of an IRB. First, the research would take plxf
KNaw
in China, a country widely perceived by Americans as dW
B If We
swe of human rights and about which accurate, comnreS
ciples
hensive information is difficult to obtain. Given a UfaZf
fe- be re;
perspective of human rights in China, the IRB must ques4
non how, and by whom, the risks to subjects were detaJ
ft kncd
mined. Does the consent form reflect the actual risks?Some!
ft ^
cm ence suggests that discrimination, stigmatization, and®
ft ^S'
Invo “wry detention following positive diagnosis of HD®
or AIDS has occurred.11 Should the sponsoring researchers^
ft ethic
or their IRB be expected to find out the extent of these!
nsks. If so, given the difficulty of obtaining sound infonra-S
non, to what lengths should they go? If not, who should bef
^w’couh
responsible for risk assessment?
S
»,clca
Second, m a totalitarian society, how meaningful is thel
non
B efin
American consent form or the Chinese statement? Can cothS
hdennality really be assured? Who else, besides the research||
ers, would have access to the data? What are the pottntial3
nsKS to subjects should the data fall into the hands of gov^H
O' toremment officials? Third, given that the American research-fl
ers would not be present when the interviews are conducted^
me
vaj
how much responsibility do they and their IRB have for thdl
protection of the Chinese subjects? Fourth, if risks to sub-fl
jects are believed to be significant, should American research- fl
ers be participating in this study at all? Finally, by whatfl
F sei
criteria should the IRB evaluate this proposal?
wi
These questions reveal ignorance and suspicion about ■ »'
de
wM'
con itions in China. We may never know with accuracy
it
what the social consequences are for persons diagnosed with fl
IK
or AIDS in China, or, for that matter, how any pat' fl
to
ocular research project will take shape in a foreign country.. 1
cc
Our ignorance of circumstances elsewhere reveals the eX-O
cc
tent to which IRB review assumes IRB members’ familiar fl
tt
Kto t^c
c iari
|K.m'ise
O'1115
wfcr
!fe- We
^■V.
B^' r ^ir
AIDS research in China: a case of unknown risk
A collaborative research protocol between U.S. and Chise researchers raises issues not only of protecting human
proQ
i 7'
perCePtl0n’ and ^horiry. Th^
protocol involved a mujtidisciplinary American team that
proposed to provide training to a grouD of Chines J
„ risk-beh™, UsS A Ss
"“'dd“““<STDs),|„d„d|„EHtV1„JwSTb'e‘™nS.
ng was to be done in the United States, following which
88
JB
s
I
The Journal of Law, Medicine dr Ethics
• -social and political context of medical research
i0 g^ith
the
"U as investigators’ integrity and good faith. Although
Ir
■F
.
her contextual knowledge nor mtegri1/ =“ e'7er
,
conduct
OS these assumptions have shaped how the role and
?adini3
of IRBs have come to be perceived.
ai ittfielfl
no Hiy jJ'JU I i:,e5Pln international research, given the range of soaopoish hehavi^M ®L,1 circumstances worldwide, these assumptions may not
C° ’ rlleW gu fa their absence, an IRB has two options: (1) it may
■rti^rhat research conform to accepted Western ethical
■ Jtre,eaZ'l
? PCrsona^M| '’l^idards or (2) it may estabfish some other set of criteria
11
SeCUrpT?! ' Procedures for approval. The option chosen depends on
;|fcher Western ethical standards are believed to reflect
1 Ser°P^J
i lEs of human rights that are universal, absolute, and
ent form
fence inviolable, or whether, in some cases, it may be con' 10 en^S
IRB review. Depending on the type of protoco , IRB mem
bers may also lack sufficient expertise to challenge study
design. Most problematic is the fact that the dominant play
ers on IRBs are also members of the medical and researc
communities. These individuals are likely to value saennfic
progress as well as have a personal interest m avoiding de
mands for revision when their own protocols come under
review, all of which may bias the IRB toward research ap-
1 1 ItUtio^jS
’echineseggj
-nrialir»^3
be puflUjl Ki examine each position in turn.
parridpatc.»iJ
^ Narrow view: an ethic of moral fundamentalism
ls
n
f If Western ethical standards reflect a set of ethical pnn*'^JT1erican$a$^J B rifStat is universally applicable, rhe IRB’s manure on
ac 'are, coninJ
S- bePread narrowly, requiring that approval be granted only
•’ ena^sta
K w those protocols that satisfy the ethical mqu.rements oute IRB
B lined in federal and institutional policies. This view has been
were deter t characterized as “moral fundamentalism.’’ Proponents o
a I risks? So® K this view reject the possibility of any relaxation or compro-
ginaiizarion, aod
Jia.enosis of HIV
researdien
e -nt of these
sound infonna) should be
W mise of Western standards, arguing that doing so sugges
<' ethical relativism and creates new opportunities for exp oit■ ing smlnerable populations.13 By basing IRB aPP'™*™
K W«tem ethical standards, approved international.r«arch
B could be expected to entail appropriate researc1 desgn,
1 dear and thorough consent forms, equitable subject^selec“i tion, and a reasonable balance of medical risks; andlen^aningful is the
efits. Despite these provisions, Western standard>
ofnr--? Can conH fer insuffident protection for human subjects,
es “researchI. cause they neglect sodopolitical, cultural or
e uie potential
E tors that pose risks that are not normally encountered in
hands of govK Western countries. Overly rigid adherence to moraljund
ic research| mentalism may also diminish opportunmes or po^nafiy
valuable research. Finally, this approach suffers from
have for the J |
-' ' i limitations accompanying IRB review m 8generaL
ener^
"i s to sub- '
* If ■
inform^ con
As is well known, IRBs usually focus on informed
Q esearch—
documents,
them
'
■
sent
reviewing
primarily
for
cogency
dly, by what
withresearchprotocobandcl^
does aiTlRB question research desist or momtor^rch
oi n about
it anoroves. It, assumes, on good faith, that researchers will
ith accuracy
noplace subjects at unnecessary risk, will follow
proj
gnosed with
tocol
as
described,
and
will
prov.de
an
adequate
mtormed
iypar- 1
consent process.11 Part of the reason research designs rarely
‘gi .ountry. I.
contested may be due to increased awareness of the impor
eals the extance of human subjects protection smee the mstmmon of
•s’ miliar- a I
Pr° Once a consent form is approved, whether it contrib
utes significantly to the protection of human subjects de
pends on factors that are not easily regulated. Meaningful
informed consent involves a dialogue between researchers
and individual subjects to explain the study and answer
questions. To be effective, the language used to explain a
Xidy and its risks and benefits must be tailored to the smdy
subject. The subject’s understanding must be verified, and
the greatest possible effort must be made to ensure that
subjects’ decisions are not influenced by desperation, in
timidation, or manipulation.-Became
there is often no way to know whether subjects decisi
are truly informed and voluntary.17 Unless given evidenc
to the contrary, IRBs generally assume on good faith tha
researchers will provide an effective informed consent pro
cess, will follow the protocol as described, and will not p.ace
subjects at unnecessary risk.
In international research, informed consent is mor
problematic If populations are unfamihar with basu; bio
medical concepts, the purpose of a particular study
may be incomprehensible. Subjects’ concerns about the risks
and benefits of participation may differ from what Western
researchers consider important. Subjects may be so desper
ate for medical care that obvious risks seem insignificant.
Further hindering the process, subjects may be= >llltera« °r
may expect some other person to make their decisions for
them. Informed consent under these °rcumstanC“ "
be considered ethically equivalent to the same process
the U^SXif Western ethical standards are^accepted
as universal, IRB approval will be based on specific J? /
that are nor specified in the approval enten , Ae effern^
ness of this standard in protecung human subjects mlgh
limited. Alternatively, if the IRB determines that cirtmm
stances are such in the host country that « c^
cannot be upheld, it may refuse to approve poteri Jy
able research. Despite the shortcommgs of rhu
stance of moral fundamentalism is currently
sible approach for IRB review. Gwen the P«^and
culty of assessing risks in distant countries a
]:nesfOr
the absence of clear federal and institutional guidel
89 '
,.O L
Volume 27:1, Scrmg 1999
review of cross-cultural research, it is at present morally
and practically difficult for an American IRB to demand
more of research conducted in foreign countries than is
legally required for research conducted domestically.
Broad view: an ethic of moral relativism
In a contrasting approach to cross-cultural research, moral
fundamentalism has been characterized as “ethical imperi
alism, 18 charged with ignoring multiculturalism and post
modern criticism ”In this view, notions of human rights
and the protections owed to human subjects are believed to
be derived culturally, not universally.20 In terms of IRB re
view this approach suggests that Western ethical standards
should be modified to correspond to those of the host re
search environment, research approval being based on
whether human subjects are adequately protected given the
sociopolitical circumstances, cultural values, and ethical stan
dards of the host country and subject population. The merit
of this approach is that it acknowledges the diversity of
human communities, and in doing so calls for careful evalu
ation of the values and circumstances of research subjects.
Ideally, this approach should not only lead to better protec
tion for subjects; in some cases, it may also enable research
to proceed that would be prohibited by Western ethical
criteria.
The chief criticism of this approach is that it suggests
emical relativism that ethical standards vary with socio
cultural context. In concrete situations, it presents the prob
lem of whose or which values take precedence in a given
research environment. The values of the dominant social
groups in host countries, which usually include medical re
searchers and institutional and government officials, may
not be consistent with those of the subject population. If
the aim of the IRB is to ensure that subjects are adequately
protected, who decides what protection entails? Also un
clear is whether an act constitutes a harm if it is not recog
nized as such by the persons or groups it affects. For ex
ample, would consent given by a group leader rather than
by an individual consutute a violation of autonomy if the
1X1
uocs not perceive it as such?
From a sponsoring country’s perspective, if ethical standaros are taken as culturally relative, then conceivably re
searchers could be expected to suspend their own values
when conducting research in other countries. This is a trou
bling proposition for three reasons. First, researchers have
past histones and personal values that they would probably
find difficult to abandon while engaged in work that repre
sents many of their most firmly held beliefs. To expect them
to do so would be to ask for a sacrifice of personal integrity
that is botn morally abhorrent and infeasible in practice.
Second, if researchers were permitted or expected to sus
pend Western ethical principles whenever such principles
are deemed incompatible with the research context soon
SD follow would be widespread exporting
exporting of
of controvers
controversiali .
intereS
^search to countries where vulnerable
populations
nerable populations
c£hic’23oC^
ce easilj- exploited. Finally, accepting different ethical
cards for each research protocol and subject popuI^H
populari^ ® »
va^1
zay undermine public confidence in the ethical integrity of 3? I be^0^
medical researchers.
-------- hers.
■
inherer
_ If one accepts that ethics are to some extent culturall
culmMn„^®^s
that h
M
cenved, in order to receive IRB approval, each intej® ftjificantsoc
conal research initiative would have to be evaluated o « Igrisksas^
mique ethical criteria corresponding to the values and
Iffictshctwc
oocultural context of the anticipated subject population « Kffsarisf’'
Assuming this contextual information can be obtained andlli
corresponding risks assessed, theoretically an IRB could
Eftance of
work with researchers to develop procedures that would W
provide maximum protection for subjects. The limiting fac ® BKfconfhc
tors m this approach lie in the derails of how significant® ^<IRB re
sociocultural factors and risks would be identified, and how -'Ww
m view of this information, ethical modifications would be 'W
ende. Neither task is amenable to formulaic procedures or
rourines. But, if these issues cannot be resolved in a fair and
culturally sensitive manner, an ethic of moral relativism mav
al too easily lead to greater harms for subjects. -
liH
Rould
’ ‘io this is
IRB review of international collaborative research: a M
negotiated ethical standard
k appears that whether ethical standards are considered <
absolute and universal or culturally dependent, the protecnon of human subjects is far from assured. Despite their
limitations, the two ethical approaches for IRB review de- H
scribed above reflect important truths that should be ac- . '3
knowledged in the research review process. In what follows, I propose that by combining these approaches and '
scvcr^ ^e CIOMS guidelines, viable review criteria for ‘
cross-cultural collaborations can be developed. My goal is S
a culturally sensitive approach to subject protection, structured within a framework of checks and balances that validates the ethical priorities of both the sponsoring and host
|
cultures.21
The weaknesses of the two approaches previously de
scribed demonstrate that approved
research
must accom- ----------- -----------modate the ethical values of both the sponsoring and the
host countries. Because the sponsoring researchers are re
sponsible to their funders and institutions for complying
with federal and institutional ethical standards, and because
publication results may depend on it,22 it is essential that
.
the research protocol satisfy Western standards of respect
for persons, beneficence, and justice. For this reason, the
sponsoring IRB should have the last word on whether a
protocol is approved. But because local circumstances may
affect how Western ethical principles serve to protect sub
jects, in the details of how research is carried out—how
subjects are selected, how informed consent is obtained, or
how diagnoses disclosed—host countries should be able to
[fiostcour
BOrtl
^?SeC
rural noi
SfidiWe
ggarch
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Mpy van'
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90
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&
The Journal of Law, Medicine dr Ethics
Ki.Western standards to correspond to the context and
RXests of subject populations. This “negonated
BfSoccupies a middle ground between fundamental
ly J relativism in which the ethical standards and sociovalues of both sponsoring and host countries may
cc o2
ai10n^
ethi,
I
’li.
lEheremin this proposal are two implementation probhat have already been noted. First, how should sigEmr social and cultural factors be identified, correspondiScs assessed, and by whom? Second, how should con8; between participating countries be resolved? MutuE bsfactory answers to these two questions must be
BT ed if a negotiated ethical standard is to have any
E*.;of success. In what follows, I first explore how an
Kr could go about assessing risks; I then outline a process
Kanfiict resolution. Finally, I propose a five-step process
KlRB review of international collaborative research.
SO
aJuatecfO
JC
0
-ainediBi
la <411
ignific^l
aj
•v
assessment: using subject representatives
|Euse few sponsoring researchers or IRB members are
f
Ere than superficially acquainted with the cultural con’S naSSl Bt of foreign subject populations, a reliable means ot asfeing subjects’ risks and concerns is essential. One way to
Kfothis is to include representatives from subject populajfons or their advocates, as members or consultants to the
n •
fest country’s IRB.:i Subject representatives should be choIfeh for their abilitv to grasp the aims and methods of the
proposed research, to identify and articulate any sociocultural norms or values of their communities that conflict
jf’with Western ethical standards or pose additional risks tor
^subjects, and to communicate among potential subjects,
?s researchers, and IRB members about the interests of each.
Information sought may pertain to social inequities related
fto race, ethnicity, socioeconomic class, gender, or die po
litical climate. Other important information would include
oa.„
j ffiny variation in obtaining informed consent, such as idenEifying persons to serve as intermediaries between resear
Bjers and subjects; any kinds of gifts or other inducements
h<I
11 I’that may or may not be appropriate given a community s
Wgift-exchange traditions; and any additional concerns fek
fcamong the subject population regarding confidennahty and
,I
- I
« rW
la jgl
a ..^11
the
re
n,
isc
Si
1
w W1
^privacy.25
,.
,
I The use of subject representatives suggests a direct and
feasible way to present subjects’ concerns to an IRB bur
their use creates additional problems for researchers. First,
V if subject representatives are included on an IRB, who should
I select them? Reliance on the primary investigator to make
the appointment may result in a bias toward research. Sub■ Sect populations may not be sufficiently organized or in. formed to appoint their own representanves. Moreover,
■ individuals with the education necessary for the assignment
. may not be typical of the subject group as a whole. But if
i ' the subject representative is not “representative, a token
I
iat
a
ic
a
iy
V
r
>
it
appearance on an IRB will not serve subjects well. Second,
if the subject population is diverse, one or two representa
tives may not be able to represent different perspecuves
adequately. How can an IRB be assured that the concerns
of all participants have been fairly represented? Third, if no
subject representatives are available or feasible, it may be
necessary to hire one or more consultants to do the investi
gation. Again, questions arise about what qualifications an
experience would be required for these consultants, an
whether it would take more than one consultant to provide
an accurate assessment of the concerns of a diverse popula
tion. In short, even though including subject representa
tives on an IRB offers the possibility that subjects’ concerns
can be identified, their participation does not guarantee that
all concerns will be heard or that the IRB will be respon
sive. Cost issues associated with travel, accommodation,
and any interpreters for subject representauves create addi
tional burdens for researchers. But as unsatisfactory as it is,
within the current structure of medical research, this ap
proach offers the greatest likelihood that subjects concerns
will be addressed.
Resolving ethical disputes: elements of a process
If the ethical standards of the sponsoring country are to be
modified to accommodate the cultural norms and values ot
the subject population, some criteria or process must be
developed that offers maximum protecnon for subjects while
acknowledging the ethical values of the host and the spon
soring countries. One such approach has been proposed by
Nicholas Christakis and Morris Panner? who identify a set
of principles to serve as basic guidelines for ethical conflict
resolution.
, ..
First, subject representative(s) in the host country should
be presumed to have the greater insight into the social, cul
tural, and ethical concerns of the subject population. It a
conflict arises between the host and sponsoring county,
the host country’s standards should prevail, if they are the
more rigorous. Second, researchers should adhere to the
ethical judgment of their home institution, whether or not
the collaborating institution approves the research. This ru e
acknowledges the moral and psychological difficulty of sus
pending one’s own values and the risks inherent m permit
ting it. What is more important, it would prevent research
from going forward without approval from the sponsoring
and the host countries. Third, ethical guidelines once ac
cepted, should be applied equally to all research subjects.
In other words, there should be no favoritism or exclusions
from protection in the subject population. Fourth, it re
search is not approved by either country’s IRB or fails to
meet international standards, rather than abandon the re
search, the causes of the ethical dispute should be reso v
by means of formal and fair negotiations. If consensus is
reached, that agreement will supersede other ethical stan-
2^^
91
I
‘'.■'■’•'-I*''
volume 27:1, Spring 1999
taining that the research goals are appropriate, givgu W
health needs of the country; that an appropriate
potential or anticipated benefits to the host popul3Jj3
researchers, and the national government has been
Eshed, in view of the nature of the research and then^H
involved; that the risk-benefit ratio for subjects is reasa. ;
able and subject selection equitable; and that any benefitor products of research will be made available to thepor^
bdon of the host country. With the aid of subject repnaill
tadves, the host IRB would also identify additional riddel
logistical problems arising from the social, political, orfBI
rural environment of the subject population and tranj^
Western ethical standards, such as the requirement nf
formed consent, into meaningful practices in local conwjO
nities. Based on this assessment, the host IRB would
recommendations for revision of the protocol.21
Fourth, the revised protocol would return to thespo&$
soring country’s IRB for final approval. At this point,
ethical conflicts or logistical problems related to the revi4
sions would be negotiated between the spq^oring research®
ers and members of the host IRB, according to the pnn*^
dples proposed by Christakis and Panner.29 If negotiation^
lead to consensus, in order to receive final approval, anymodifications agreed on must be identified and explained
to the sponsoring country’s IRB with the understanding
that, under the circumstances, Western ethical expectations,
could not be fully upheld. The IRB may accept these modk
fications, if it is satisfied that: (1) the research is ofsiCT
importance that it warrants modifying Western ethicalsoog
dards; (2) the host investigators have a thorough undci^
standing of the risks to the subjects, given the social,
rural, and political context of research; and (3) these rdfl
have been sufficiently minimized in the modified researub
design. If modifications are accepted, approval by the spott*|
soring institution may be considered final. If conflicts
sist, negotiations may resume until consensus is reacnetL®
no consensus is possible, the research should not Pr0CC*S
These guidelines offer a culturally sensitive means|i
research review in which the ethical standards of spoo^j
ing institutions may be upheld in the main, while, at n®
local level, specific practices in implementation can be moBj
fied to the research context. As cumbersome as the
posal is, it offers an IRB a structured and balanced P1^0^
by which human subjects protection in cross-cultural
search can be uniquely evaluated relative to contextual Gp
cumstances. However, many questions remain unanswern^
Specifically, these guidelines assume it is possible to p^
vide subjects with qualified representatives, to identity
contextual factors that pose risks to subjects, and to
velop a fair and effective process of conflict resolution. M
unclear whether these are realistic assumptions.
,
Even if they are, absent the integrity and good tai
all panicipating researchers and IRB members, unce
will remain whether the review process is fair and adeq’
dards. If consensus cannot be reached, the research should
be abandoned.
The fourth principle limits the function of Western stan
dards to a baseline or a general template, modification of
which could be considered appropriate under certain cir
cumstances. The questions remaining are when, and how,
ethical disputes should be resolved. Ethical standards should
not be altered simply to expedite research; rather, signifi
cant ethical conflict must be evident, as well as demonstrated
need for the research. In addition, while Christakis and
Panner’s principles provide a foundation for a dispute reso
lution process, it is unclear what would be the appropriate
forum for negotiations, the criteria by which ethical stan
dards might be modified, the limits or boundaries to these
modifications, and who would adjudicate such a process.
IRB review: a five-step process
Assuming potential risks to subjects can be assessed and an
effective conflict resolution process developed, IRB review
would consist of a five-step process. In this process, the
responsibility for subject protection would be divided among
the sponsoring and host researchers and their respective
IRBs. If no IRB exists for the host country, the external
sponsors should provide the financial and educational re
sources to enable the host country to establish one for in
dependent ethical review.27 For research to proceed, ap
proval would be required from both IRBs, each having a
different role and different approval criteria.
The five steps are as follows: (1) ratification of the
CIOMS guidelines by all collaborating countries and/or in
stitutions; (2) initial approval by the sponsoring institution’s
IRB; (3) review and modification by the host country’s IRB;
(4) negotiation, if necessary; and (5) final approval by the
sponsoring IRB.
First, as a means of demonstrating good faith and pro
viding a basis for accountability, any nations or institutions
panicipating in international collaborations must ratify’ or
otherwise affirm a commitment to the CIOMS guidelines.
Second, the IRB from the sponsoring country would re
view the protocol according to general ethical criteria de
fined in its national and institutional regulations. These cri
teria would include establishing that the research design is
appropriate; that a legitimate scientific and medical ratio
nale exists for conducting the study in the host country;
that risks to subjects are minimized; that the drugs or de
vices used meet national safety standards; that the proposed
research initially satisfies the ethical standards of the spon
soring country’ or the CIOMS guidelines; and that prod
ucts developed from research be reasonably available to
the population of the host country.
Third, if initial approval is granted by the sponsoring
IRB, the host country’s IRB would then review the proto
col. Approval criteria for the host IRB would include ascer-
75-p
92
^laborati
Uthrougb
H'jtwouk
. col. Ha
® commit
&iews p
fchave inc
Strain cor
S tives for
Ega rcp
grantee th
ftk:One of
g inequiti
B^disenfri
fe-the rest
g'-'substan
subject:
g non rat
sible, st
Kconcen
Conch
[RB ev;
tocols i
legislat:
may be
nnduly
Sards a
lhation
inodifit
jnodifi.
I Ti
to ackr
5n cros
malpri
■able re
Rff^viro
'T.alterna
g researc
? P Dt
K/'much
F' k?011
Bg. Practic
®|tosacr
if r'tord
tegrity
r
opiate, giYpT"!
Qpriate balL^
1 cpop^J
h
s been^ Hr
B
The Journal ofLaiv, Medicine & Ethics
addresses subjects’ protection. For example, had the colited. Absent widespread monitoring, opportunities for abuse
Jaborarive research conducted in China been approved
probably cannot be entirely eliminated. Nonetheless, the
through the process described here, it is not clear whether
success of medical research ultimately depends on the in
it would have resulted in significant changes in the prototegrity of researchers. Because the principles of respect for
col. Had subjects been represented on the Chinese ethics
persons, beneficence, and justice cannot be legislated across
committee, it might have been possible to know whether
cultures, the bottom line is trust. When trust is violated,
d< onal
Mathey felt the lack of anonymity in the face-to-face inter»PWito’caI,Sn ' T*CWS PUt t^em at additional risk. Other concerns might whether the harms are to human subjects, researchers, in
stitutions, or funding agencies, future collaborations are
on and trSBI
have included whether subjects trusted researchers to mainjeopardized. In this way, the most effective incentive avail
^^.^tain confidentiality, or whether there were hidden incen“ caicoiitaj;l
able for human subjects protection may be the necessity of
- rives ^or Participation. However, the mere inclusion of subtrust
wouldmX 1 ^:X;‘Jcct representatives on the Chinese committee is no guarX
2i
antee that subjects concerns would be voiced or addressed.
W* One of the most difficult problems with this approach is
Acknowledgments
'^pou^Xl
that, in a political climate of ingrained social and polirical
I am grateful to Eugene Hem, Ph.D, for his thoughtful
’ to the I
/ inequities, without some means of enforcement, normally
5< igreseaS^I
comments on an earlier draft of this paper.
^ disenfranchised subjects may be not be heard, especially if
tog to the Dtm.^
^^5 f°r r^e ^STCner IS r^e toss of research suppon and
’Rn^goS^^
ll^-.-substantial foreign funding. Thus, the only real leverage for
References
1 < ’r°val/am| Mp subjects lies in the requirement that the nation or institu1. Sec AJ. Hall, “Public Health Trials in West Africa: Logis
exphnv^l ». non ratify the CIOMS guidelines. If monitoring is also postics and Ethics," IRB: A Review ofHuman Subjects Research. 11
undentaud^l
no. 5 (1989): 8-10.
able, subjects have considerably greater chances that their
al pectations 1
2. See M. Barry, Ethical Considerations of Human Investi
concerns will be addressed.
gation in Developing Countries: The AIDS Dilemma,” N. Eml. /.
-P iesemixS-i
Med., 319 (1988): 1083-86.
arch is of such i
n hicalS^
Conclusion
Conducting Research in Developing Countries,” N. EmLfMed
or jh under. S I IRB evaluation of international collaborative research pro337(1997): 1003-05.
.he social, cuL •
4. See Federal Policy for the Protection of Human Subjects;
| tocols is not currently addressed in existing guidelines or
(3' these risks |
Notices and Rules, 56 Fed. Reg. 28,002-31 (June 18, 1991).
legislation. Strict adherence to Western ethical standards
3-^ee generally, DJ. Rothman, Strangers at the Bedside (New
iii Ireseardi t .may be inadequate for human subjects protection or may
York: Basic Books, 1991).
al thespon-1
g.unduly inhibit potentially beneficial research. If ethical stan6. See Regulations on the Protection of Human Subjects, 45
conflicts per- |
dards are to be modified, it is not clear what kinds of inforGER. $ 46.101(h).
> i ached. If J
7. See “The Nuremberg Code,” in G.J. Annas and MJl
W matl°n’ princiPles’ and institutions should govern these
Grodin, eds.. The Nazi Doctor and the Nuremberg Code: Human
n proceed. | » modifications or what new opportunities for harms the
Rights in Human Experimentation (New York: Oxford University
-rive means of . 1
modifications may create.
Press, 1992): at 2.
-is *s
The Buidelines for IRB review proposed here attempt
8. Sec World Medical Assembly, “World Medical Associa
v. e,attiie jIp acknowledge the variety of ethical perspectives present
tion Declaration of Helsinki,” in Council for International Orga
can oemo&gl
nizations of Medical Sciences, International Ethical Guidelines
m cross-cultural research with the aim of providing maxifor Biomedical Research Involving Human Subjects (Geneva •
e pc the pro-ll
Protection for study subjects without prohibiting valuCIOMS, 1993): at 47-50 (citing 1989 Declaration of Helsinki).
nc process I 1® able research. They are admittedly imperfect and open to
9. Sec Council for International Organizations of Medical
5-C—.ural re-.:-• j » abuse. However, without addressing every possible continSciences, International Ethical Guidelines for Biomedical Research
intextual
gjesicy, they legitimate careful examination of the research
Involving Human Subjects (Geneva: CIOMS, 1993) [hereinafter
ur. jwered.
I
CIOMS Guidelines].
. nrtv ' JI?
ttOnnlent and actual risks t0 subiects> and provide an
;it
10. This statement suggests the Chinese were aware that sub
’ u to pro- ’»-*ernative to blind acceptance or categorical rejection of
jects might be apprehensive about the consequences of being iden
ulenafy Je
that fails tQ fit the
J
tified as carrying the human immunodeficiency virus.
t0T^
1
LDesPite an IRB'5 best efforts, there is a limit to how
11. See Y.G. Wang, “AIDS Policy and Bioethics: Ethical Di
is a limit to how
01
*
IB
administrative
human hehav.
J
administrative control can
can influence
influence human
behavlemmas Facing China in HIV Prevention,” Bioethics, 11 (1997):
5.
323-27; B.R. Liu, Legal Regulations of AIDS Detection and
< JOt Paper documentation is meaningless if it bears litde reo<?ri fiaichof
Administration
in P.R. China,” InternationalJournal ofBioethics,
«non to what occurs between researcher and subject The
3 (1992): 25-27; and M.L. McCall, “AIDS Quarantine Law in
ui rtainty
®^tory of medical research illustrates that it is generally
the International Community: Health and Safety Mensures or
’ a—quatdy
z
^ai:tICed by a SOcial elite who have repeatedly been willing
Human Rights Violations?,” Loyola of Los Angeles International
sacnfice subjects’ interests in the name of science. This
and Comparative Law Annual, 15 (1993): 1001-28.
12. Sec R. Baker, A Theory of International Bioethics: Multi
’ ’
fr^°rd °f untrustwonhiness confirms that researcher inculturalism, Postmodernism, and the Bankruptcy of Fundamen
^grity cannot be assumed and that IRB effectiveness is limtalism,” Kennedy Institute of Ethics Journal, 8 (1998): 201-31.
arch and
ul cts
d any
able to the^3
sl'Lecrrcpr^j
93
7^)
^11^1
■;
--
—
y . '>-■■* -
<• --
.....
^WSIS
lu
p' a/
• ;;(J /«>
»a
aa
DECLARATION OF HELSINKI
I
ii
I
1
0
1
1
“The potential benefits, hazards &
discomfort
of a new method
should be weighed
against the advantages of
the best current diagnostic & therapeutic
methods”
y
-9
)ECLARATION OF HELSINKI
f
“In any medical study, every patient
including those of a control group if
any, should be assured of the best
proven diagnostic and therapeutic
method”
I
■
I
I
r
b
I
a
-
at
■R^sae***^^1
HELSINKI DECLARATION
the best current or best proven
treatment for control groups”.
Not “... the best available treatment”
the best local treatment”.
or ..
i
■■-J
f
."■’3
• " """
—_... .
GUIDELINE 15 CIOMS. 1993
■
5
I
I
■
j
1J
■
t-
fe
K
i
“An external sponsoring agency should
submit the research protocol to ethical
and scientific review according to the
standards of the country of the
sponsoring agency, and the ethical
standards applied should be no less
exacting than ... in the sponsoring
country”
^0
isK-
I
J*;
Mri-
H
voU.
*b;
•‘e
^-1
99
to
?/
:213.
c*
95; 5 ***.
^ru,
- ■- u.
w r
lUiS"
33
ruth Ellen Bulger, pho
it
I Toward a Statement of the Principles Underlying
Jj- Responsible Conduct in Biomedical Research
IfI
- Abstract—Biomedical research still does not have clear, wntagreed-upon underlying values (for a number of possible
h: A Pilot \
'that
w,,/'
- • . are
— discussed), and a variety oi
of new pressures are
| j?||| waking it _______
necessary to formulate such principles.^. Toward that
on.
■ W. goal, this essay first traces the development of the underlying
? Bl principles that have been formulated in the sphere of human
"1
.ip :H __
vr.-k_____
- k from ika
’nmon of
s. Wash.l’
subjects
research,
the ancient Minnrv-nrir
Hippocratic inii
injuncnon
of do
do
§ LS' no harm to the three principles identified in 1979 by the NaV tional Cammission for Protection of Human Subject of Bioir.
31B
medical and Behavioral Research: respect for persons; benefi5.
- ,cence; and justice. Using these principles as a patmm, the
the 5io
|
following “candidate principles” are proposed for biomedical re19<
search to stimulate discussion and the development of consensus
| K/i Biomedical scientists live the codes of
’■ 'I
ethics by which they work. As men'
tors, they pass on these codes to their
K students as part of the apprenticeship
L
p--
Dt. Bulger is vice president for scientific af-
K' iairs, Henry M. Jackson Foundation for the
Advancement of Military Medicine, Rockville,
Maryland.
Correspondence and requests for reprints
’Id be addressed to Dr. Bulger, Vice Presifor Scientific Affairs, Henry M. Jackson
foundation for the Advancement of Military
Medicine, 1401 Rockville Pike, Suite 600,
Rockville, N£D 20852.
among biomedical scientists: honesty of scientists (which encom
passes the essential values of integrity, objectivity, verifiability,
and truthfulness); respect for others (including respect for re
search subjects—both humans and other animals—colleagues,
and the environment); scholarly competence (which is related to
the processes of obtaining and passing on knowledge); and stew
ardship of resources (involving obligations^ to protect society
from the problems intertwined with scientific advances). Guid
ing principles of this type must be articulated so they can be
transmitted to upcoming scientists, who then can productively
and responsibly help shape the future of the research enterprise.
Acad. Med. 69(1994):102-107.
process. Some attributes of these
codes have been listed, but there is a
lack of both clear, written articulation
of their underlying principles and
meaninaful development of consensus
about tbpm among biomedical scientists. In the 1950s, Pigman and Car-,
michael wrote a prescient article
pointing out a “failure of scientists as
a group to consider ethics” and
stressing that basic science has been a
vital force for the advancement or de
struction of society7. They stressed
scientists’ obligations to society to
explain the nature and purposes of
science, to clarify attitudes toward
patents and secrecy restrictions, and
to affirm obligations to employers,
associates, other scientists, assist
ants,
----, wgraduates, .and those in other
professions. Feeling that the pressing
ethics problems related to authorship
issues, they
they^ discussed
discussed, only those
problems in depth and did not further
develop the idea of a code.1
Robert K. Merton gave the follow
ing as the norms of the scientific com
munity. sharing the results of their
work; being critical and testing in the
laboratory the work of other scien
tists; conducting their work without
regard for material gain or for reputa—
""
'
'
’
r
77
ACADEMIC MFniCiN-
102
flpl
J<.'< -aS.
■.-■•
'i.l-w B'.-
■
:
-
4
tion; and assuring that scientific
truths and claims should be true ev
erywhere.2 Recent considerations of
scientific norms have dwelt not on
what constitutes responsible scientific conduct but on the definition and
tne causes of misconduct.3”5
The present essay traces the devel
opment of underlying principles in
the sphere of human-subjects re
search and, using these principles as a
pattern, proposes candidates for nnderiving values in' biomedical re
search, to stimulate discussion and
the development of consensus
among
scientists.
codes to provide guidance to health
■
accour
X >
--■
care professionals, fiarzant abuses
. 11Et’- „ usln
l’
concerning the use of '—an.; as re
teachi
search subjects continued to occur in
I
scienc
the United States. For example, in a The relative clarity of under
values
that
now
exists
in
cknir
respoE
study that began in 1922, rural black
I
Hov
search
is
not
present
in
basic
bin,
men with, syphilis, who were the re
ical research. Underlying
search subjects, were allowed to go
pri
estabh
have not been enunciated in a
untreated long after pemdllin treat
tificce
that provides a similar ana
ment had been shown to be efhcaframework
for
areas
of
the
basic
ki.1
cious for this condition (and after the
Nuremberg Code had been articu medical scientific endeavor Thk a!
such a
lated).9 In another instgnref -debili- sence of ethical guidelines becoJT-i M^^-pf int
more
obvious
as
one
works
with
J
tated elderly patients at the Jewish
dents in formal courses (such as tho^l ■|Sprop€r
Chrome Disease Hospital irrBrodkmandated
for trainees supported uJ
lyn were injected with uve^cancer
do not
the National Institutes of Health14) tll
cells to determine if the
would be
studer
PRINCIPLES UNDERGIRDING
analyze case studies that
rejected, in spite of the fact th At aspects of the responsible conduct rfl
HUMAN-SUBJECTS research
proper imormed consent was not ob research scientists.
questi’
tained.
10
A
series
of
unethical
re
From at least the time of Hippocramere are several possible reasons i T 7 dPTleS
There
search experiments was exposed by for
f
’
___________ ethic^
this absence
of enunciated
J£n'
:es, who promised that "into whatso
Henry K., Beecher in a landmark
ever house I enter, I will enter to help
principles to guide actions in
speech and subsequent publication.11
: c
basic science arena: (1) society had m
needepreviously allowed the self-correcting fL -. .
he
orta*
-JS,
nature of science and the intern^ ’ fg:•••■< mg al
of 1974 established a National Com
low
to their patients have been scrutin- mission for the Protection of Human oversight mechanisms of the professugget
sion to suffice;
(2) members
of society ri w'
?his scrutiny has b^n p^Srly roral^se^ch
10™6^^"
had
Subjects of Biomedical
and1 Behav ■nrpvimiekr
’ W > '. respec
k-J more
—___ i shared
.... pohti
Research to provide principles
tence;
miportant in those cases when the ioralguide^for
to
> 1<
and guidelines for the use of humans
customary therapy is not helping the as subjects in clinical
fieldsi (3) flagrant ethical lapses W
as subjects in clinical research12 Be
atienf who then sometimes becomes tween 1974 and 197)/the N H
t!le c-onduct of basic biometfi- I
.1974 ^ote
and 1978,
the National
- subject of a kind of care that tween
CoXission
sev^l
DOt
(4> I
Commission wrote several reports
Honei
^orders on experimentation.
that enunciate
tv i
the specialized vocabulary of science
that
enunciated
basic
e
thical
prinrivalue
This practice of learning from ob- pies and
b It
PnnC’' restnm Public access to and underples and
guidelines that were to un- Standin» of scientific issues; (5) the. «
nation and/or experimental treat- derlie
IthS^Xe^h^
Screw
ents during the care of the patient, human subjects Tn a
Previous size of the scientific commu- &
‘.I.Ensm
though typically arising from honor- came knowt Tt'th R
W3S smaller>
^te of scientific
I
Proce
Proce
’hie motives, has led to abuses of the pShsSd^
°
*scovery slower, and the competition
research funding
I - jectiv
value
lysician-patient relationship. The • ’ — •
1979, the c®™2115510!! for
for research
fnnriino- less intense than
identified three comprehensive ethi
bhd
.rocities committed in the name of
is presently the cas^,
ca^e so
cn fbweTethical
fpwpr p+hiral
binH
cal principles that were to serve as an
c|
i)
issues challenged the scientific comscience on prisoners of war and civilis during World War H are a con- analytical framework to assist ■physi mumty; and (6) the value-laden naIndee
cians/scientists, human subjects, and
[
■
Ht reminder t-----ba-f~ —m ouujcCt
.»
ture of scientific endeavors previously ■
the
reviewers ot research proposals in unBW , raouse can occur. During the Nurem derstanding the ethical .issues inber- had not been widely recognized.
r
there
berg military war crimes trials, a set
More recently, however, the greatly ’
___ tv
and
ent
in
such
research.
13
The
principles
-r.
< standards, called the Nuremberg
expanded public support of biomediverifi
beneficence] cal research,’ the frequent press ac, de, was drafted for judging the are respect for persons] beneficence,
formi
and justice.
P^icians/scientists who conducted
counts of cases of alleged scientific
M|searc
The development of some princit se waniae numaa experiments.7 pies
fraud and/or misconduct, the in"■>
r; oiscu
■
s
Nuremberg
CodTh
J^md^a
. e
CoHa hac
__
, . governing clinical research creased pace of developments in bio- I
integ
ethics, from Hippocrates’ time
Sv*mulus
tor
the
development
of
Otho,
medical
sciences,
the
more
frequent
Swxm us fop
other
' -W and i
through a complex and tortuous his emergence of ethical dilemmas recodes
cooes totor protecting human subjects
ment
Kjaas niora
tne Declaration of Helsinki* tory over the last 50 years, may be lated to science, and the heightened |
a pted^by the 18th Worid^M^diS regarded as a victory for practical public recognition of the social im' •iW
4 ■brf'j ' . tai o
ethics, because clinicians these days
Assembly, Helsinki, Finland, in 1964
out a
pacts of technological advances have
understand the values that drive and led to a demand for a new level
phus€
revised in 1975).
undergird their efforts far more accountability from the saentih-' |
^po.
spite of the development of such
clearly than they did 50 years ago.
tfesjx
community. One aspect of this new
*
eI
■ferries R
feB'Pletb'
" S'.f
»
I
I
; I
751
104
JME 69 . numss>2 . FEBRUARY 1994
103
—"
■ ]
■I
“honesty, performing one’s craft with ations in which one’s personal nnanskill and thoroughness, respect and cial gain is effected by the scientific
fairness in dealing with others, and result produced in the research un
responsibility to people and institu dertaken. For example, a scientist
tions.”15 The majority of the basic doing a clinical trial of the efficacy of
values mentioned in these reports a given drug should not own stock in
(honesty, integrity, objectivity, veri the company that is producing the
fiability, and truthfulness) could be drug. However, it is more dimcult to
viewed as parts of the overall category assure objectivity when favorable ex
of honesty. That is, the honest scien perimental results would lead to more
tist would act with integrity and publications, additional research
would adhere to the facts; the work funding, and/or job advancements
would therefore be able to be trusted and additional prestige in the com
as being truthful and as objective as munity of peers.
A variety of experimental methods
possible.
_
_
Basic to the conduct of scientific are used by scientists to safeguard
research is the attempt to honestly honesty. The use of concurrent con
observe, record, and interpret some trol experiments; blind experiments
aspect of the material world—what in which the investigator does not
the modem scientist would express as know which observations come from
experimental subjects and which
“seeking the truth.” The postmodern
from controls; experiments involving
scientist might instead point out that
such objectivity is impossible, since multiple, independent observers; and
all information is processed by the the serial repetition of experiments
observer, including the most truthful are all examples of such mechanisms.
scientist. Thomas Kuhn points out In addition, the scientist must be prethat a person who knows what it is to pared to profit by aberrant; or unex
be scientifically legitimate may still pected experimental results, since
reach any one of a number of incom appreciation of the unexpected exper
patible conclusions, since “the partic imental result provides the opportu
i'
ular concluskns he does arrive at are nity for new insight or discovery.
■s
HONESTY of
honesty
OF scientists
SCIENTISTS
Only by honesty can trust relations
probably dete^rined by his prior ex
i'
be
built up among scientists. The
perience
in
omer
fields,
by
the
acci
) ‘
Honesty would most likely be the first
trustworthiness of the individual sci
dents
of
his
investigation,
and
by
his
e
value invoked by scientists. For exentist is therefore crucial. Steven
ample, the National Academy of own individual makeup.”16
Shapin describes trust relations as
One
way
to
attempt
to
ensure
ob
e | | 1 Sciences report, Responsible Science.
constitutive of the making, mainte
jectivity
is
for
the
scientist
to
be
- ‘ ;;O-- Ensuring the Integrity of the Research
c
J /W/
*’■
•
honest about personal biases. For nance, and extension of scientific
Process, lists .honesty, integrity,
obknowledge.17 The very character of
a •
jectivity, and collegiality as the set of example, the preferential use of mid
science would change without trust;
dle-aged
wrue
men
as
the
traditional
1 I
____
values, traditions, and standards that
with an increase in skepticism and
(and
somed
—
es
as
the
only)-subjects
kind scientists into a community (p.
distrust, “much of our modem struc
Honesty is the basis of integrity. for clinical studies of disease- pro
ture of scientific knowledge should be
cesses
was
based
not
on
any
overt
be
Indeed, what is called “integrity of
lief
tha
t
white
men
were
more
worthy
unwound, put in reverse, and ultithe research process” is defined by
•
■ H
or
impor
t-?-t,
but
on
the
unexamined
mately dismantled. Instead of ^bora
reP0It 35 “adherence by scientists
belief
that
the
data
would
be
general!tones for the production of new
’
■
and their institutions to honest and
zahle
to
groups.
Only
with
the
knowledge,
we should build, great fa
' i .
verifiable methods in proposing, percilities
for
re-inspection of
recognition
and
testing
of
this
belief
...
'
■’the close
’
forming, evaluating, and reporting rewhat
is
currently
taken
to be knowl
■
t ■ ®| search activities” (p. 17). In a second was it pnydKe to appreciate the lack
edge.
Grants
will
be
given
for check
I
tho rpnnrt
discussion of values, the report lists of uniformity of responses by sex,
ing routine findings; published re
race,
and
ethnicity.
i
integrity, honesty, trust, curiosity,
will look more and more like
Another way for the scientist to fa ports
? and respect for intellectual achieve•
”17
cilitate
honesty
is
to
avoid
conflicts
of
laboratory
notebooks.
tnent; of these, truthfulness, both as a
Honesty also involves being com
uioral imperative and as a fundamen interest wizz the possible results of
plete in descriptions of methods used
the
work
to
be
done.
Conflicts
of
in
tal operational principle, is singled
so that the ex
out as most basic (p. 17). The Massa- terest ran be based on either financial and results obtained
be repeated by others,
periments
can
or
intellecouzl
considerations,
or
on
chusetts Institute of Technology’s
use
Report of the Committee on Academic combinaticzs of the two. It is impor It involves the honest (accurate)
of
the
ideas
or
words
of
others.
Responsibility lists as essential values tant, yet relzzvely easy, to avoid situaccountability is the necessity of
using more formal mechanisms for
teaching trainees in the biomedical
sciences about how to conduct science
responsibly.14
However, as scientists and their
professional societies have begun to
d«
T , / -I
establish guidelines concerning scien
ex
tific conduct, they have used catego
ay
ries based not on underlying princiJ/- J pies but instead on spheres of action
0- '
such as authorship practices, conflicts
b- f
of interest and commitment, and
e$ 1
proper recording and analysis of data.
iise
Although important, such guidelines
X*
do not provide the needed answers to
jy
to r
■ students concerning their less administrative and more ethically complex
|O ! ’ questions in the same way that prin|8ir ciples can.
Mgr ■ In order to stimulate the
tne formu
lormu-
is
’ lation of ethical principles for scienah
tific conduct that could provide the
te I
needed analytic framework for thinkdl
’W
ing about obligations to society, the
al ~
following “candidate principles” are
>•:
'
suggested: the honesty of scientists;
V
k v respect for others; scholarly compef ' tence; and stewardship of resources.
i
I
riW
| 'v
v1
! Ji
fl s
tto itoc
. .
I
-T 1 I
1 .s
-1 ,»*«>
I J
ACADEMIC MEDICINE
104
............. ....
J
3
Ii
I
is
.....................
II
I
■
;-
I
RESPECT FOR THE OTHER
I
■
|
I
posive, and they have prima facie
rights to live and be left alone.” He
The second basic principle relates to therefore finds that it is imperative to
having high regard or esteem for reduce waste and dupEcation in the
other people and things. These use of animals, to fund the develop
“others” include research subjects ment of alternatives to animal test
(both humans and other animals),
ing, and to make people aware of the
the environment, and colleagues (in tradeoffs necessary in trying to
cluding employees, students, and “achieve human well-being, health,
trainees).
safety, and knowledge at the expense
of animal suffering,” since it is soci
Human Subjects
ety that will ultimately decide if such
use is warranted. In 1959, Russell and
The ethical principles and the obliga Burch grouped the ideas that scien
tions that are part of human-subjects tists conducting reseamb on animals •
research form a crucial segment of the need to consider into the threeTVs of
ethical concerns for biomedical re refinement, reduction, and replace
search. They have been well de ment.19 Bulger extends the discussion
scribed. For example, the Belmont re of Russell and Burch and adds to this
port, mentioned earlier, discusses a fourth R: reuiew.20
respect for persons, including the idea
Refinement provides for such ac
that individuals should be treated as tions as a decrease in incidence and
autonomous agents and that persons severity of the procedures used, in
with diminished autonomy are enti cluding avoidance of unnecessarv
tled to protection.13 Participation as a physical or mental suffering or injury;
research subject should be under the introduction of new, less invasive
taken freely and with the awareness instrumentation to decrease pain; and
of any adverse consequences of that the use of skilled, qualified investiga
participation. Beneficence requires tors in optimal physical facilities. Re
that possible benefits be maxi mi red duction of animal use relates to doing
while possible harms are minimized
a thorough literature review to ensure
Justice requires that persons receive that the experiments have not been
benefits to which they are entitled previously undertaken, that the data
and that undue burdens are not im- obtained
____ __ be important and therefore
posed on uhem. These principles form valid methods with adequate record
the basis of the requirements of in- keeping be used; and that the results
formed consent (sufficient informa- be rapidly published to avoid nntion, adequate comprehension, and needed repetition by others. Replace-'
voluntariness), the adequate assess- ment focuses on the use of alternative
ment of risks and benefits, and the methods such as chemical tests in
fairness Oi procedures and outcomes stead of bioassays, audiovisual aids in
in the selection of research subjects.13 teaching, and microbiological agents
Institutional review boards have the used in screening for carcinogens. It
responsibility to assure that
1'
these includes the substitution of animals
procedures are adequately followed.
lower on the evolutionary scale. Ade
quate internal review has now been
Animal Subjects
largely replaced by governmental reg
ulation of animal care and use. Inves
Similarly in research using animals, tigators must be cognizant of and re
respect for animal research subjects sponsive to their obligations, as
entails a commitment to the humane specified by regulatory agencies,
care and treatment of experimental when they use experimental animals
animals. Arter a careful and sensitive in their research.
analysis of factors involved with the
use of animals in biological research,
The Environment
Caplan13 concluded that animal ex•perimentation is always morally Respect for the environment is also
tragic and that “many animals used an issue in laboratory research.
in experiments are sentient and pur- Avoiding unnecessary duplication of
VOLUME 69 - NUMBERS ■ FEBRUARY 1994
/'
experimental procedures not o
T'TI; t
minimizes the number of anim*/
r
used, but decreases waste of all tvn Many laboratories are now invohS
:
with recycling of paper, glass ^11 L
® &■
metab In addition, the reclaiming r>f
■
certain expensive chemicals, such as
osmium tetroxide, can become a rou
'"
tme laboratory practice. Procedure^ 4^
for the safe.disposal of microbiology
cal, chemical, and other wastes (such W
as syringes and needles) must be es- -Bw
tablished and routinely carried out. ■
.T of
Colleagues
.'Op B
OB’
Many factors in modern academic life ■ ’
C
form barriers to respect or collegiality
“
among faculty or between faculty and
;■ '
students.21 For example, tensions
Bi
SSI®
&
have developed between clinical and
tr
basic science faculty, between
'
&» - © sc
and PhDs in iclinical
...............departments,
k
and between PhDs
hDs _____________
in the university
CE
and in the medical schools over sal—•
differentials, time available for •
search, time required for the teaching|9
of students, and independence of re-|j|
search topic selection. Respect for the;
students is of utmost importance, for^H
it is they who will become the life-4®
blood of future research. In additionJIB
f'fc
the frantic pace of life in the highly.;®
g;ca
competitive environment of research-’^H
intensive medical centers limits timet®
available for establishing collegial re-’MI
lationships. The increasingly litigious
i'til
nature of society limits the open selfevaluation of scientists’ activities. TJIm
However, respect for colleagues canj®
be expressed in many ways that are
unique to and necessary for effective .||
laboratory
research.
Laboratory^!
safety is one such issue. Since the lab- : w
oratory’ is frequently a shared envi- J®™
ronment, common reagents need to
be carefully prepared and accurately
labeled. Dangerous chemicals, radio- > /
active reagents, and microbiologic
agents require safe handling proo*'
dures, and spills of harmful chemicals
must be cleaned appropriately. lud1'
viduals working in the laborato
'|||||
need to have access to written ma*
C
rials that provide information abo _ .-.a
the safety’ requirements of all chemi’
'$18
cals that are used.
edby
Colleagueship is also express*
iil*-
B-1
If
h
E
ife
B
S'
I
>05 |
^EW
--------------------------------
Doctnr’c P
)rug Studies Turn Into Fraud
— —KJ -JL-^X
By KURT EICHENWALD
and GINA KOLATA
eVer
a wonder boy in the lucrative
fcidde^'^^35^
RESEARCH FOR HIRE
Second of two articles.
the drug industry. Fictitious patients
were enroUed in studies. Blood pres
bulging, Dr. Fiddes and his wife sure readings were fabricated. Bodi
«uld afford to drive matching ly fluids that met certain lab values
t
• .
°
BMW s; a Ferrari parked in
his
were kept on hand in the office rerage was ready for special occa- W tehratOr’ ready t0 56 substituted
sions. After a short time in reseSS
for the unne or blood of patients who
the once small-time family practi did not qualify for studies.
tioner was planning his dream house
f0r 1136 ^eniment and
on a Cayman Islands beach and envi the industry never noticed any probsioning the day he would make mil- . lems with Dr. Fiddes’s bogus paper
Uons more by selling shares In his work, which they reviewed during
busmess to the public
audits. Even when some of
But amid the glitter and cash was
alerted those
a fact that no one outside his office monitors“toS ^P'oyees
their suspicions, no in
knew: It was all a scam.'
vestigations were initiated. Instead
„F0KD,r' Fiddes was “"ducting re
wandtigs were filed away search fraud of audacious propor- while Dr.
Fiddes’s sterling reputa
tion as a researcher grew
I sta^!7, ta JUne 1996' the scheme
stated to unravel when the manager
nlu a®‘^lboring doctor's office, DenneUe Del Valle, told a Government
frani >,nTOrS °f CrimeS’ UeS “d
fraud she had heard from Dr. Fides s own employees. Eventually to
prove the claims, Ms. Del vile
—— «>«bO
practice here into a research ju^
naut. recruiting patients for drug ex
periments at a breakneck pace His
him a ma^
gidustry desperately scouring the
test subjects. Companies
small showered him not
more than 170 studies to
,Ut Wlth m,nions of dollars
Compensation for his work
. t.r/e was good. With bank accounts
audi^S
VP 01 paper tot0 the
auditor's hand. On it was written a
Continued on Page A16
...
fcrc-, —-
i.'t
I'
A Doctor’s Drug Trials
; WereGrounded in Fraud
Continued From Page Al
Through ms lawyer, Dr. Fidd
“SmSSX
1' roT °'
•.'Chat most rvseJchen
because drup rr»m«
3 testing operation that was one 2
yg1?
j
6 Jorce^ t0 cheat
to a Close this weet
c.^5 “d SeVeral ac“n>PuSap?ead^
■
_
m
10 fraUd* druS’study results for virtu
aBy every company in the busing wX
hustoesa was
Stin, at his own research
-'Fiddes laid much of
m
-thxng that happened on Lj
;tors - again, without providing^vSX
’
the assertion Whhe
u
.-beneficiary of the Ulegalactivitt he^L*®
-toed that it was the saTS^ he main-orkmg for him who
■‘trften without his knowledge The inform ’
—Doo provided by Dr. Fiddes hac nt
.
DSDShtiOnaJ
^inVeSli8ati0ns- reSU ted
LOr^X
refusaJ t0 acc'Pt the blame
“ —
■.
Ihi
t'
vDr. Fiddes was anguished at being labeled a
<1
I
ft
B'
EB
■r
»«nk from being a widely resoected rnmi2
member to now bemgX^^S
more than a comZn
wrote. -My mother often sVid
^aeiine tor
• -making money.
-SLX/X d° ren,aln basically the same
even though now, since thev am r>aw t
The Career
•From Family Doctor
;To Drug Researcher
SouU>-
*■
'rom memos “0 oVS
...temal documents, inVestigat0r5? /?er
FiddeS always wanl«i to be a
Sg.-srsivs-=
company, which is now defunct
office ruled by a dX h
fu_ r-a-i Ji
-m.
avresea»‘ch
a™ ®* the magnitude of
peat^^^^X’w^ T
wDrked-Faced ’**> S'
cepto, there seemed little thev
that the system o -
|B!
—‘ufc T”’11’ watog to a chilly ice
j, company and court records person a’l a g
b ■ -SJ
1
•Xw^TF
p:ith
^t™e Came “ c'>oose between
*
r,gUre skater or enrolling in a
^ystty. young Robert Fj(ides
"a
^d«n>c path And there he showTtha!
drive, gaining acceptance to medical
at the University of British Co" mbu
*"
accord^g m
ms curriculum vuae
6M
-«^new^--
IbA
HHb
|K|
Ik’”
Wh° believ«l
.^toX^Sl”510° P°Or-
.. too (T5
I
5"/5^
Maybe he Mt wanted too much
BIbt
I
|r.
Br
*
K
came (o Long Beach. Calif, for a job as a
hospital intern. He went on to join a medical
partnership, but in 1981 opened his own prac
tice in Whittier with a medical assistant,
La Verne Charpentier, In a convened house
with an awning and flower garden. It was the
perfect image for an old-time family doctor,
and the practice blossomed.
Dr. Fiddes’s wife would later write of
those early days in a letter to the judge who
sentenced her husband. “His patients adored
them and showered the office with every
thing from home-baked cookies to hand-cro
cheted dolls,” she wrote. “Both Rob and
Laverne worked long and hard to provide his
patients with the best care.”
Eventually, Dr. Fiddes formed a group
made up of several family doctors in the
area. But by the late 1980's, an obstacle
emerged that Dr. Fiddes was unable to side
step. Managed care was sweeping California,
and Dr. Fiddes chafed at the new rules. “He
felt his hands were tied in performing what
ever tests were necessary to assist in the
proper diagnosis of the patient,” Mrs. Fiddes
wrote in her letter. Patients “felt equally
frustrated with the new system.”
Growing restless, he decided to pursue a
law degree, attending night school In 1987,
he passed the California state bar exam.
But by then, the medical profession had
changed so radically that an entirely new
specialty presented itself: Doctors were test
ing the safety and effectiveness of new drugs
for pharmaceutical companies, using their
patients as subjects. Recognizing the oppor
tunity to get away from managed care. Dr.
Fiddes jumped at the chance.
His new climcal-tnals business grew rap
idly. Dr. Fiddes appointed Ms. Charpentier
as his first full-oroe study coordinator, and
raided a private research firm in the area,
California Clinical Trials, to build his staff.
He began to dream of eclipsing his biggest
rivals and taking hrs new enterprise public,
at times doodling his ideas for a corporate
logo onto pads of paper.
As the business grew, former employees
said, a pattern soon emerged. Dr. Fiddes
would meet with patients in his first-floor
office, then refer them to the study coordina
tors on the second floor. Often, the patients
who arrived there felt reluctant to take part
in the trials.
"They were pushed to go up there,” said
Susan Lester, the former study coordinator
who blew the wtusrie on Dr. Fiddes. "They
often would say, T don't want to participate
in this, but I don! want to make him mad.’ ”
In the early days, Ms. Lester and other
coordinators would tell wavering patients to
take their time, perhaps by sleeping on the
idea, before signing an agreement to partici
pate. But Dr. Fiddes and Ms. Charpentier,
who also declined cxerview requests, quickly
put an end to such solicitousness.
"I was told that c was a big mistake to let
them think about ysning.” Ms. Lester said.
"They said, 'You den t tell them they have
any choice about a. You put them in.' "
W-
K
KI
l.w.
.......................
The Fraud
Falsifying Records,
Endangering Patients
Kimberly Carlon's interviews for a job at
the Southern California Research Institute
had been going well She had only one more
hurdle to clear: speaking to Dr. Fiddes him
self. If he approved of her, Ms. Carlon, a
certified respiratory therapist, would be
come the research site's latest study coordi
nator. Sitting in front of Dr. Fiddes’s desk in
early 1996, she listened as he described a
hypothetical situation. Suppose, he said, that
a patient was available for a study, but was
taking medicatkxi prohibited by the study
protocol The answer seemed obvious, Ms.
Carlon replied: she would send the patient on
his way.
WeU, Dr. Fiddes told her, that was not the
way he did things. At the Southern California
Research Institute, he said, the patient would
be entered into the trial; that would require
the center to falsify records so that the
violation of study rules could be hidden.
Ms. Carlon got the job. But she would later
describe her discussion with Dr. Fiddes as
the first moment she should have realized
Mitiicuiuig W«5 wTuiig.
Like every other study coordinator who
passed through Dr. Fiddes’s research center,
Ms. Carion found herself being pushed to
break the rules. When she ran a 1996 study
for a new asthma inhaler sponsored by Fisons, a British drug maker, she found a
patient who had been enrolled even though
she had an incurable lung disease that should
have disqualified her. When a monitor hired
by FIsons asked to see the patient's medical
chart, Ms. Carlon approached Delfina Her
nandez, a more senior employee, and asked
what to do. .
Ms. Hernandez quickly fetched the pa
tient's medical chart, and pulled out every
page that made reference to the lung disease.
Then, according to investigative documents,
she turned the remaining records over to the
monitor. The violation went undetected.
Ms. Hernandez, who later pleaded guilty to
fraud, declined to comment
Again and again, study coordinators were
Instructed by Dr. Fiddes and his top aide, Ms.
Charpentier, to ignore the requirements of
the drug studies. The rules called for exclud
ing smokers from an asthma study? The
coordinators were told to put the smokers in
anyway, and not mention their habit m the
medical records. A certain blood pressure
was required for patients to participate in a
hypertension study? Then the coordinators
were expected to write that level into the
chart, regardless of the truth. Patients’ med
ical records contained health histones that
precluded them from participating in a test?
Then the offending pages were npped out
and destroyed, and the patients placed on the
experimental medication despite the dan
gers.
Over time, the frauds orchestrated by Dr.
Fiddes grew ever more audacious. Eventual
ly. according to Government documents, it
was not just the records that were being
falsified. Instead, medical tests were rigged
— and at times, patients simply invented.
Outside monitors reviewed the documenta
tion, but since there were real lab records for
the rigged tests, they had no due that they
were being deceived.
The office refrigerator became the source
of human bodily fluids that met the require
ments of various studies. A jug of unne was
often found there on Monday mornings, pro
vided by Carol Rose, an employee. Ms.
Rose's urine contained high levels of protein
— just the trait patients needed to qualify for
certain studies. Dr. Fiddes paid Ms. Rose $25
each time she collected her urine and
brought it to the office, where over time it
was divvied up among specimen cups la
beled with other people’s names and pre
sented for testing.
The refrigerator also proved useful when
the research center was conducting studies
on hormone replacement therapy for meno
pausal women. The studies required women
with blood serums that showed low levels of
BOS'
estrogen and high levels of follicle-stimdaring hormone — signs that a woman is Eing
through menopause. To make sure tha: die
patients' tests qualified. Dr. Fiddes sent bit a
memo specifying the hormone levels re
quired for the study. "We need some senm
that scores these numbers m the fng sc. ail
times,” he wrote.
Another study on an antibiotic requred
that patients have a certain type of baaena
growing in their ear. No problem for Dr.
Fiddes. He bought the bacteria from a ommercial supplier and shipped them to tescng
labs, saying they had come from his panras'
ears.
Dr. Fiddes’s coordinators, paid bomses
for recruiting patients into studies, sooe be
gan improperly enrolling themselves and
members of their families. Often,
were changed to avoid detection by drug
company monitors. At times, family mem
bers took part in several studies at once — a
violation of the rules because studies reqnre
that participants not be taking other medica
tions. so that the data obtained relate onrr to
the drug under study.
Employees “were running around tang
E.K.G.’s on each other, if the patient cadcn’t
pass,” said Sloan A Bergman, a former
study coordinator who quit working for Dr.
Fiddes after less than a year because of
ethical concerns. "I wasn’t happy, ta I
needed a job.”
Yet all the while, there were constant
reminders that the true cost of the f termed
drug testing was being borne by sick and
vulnerable patients.
in the summer of 1995. the research esotute began work on a study of Coxaa.'. a
hypertension medication sponsored by
Merck & Company. Among the patients en
rolled by Dr. Fiddes was Arlene Roberts, a
70-year-old woman with high blood pressure.
Instead of dropping, her blood pressure rose
dangerously when she took the drug Dawn
Simons, the study coordinator, became
alarmed and sent Ms. Roberts to see Dr.
Fiddes. Rather than taking her out of the
study, Dr. Fiddes prescribed two other hy
pertension drugs. The triple dosage not only
violated the study rules, it made it impossi
ble to gauge the effect of Cozaar.
A few days later. Ms. Roberts returned.
Her face was bruised, her speech was
slurred and she had trouble walking. She told
Ms. Simons that she had passed out over the
weekend while bathing. Ms. Simons took her
pulse and found that her heart was barely
beating — a result, the coordinator thought,
of bombarding her body with hypertensive
drugs. Worried that Ms Roberts was beaded
toward cardiac arrest, Ms Simons asked Ms.
Lester, her fellow study coordinator, for as
sistance. The two helped Ms Roberts, who by
then could barely walk, to Dr. Fiddes’s crffice.
"He said, ’It’s no big deal She’s probably
making more of it than it really is.’" Ms
Lester recalled in a recent interview.
Ms. Simons, dismayed at what was hap
pening. thought Ms. Roberts should be
dropped from the study. But Dr. Fiddes
refused, keeping her on the medications for
several more weeks. Ms Roberts was soon
seeing another doctor in a hospital for the
problems that emerged during the study. Ms
Simons, the study coordinator, resigned from
her job, but not before surreptitiously copy
ing all the medical records and turning tnem
over to Ms. Roberts in case she wanted to
bring a lawsuit. Ms. Roberts, who recovered
at the hospital, never sued.
Dr. Fiddes received payment in full from
Merck — his reward for keeping Ms. Roberts
in the study through its completion.
Avoiding Detection
The F.D.A. Ignores
An Early Warning
Use Beverly finally decided that Dr.
Fiddes had to be stopped. While working for
him for five years handling laboratory tests
4ii
like blood work, Ms. Beverly had seen sighs
of his willingness to cheat on drug studies
And so in January 1995, almost immediacy
after leaving her job, Ms. Beverly telephoned
investigators with the Food and Drug Kdministrabon.
She reported her own experiences, sucl^as
the time in 1990 that Dr. Fiddes had asked
her — without explaining why — to fintf a
way to alter lab values in unne tests. She ifco
provided the names of study coordinators
who knew that testing data were being rttanipulated to enroll larger numbers of pa
tients With her revelations, the’ Governnftht
had its first solid lead on what was happening
in Dr. Fiddes's office fully 17 months before
Ms. Del Valle exposed his crimes to^an
F.D-A. auditor. Investigators wrote membs
about Ms. Beverly’s allegations, and for
warded them from Los Angeles to the clini
cal investigations branch of the F.DA.
There, the memos were filed away. No
investigation was begun.
Brad Stone, a spokesman for the F.D1A..
said that, because aspects of the case hdve
not been finished, the agency could not com
ment at this time.
Is!
Dr. Fiddes had always found it easy.no
elude defection by the crews of compohy
monitors and Government auditors that vis
ited his offices, even when his employees
spelled out their suspicions about what was
happening. It was not that he was particiffitly adept at dodging their questions; rather,
they seemed reluctant to challenge such1'a
prominent figure in the drug-testing holi
ness. "This business can be run on wo nds,
and I have learned the words," Dr. Fid^Jes
wrote in a 1995 memo. ” ’We have no prob
lems’ is our mono, and tell this to ewery
monitor.”
•
When Dr. Fiddes’s efforts to enroll To
tients were thwarted by system safeguards
intended to insure accurate test dataxhe
often found ways around the problem, bi
In a 1995 study of an experimental pain
reliever for arthritis called PHZ 136 that was
sponsored by the Zambon Corporation. Dr.
Fiddes faced a particularly difficult impedi
ment. The patients were supposed to have
arthritis of the knee, as verified by X-rayS.
Dr. Fiddes tried to recruit patients. Again
and again, he sent their X-rays to an inde
pendent radiologist for review. And almost
every time the answer came back the sam^.
The patient did not have arthritis, and sotttd
not qualify for the study. Frustrated, Or
Fiddes told the coordinator of the study, Mt.
Lester, to look through his medical filesldr
patients with arthritis of the knee. Then, he
said, she should offer each of those patients
$25 to come in and get multiple X-rays, which
he could substitute for the X-rays of patiebts
who did not qualify. But Ms. Lester drew1 the
line, and refused.
-he
The ever-resourceful Dr. Fiddes found
way around that obstacle, however. Through
his staff, he got in touch with the project
manager at Pharmaceutical Product Devel
opment Inc., which was managing the study
for Zambon, and asked a question: Becaraft
he was a doctor, couldn’t he just interprets hrs
patients' X-rays himself, rather than sent
them to a certified radiologist?
!eo
The company was happy to oblige. Re
searchers “may interpret knee X-ray fil»
obtained on candidates," Julia Dixon, thfe
project manager, wrote in a letter to W.
Fiddes. "There is no need for a radiologidil
consult.”
tbFrom that moment on. Dr. Fiddes had-no
trouble finding patients who qualified for the
study. "That kind of opened it up for him
right there and then." Ms. Lester said. "Ev
eryone understood that if he was going iK
read the X-ray, he was going to be."
-1
Not long afterward. Dr. Fiddes received a
letter from one of the testing companyts
study monitors. "CONGRATULATIONSica
meeting your enrollment deadline!” the
monitor. Cheryl Grant, wrote in a letter
dated Feb. 19, 1996. "1 performed a JOO
percent source document verification, and
found no outstanding issues.”
>51
Through Pharmaceutical Product Dgvel-
lift
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The Cover-Up
opment. a testing company. Dr. Fiddes was
paid $45^68 tor his effort in the Zambon
study. The company never detected his
fraud. Zambon declined to comment, citing
confidentiality of the study, as did Pharma
ceutical Product Development But Nancy
Zeleniak, a spokeswoman for the testing
company, said its monitoring was of the
highest quality. "We have standard operat
ing procedures for detecting fraudulent or
fabricated data,” she said. “We are helping
to set standards in the industry."
Another company came closer to putting
him on the spot Several former coordinators
for Dr. Fiddes said they had reponed his
unethical conduct to Pat Pryor, an independ
ent study monitor working with Pfizer Inc.
Tipped off to the discrepancies. Ms. Pryor
sharply challenged Dr. Fiddes and his staff
in her reviews of their paperwork.
Dr. Fiddes chafed at the challenges, feign
ing outrage. "Our integrity and reputation
tor performing high-quality clinical trial
work has been injured, and we are jusnfiabty
upset,” Dr. Fiddes wrote in a July 1995 letter
to Pfizer, complaining about Ms. Pryor’s
demands. He insisted Pfizer “have a new
monitor assigned to our site Immediately.”
Not long afterward. Dr. Fiddes annmmrrd
the news at a staff meeting: Pat Pryor wokl
not be returning to monitor the Southern
California Research Institute.
Pfizer said that the company replaced
monitors if there seemed to be a confixx “In
order to insure the most objective and best
monitoring, we generally recommend that if
there is personal conflict, and no cenaaayoC
irregularities, that a new neutral person is
assigned to review all of the data,” said
Betsy Raymond, a spokeswoman for Pfizer.
But in the Fiddes case, that policy d»d not
Improve the monitoring. "We have an exten
sive system of checks and balances.” Ms.
Raymond said. "Even with all of that, we
didn’t uncover the fraud.”
Why was Dr. Fiddes able to fool the moni
tors so easily? Because the oversight system
is mostly designed to catch errors, not fraud.
TO protect patient confidentiality, nxnmrs
are forbidden even to know the names al test
subjects, meaning that no spot-checks are
ever performed by the companies to sake
sure that researchers are not making up Lab
values or inventing patients.
But Dr. Fiddes’s luck in avoiding detecnon
would not hold. By May 1996, more than half
a dozen study coordinators — including Ms.
Simons and Ms. Bergman — resigned, tear
ful that the fraud would cost them their
nursing licenses or certifications. Ms. Lester
likewise decided she could take no more, and
wrote a letter to Dr. Fiddes declarme Stax
she would no longer participate in franiulent, unethical work.
A response came quickly. Ms. Lester was
• ordered to clean out her desk immedandy,
and was escorted from the building On her
way out the door, she bumped into Kariryn
Davis, another Fiddes employee. With jtars
in her eyes, Ms. Lester made Ms. Dans a
promise.
“She told me before she left that she was
going to bang Dr. Fiddes to his knees.” said
Ms. Davis, a former employee. "I had nc lira
that she meant it seriously."
Alan Knox, the chief financial officer of the
research center, was working in his office in
the summer of 1996 when its chief operating
officer burst in. The officer, Elaine Lai. de
manded that Mr. Knox pull a series of in
voices documenting payments to an employ
ee, Carol Rose.
Mr. Knox fished the invoices from a filing
cabinet As he read them, he grew concerned.
Written dearly across the $25 invoices were
the words “urine sample." For the first time,
he was seeing the evidence that Ms. Rose was
being paid to substitute her own urine for that
of patients.
Wary of what was happening. Mr. Knox
copied the invoices, and kept the originals. As
he handed the copies to Ms. Lai, he asked her
and Ms. Hernandez, the longtime senior em
ployee of Dr. Fiddes, what was going on. Well,
came beck the response, apparently Susan
Lester nad gone to the F.Da^ ana worse, was
contacting other former coordinators and try
ing to persuade them to talk to the Govern
ment about the way Dr. Fiddes conducted his
research.
“I remember inquiring with Delfina and
Elaine and saying. ’What's the big deal?’ ”
Mr. Knox said in a recent interview. “They
looked at me, they looked at each other and
said, ’We have to tell him the truth.’ " As he
listened to them recount the trickery that had
taken place at the institute, he said, "I was
just taken aback by the level of fraud."
His first thought, he said, was that Dr.
Fiddes and his top aides should confess every
thing to the F.D.A But unknown to him. they
were at that very moment planning a cover
up that would involve destroying incriminat
ing documents and manufacturing new ones
that might place the blame tor any problems
on Ms. Lester.
Dr. Fiddes was most concerned about the
unne substitution, out of fear that Ms. Rose
would talk, according to notes of investigator
interviews. So, in August 1996, be called a
meeting at the Hilton Hotel in Whittier with
Ms. Lai, Ms. Hernandez and his longtime
assistant Ms. Charpentier.
To solve the Carol Rose problem. Dr.
Fiddes told the group, he would create a bogus
medical chan and false patient history for
her. If asked, he would say that unne had been
collected as pan of her medical treatment
The folkwing Saturday, Ms. Lai called a
meeting for what she called “chan review.”
The actual mission was to go through the
medical charts and destroy any evidence of
wrongdoing.
Days later, on Aug. 21, Ms. Lai called tor
another meeting for strategic planning. In a
memo to Dr. Fiddes, Ms. Charpentier and Ms.
Hernandez, she made clear the need to move
quickly.
“F-DA. is busting down our door on Mon
day," Ms. Lai wrote. "You MUST be able to
dump your files to your car when F.DA.
knocks."
Ms. Lai added in the letter that they had to
agree to scripted responses to all quesaons
the Government might ask.
As Dr. Fiddes and his allies were seretly
working on their cover-up, Mr. Km was
reaching out to regulatory experts win be
thought could help the company m es talks
with the F.D.A. He got in touch with Girrhrn
McKelvey, a quality assurance consutaar tor
clinical tnais. who was quickly hired rr belp
out. Ms. McKelvey was stunned by the nazrutude of the fraud she discovered a: Zt Fiddes’s office. But even more incomprenEsbie
was the blase attitude Dr. Fiddes denxrstrated as he calmly informed her of hs t3«er-ap
plans.
“I explained to him that what had harcesed
here was considered criminal, and tna be
could be prosecuted for conspiracy and
fraud," Ms. McKelvey said in an Interview.
“Dr. Fiddes replied that they were going to
blame Susan Lester for all of the problems,
and he was going to say he had no knowledge
of what was going on.”
About that time, Ms. McKelvey learned that
Dr. Fiddes had moved all of the patient
records off site. When she asked where they
were, she said, he replied that they were in
storage. Days later, when she pressed for
them again. Dr. Fiddes told her the records
had been lost
“I was starting to get really scared,” she
said. "1 don’t like to be messed with.”
As the situation detenorated, Ms. McKel
vey decided the situation was too big to handle
‘You MUST Be Able
To Dump Your Files’
alone, and required someone with mor
pertise in dealing with the C-T.-emrr.ent
om v ska.
4^.^. • ri .u - . *
.
uum nuuiaci i.cmn ut*, a
suitant who specialized in the F DA.
Hamrell arrived at the research site 1
briefing from the company's top execut
including Dr. Fiddes and Mr. Knox
made no bones about all the protocol \
tkxts they had committed. Why would
Fiddes be so open? Because, as Mr. Har.
learned quickly, he still bebeved that he c
outsmart the system.
“He told me that he knew the law b<
than the F DA., and that the F.DA. cou
touch him,” Mr. Hamrell said. “He told m
was a lawyer, and he wasn’t responsible
Many of those who worked for him, like
Knox and Ms. McKelvey, saw the wrttin,
the wall and resigned soon after being hi
But others who for years had accepted
Fiddes s repeated assurances that even
tn the industry did the same things »
shaken and agonized about whether to •
fess.
“I want to spill my guts, but what is gom
happen to me and my future?” Delfina 1
nandez, one of Dr. Fiddes s top aides, wrot
her diary as investigators dosed tn. ”(
forgive me if you think I dd wrong. ;
punish me if 1 did anything to hurt thpatients.”
She soon found out what wculd happen
her future. On Feb. 16.1997. teams of Fede
agents swarmed into the Southern Cabfor
Research Institute's office. The entire st
was ordered to move to the front of ’
building, as the agents seized box after box
documents. One agent with a video camt
filmed every employee's face for use tn futt
fdentificauons.
With employees facing such intirmdati
law enforcement tactics, cracks began
emerge in the conspiracy to lie to invest:;
tors. Ms. Hernandez was the first to decide
provide evidence to the Government, and t
other dominoes quickly fell By Septemb
1997, Dr. Fiddes, Ms. Hernandez and .*>
Charpentier agreed to plead guilty. Ms. L
pleaded guilty soon afterward.
Now, with Dr. Fiddes compelled to coopt
ate as part of his plea agreement, the Gover
ment hoped to learn more from him th
would help in the battle against researt
fraud. On Oct 10, at 10:30 AM.. Dr. Fidd<
met for an interview with William Leitner ar
Hetal Sutana of the F.DA.
For five hours, the agents grilled D
Fiddes. He told them that fraud was rampar
in the research industry. He named names <
doctors he suspected of engaging in practice
similar to his own. And he described som
telltale signs that should raise suspicions c
possible fraud.
But, the investigators asked, what evidenc
of fraud is there in the records reviewed b;
monitors and the Government? What couh
the watchdogs have seen that would hav»
allowed them to detect his fraud0
Nothing. Dr. Fiddes replied. Had it not beer
for a disgruntled former employee, he woulc
have still been in business
__
NATIONAL MONDAY, MAY 17, 199>
1
Finding the Loopholes
The oversight system for trials of new drugs was developec curing the era of university
research. But. as research has become a lucrative business "or private doctors, oversight
has not changed to account for the chance that some migfr cheat to make more money.
Dr. Robert Fiddes relied on holes in the blanket of oversight r perpetuate a huge fraud.
OVERSIGHT
LOOPHOLE
Must be registered with
the F.D.A.; those who
have been found
breaking the rules are
barred from participating.
For drug studies, usually no
qualifications other than a
medical license are required.
Q Drug company
provides rules for
conducting a
particular study to
doctor.
All studies involving
humans, as well as ads
for recruiting patients,
must be approved by an
independent ethics
board.
Such boards have been
criticized by the Government
as being overwhelmed by too
much work.
Q Doctor speaks to
patients about joining
studies.
None.
industry monitors do not
xnow patient identities.
Cannot check what doctor
said to sign subjects up.
Q Doctor presents
informed consent
form to patients.
Forms must be reviewed
and approved by ethics
boards.
No one checks if patient
understands or has read the
form; adequate consent not
obtained about half the time.
0 Doctor conducts
tests to see if
patients qualify for
Monitors review
paperwork from tests to
be sure it meets study
requirements.
No method exists for
detecting if a doctor falsifies
tne underlying lab records or
writes down inaccurate
results for tests such as
blood pressure.
Monitors check these
records both during and
after a study, and may
conduct audits comparing
results to more detailed
patient records. Govern
ment monitors may audit
these records as well.
Not even spot checks with
patients by industry monitors
are permitted. So if test is
faked, ii is undeieciabie. The
Government rarely checks
with patients, and usually only
when they have evidence of
fraud.
RESEARCH STEP
0 Doctor signs
contract to test
drugs.
study.
0 Doctor provides trial
medicine to patients
and conducts tests
sucn as screening
urine and blood.
a
B
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te
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3/^
From Parties to Prison
I
r
in the mid-1990's. Dr. Robert Ffddesand
his staff celebrated another successful
year of drug stud.es at a Christmas party.
The festive mood soon ended, as some of
those present revealed his research fraud
■eadmg to several guilty pleas.
LAVERNE CHARPENTIER
A -ongum6 meClcal assistant for Of F.ddes
Xn 2a,n
35 3 StUdy coora'"ator ■
he turned to drug research.
SUSAN LESTER
Wc.'ked as a stjcy coo.'d.nator f
Cr. nddes ceg.nnmg m 1994
Pleade<1 5Uil,y,0 conspiracyIS scheduled for sentencing this week
IN TH£ case E.'ew the Whistle;
•he wrong- -g in ,095 Continm
.0 work m c.'ug research
,
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' -1®
ROBERT FIDDES
REBECCA nDOES
month sentence in a Fec^ bnson^nXXm.a,00"^^ s6™9 3 15‘
Wife of Dr. Fiooes. ano an
administrator at his office
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A flood of advertisements has led to a big increase in the number of private doctors who enroll thenpatients as subjects in drug testing. Aggressive recruiters can earn as much as $1 million a year.
Drug Trials Hide Conflicts for Doctors
By KURT EICHENWALD
and GINA KO LATA
When Thomas W. Parham vis
ited his doctor in the summer of
1995, he expected just another rou
tine checkup. But his doctor had
something else in mind.
The doctor, Peter Arcan, sug
gested Mr. Parham might want to
join a study of a new drug to shrink
enlarged prosutes, according to
records of the encounter. Mr. Par
ham was puzzled — his prostate
was fine. But Dr. Arcan brushed
aside the retired metal worker’s
questions, saying the expenmental
drug might prevent future prob
lems. Satisfied, Mr. Parham, a 64year-old resident of La Habra,
Calif., agreed to participate.
But there was one question Mr.
Parham did not ask: What was in
it for Dr. Arcan?
The answer was money. The
drug’s maker, SmithKline Beech
am P.L.C., was paying $1,610 for
each patient that doctors signed up
— money that covered, study ex
penses while allowing a portion to
end up as profit for Dr. Arcan and
his associates. .
Mr. Parham had no idea. “Noth
ing was mentioned about money,”
he said in an interview. “It’s a
situation where you have faith in
your doctor.” Through his secre
tary, Dr. Arcan declined comment
RESEARCH FOR HIRE
First of two articles.
With his decision, Mr. Parham
bad unwittingly joined hundreds of
thousands of other patients re
cruited by their personal physi
cians into a booming venture: the
business of testing experimental
drugs on people.
Once clinical research was a
staid enterprise primarily admin
istered by academic researchers
driven by a desire for knowledge,
fame or career advancement
Now, it is a multibillion-dollar in
dustry, with hundreds of testing
and drug companies working with
thousands of private doctors.
hm become comm^iti^bought
and traded by testing companies
and doctors. Almost daily, the in
dustry urges doctors to join the
gold rush, bombarding them with
faxps and letters blaring such
come-ons as “Improve Your Cash
Flow” and “Discover the Secret
For Obtaining More Funded Stud
ies.’’ In an era of managed care,
the pleas are seductive: the num
ber of private doctors in research
since 1990 has almost tripled, and
top recruiters can earn as much as
$5<AD00 to $1 million a year.
This new system is a boon for
drug companies because It reaches
out to a vast pool of test subjects
who have never before been avail
able for experimentation. But it
also injects the interests of a giant
industry into the delicate doctor
patient relationship, usually with
out the patient realizing it
These changes have prompted
little public debate, mostly be
cause the full scope of what Is
happening is hidden. The industry
treats research agreements as
corporate secrets and contractual
ly forbids doctors to disclose them.
As a result, few people outside the
industry, including Government of
ficials, have seen the contracts or
know the magnitude of the money
involved. *
But in a 10-month investigation.
In New
this new
patients
The
Yorkindustry,
Times obtained
contracts and thousands of
other confidential documents that
present a view of the research
industry that has never before
been available.
These records, and interviews
with participants, reveal a system
fueling a pharmaceutical renais
sance, but fraught with conflicts of
interest; that places a premium on
speed and meeting quotas; that
. relies on Government and private
monitoring that can be easily
Continued on Page 28
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Fast-Growing System of Drug Testing
Hides Conflicts for Doctors
Continued From Page I
fooled and that some researchers said is
inadequate, and that secretly offers a share
of the cash to other health professionals who
might influence patients to join a study. At
bottom, the only thing separating a trusting
patient from a study that could be inappro
priate or potentially harmful is the judg
ment of a doctor tom by these unseen con
flicts and pressures.
The documents, including contracts, pro
tocols or related financial records from
more than 300 recent drug studies, were
provided by a number of people in the
industry concerned about its direction. The
Times also conducted a computer analysis
of more than 200,000 filings with the Govern
ment and related data submitted by doctors
who want to conduct research, and inter
viewed doctors, patients, ethicists, industry
executives and Government officials.
These are among the specific findings of
The Times’s investigation:
Wrug companies and their contractors
offer large payments to doctors, nurses and
other medical staff to encourage them to
recruit patients quickly. And doctors do not
even have to conduct trials to get paid:
There are finder’s fees for those who refer
their patients to other doctors conducting
research.
q Doctors who recruit the most patients
receive additional perquisites, such as the
right to Halm a coveted authorship of pub
lished papers about the studies — even
though the true author is a ghost writer
using an analysis from the drug company.
Those who fail to meet the recruitment
gOals are usually dropped from future stud
ies.
TTesting companies often use doctors as
clinical investigators regardless of their
Kevin M*k>ney for The New York Ttoee
Researchers “are enticing
and cajoling patients who are
in no position to resist their
blandishments to enter
clinical studies.”
Dr. David S. Shimm. a member of the
ethics committee at Porter Adventist
Hosoital m Denver who has written
spsoalty, at times leaving patients in the
care of doctors who know little about their
Htdinnti For example, psychiatrists have
cccducted Pap smears and asthma special
ist have dispensed experimental psychiatnc drugs.
qA growing number of doctors conducting
dr=g research have limited experience as
c±mcal investigators, raising questions
ateng some experts about the quality of
their data.
-la interviews, industry officials and re
searchers said the emerging drug-approval
system was dedicated to quality and offers
significant benefits. Since patients are seeizj their own doctors, researchers said, it
a level of continuity and personal con
tact to the process — something unavailable •
from full-time researchers.
Moreover, industry officials said, the new
poci of test subjects is a resource of incalcu
lable value that is allowing the development
of an avalanche of new compounds. Drug
tests “can get delayed if the patients aren’t
ck: there and available,” said Chris
Knebier, the chairman and chief executive
ai Covance Inc., a giant testing company.
• But some experts said patients were be
ing pushed to participate in the studies
because of the financial interests of their
doctors.
Doctors working as researchers “are en
ticing and cajoling patients who are in no
position to resist their blandishments to
enter clinical studies," said Dr. David S.
Shimm, a member of the ethics committee
al Porter Adventist Hospital in Denver who
has written about research conflicts.
-“What the patients are not seeing is that
the clinical investigator is really a dual
agent with divided loyalties between the
patient and the pharmaceutical company,”
he said.
-While patients must sign detailed consent
forms to enroll in drug studies, they are
often in no position to question their doctor’s
suggestion that they join.
“The physician has enormous power over
you,” said Uwe E. Reinhardt, a health care
economist at Princeton University, who
himself recently agreed to participate in a
clinical trial run by his doctor — in part
because he feared annoying him — and who
had no idea that money might be involved.
“You want to keep his favor. If you say no,
you’ll worry that he may not like you.”
That is what happened with Mr. Parham
and Dr. Arcan. In joining the study, Mr.
Parham said: “I just followed his advice,
just like if he said to take two aspirin instead
of one. He’s a doctor and I’m not"
-In truth, Mr. Parham should never have
b£en signed up for the prostate study. Ac
cording to his medical records, he had been
hospitalized the previous year with a chron
ic slow heart rate, a condition that specifi
cally disqualified him for the study. But,
saying that Mr. Parham’s heart rate was
only mildly slow, an administrator handling
the paperwork for Dr. Arcan sought an
exemption from SmithKline. Based on those
representations, the drug company granted
the exemption; it was not told about Mr.
III i
F1
and beyond what they ar’.:c:pated."
once unheard of in clinical research, are
But doctors who are particularly success
becoming
part
of
the
landscape.
Moreover,
Mr. Parham comful in recruiting study patients and keeping
those payments — to private doctors, re
'
"
C
a
symptom
of
his
slow
2
down their costs can make huge profits.
search firms and even to university medical
fDE Arcan dismissed the com“There are physicians who can net about
centers — are only one of a number of
nfional. Within weeks, Mr. Par$500,000
to $1 million a year doing clinical
incentives
that
are
being
dangled
by
drug
S**5'1” £ dropped from the study.
- S'•'
research,” said Ismail A. Shalaby, the chief
and
testing
companies
to
entice
the
medical
5»*edd’was hospitalized and given a
executive of Nema Research Inc., a network
community.
Jjter t* parham never brought leof doctors and hospitals in the Baltimore
There are payments to everyone in the
ler’ d it is impossible to know
area performing clinical research. “And that
MW’%
system who can come up with a patient, from
Ss participation in the study affectis not bad."
other doctors who refer them for research to
The benefits to the doctors who conduct
^^^^X^Serscores a potential
the study coordinators in the researcher’s
n
research are not simply financial. Once, re
office
who
screen
patients
to
see
if
they
IlliUS*
emerging drug-testing syssearchers said, the names that appeared on
3i
qualify.
O^nitoR wth money at stake may
papers describing drug studies were those of
None
of
these
benefits
are
scrutinized
by
lay
B^nanents to take drugs that are
the actual authors. That is no longer always
Government
regulators,
who
said
in
inter
^®**l**Xe or even unsafe. Under the
the case. Today, the coveted right to claim
views that they saw little difference between
tem of monitoring, such actions
authorship is often just another reward for
providing grants for university research and
impossible to catch and no statisdoctors who recruit the most patients — even
paying
doctors
directly.
For
academics
“
the
ntSed on such events. Within the
if they wrote nothing and analyzed no data.
money is just as important as with the
most of the planning focuses on
“They used to ask you to write," said Dr.
internal medicine guy trying to beat the
studies quickly. Patient issues,
Thierry Le Jemtel, a cardiologist at Montesaid Dr. Murray M. Lumpkin, the
gjy^rchers said, are often lost in the
fiore Medical Center in the Bronx who is a
deputy director of the Center for Drug Eval
longtime academic researcher. “Now, they
uation and Research at the Food and Drug
"^on go to the trade meetings on clinical
send you a paper all written by a medical
Administration.
vou go for two entire days, and
writer” hired by the drug company.
But unlike block grants, today's incentives
are not mentioned,” said Dr. KobDr. Jay Grossman, a pnvate-pracuce doc
can grow almost day by day, if the doctor
tor who is an allergy’ and respiratory special
M Califf the director of the Duke Cliniworks the way the drug companies want.
Research Institute, an academic drugist with Vivra Asthma and Allergy Inc. in
And the variety of the incentives is almost
HnSLuf center in Durham, N.C., affiliated
Tucson, Ariz., said he was often a lead author
endless.
IjBShDuke University. “The patient is an
The most basic form of compensation is a
wtSect to make money. Having patients, is
flat fee paid for each patient enrolled. The •
■ St the dirty price for doing busmess.”
amount of money paid to the researchers
varies widely, depending on the complexity
t
of the study, the number of tests involved and
Rie Incentives
the difficulty in finding patients.
For example, in 1996, a study of a migraine
drug sponsored by Janssen Pharmaceutica,
I
a unit of Johnson & Johnson, paid doctors .
$3,600 for each enrollment. Another study
that year sponsored by Organon Inc. on a
new birth control pill paid $1,100 for each
- The letter last July from Merck & Compapatient. And a Wyeth-Ayerst study of drugs
'ri ,'v - ny was nothing if not sympathetic. The comfor hormone replacement in women paid
'
pany recognized that doctors involved in its
i
J a hypertension medication were
$43SL
!i
Whiie all of these payments were made to
having trouble finding qualified patients. And
specify clinics, the exact amounts on a single
^RImks; so,
io, with
wim the
me letter,
xeaer, Merck
meu-A offered
uncieu a little
mut
f
test could vary slightly by region, or even by
encouragement for them to work harder.
clinic.
Instead of paying $2,955
$2355 for each test subMarry executives from drug or testing
ject enrolled, Merck offered $500 more in the
companies refused to discuss their research
U
study comparing the drug Losartan with a
programs, citing confidentiality. Those who
B placebo. For those doctors who enrolled their
Jeff ToppL-4 for The New York Tine'
gE quota of 14 patients by Sept 30, the company
did grant interviews gave consistent explawvuia kick in an aaoiuonai
♦z.uvu — making
natiOES of their payments: They are neceswould
additional $2,000
“I really feel I can offer my
jW
that 14th pauein
patient worth
if irecruited »•
in
sary compensation for the doctors’ work.
IgEg
SH-- uulL
wui ui $5,455 u
K
“We set up contracts that hopefully reim
E44 time, and the entire group potentially worth
patients
more. I know more
burse investigators adequately for the time
» more than $50,000.
K-'
what
the
cutting edge is. I
they
put
in
to
screen
patients,
bring
them
in,
,
"We will forward the first check as soon as
and provide data to us that is as clean as
H the first four additional patients are enknow what will be the
possiN*.” Dr. Elizabeth Stoner, the vice
rolled," the letter said.
SB
recommended therapy two
president for clinical research and contract
After discovering how effective paying
manage
ment
at
Merck
Research
Laborato
years from now.”
doctors to recruit patients can be, the drug
ries in Rahway, NJ., said.
industry has opened the financial floodgates.
Dr. Jay Grossman of Vivra Asthma ano
Additional rpayments
be made, she
| Special cash bonuses for signing up specified
Specified
-v------ - can
Allergy in Tucson.
numbers of people by a given date, a practice’ said, when there is “additional effort above
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hospitalization.
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on pub-ications because he had been i ix
pauent recruiter in the clinical trials. ?«-:
though he rarely did much — if any — of 2e
actual writing. "That's common,” he sail
"It’s orchestrated by the drug companr^
medical writer.”
For example. Dr. Grossman cited a smof
for a Smith Kline Beecham asthma medica
tion that was published in The Jouma.’ aT
Asthma and another on an allergy medica
tion sponsored by Boehringer Ingelnenc
Pharmaceutical published in The Journal rf
Allergy and Clinical Immunology. While cce
articles are wrinen by a drug compary
writer. Dr. Grossman said, he often suggest
modifications.
As drug companies compete for top stucy
doctors who will quickly accrue patienx i
financial arms race has developed, with
company seeking new ways to use cash and
benefits to spur the research.
One practice is to offer finder's fees jc
doctors who are not conducting studies fcr
referring patients to doctors who are. Faexample, a letter from a testing compary
handling the research on a vaginal suppostory for the Bayer Corporation in 1996 proc- •
ised "a $75 referral fee for physicians «nf
area/federally funded clinics, Le, Plann-d
Parenthood, etc.”
Even study coordinators — the nurses aai
medical assistants who oversee the adminstrative details of a study and screen panrm
to see if they qualify — are offered fees fcr
finding test subjects. In 1995, for example.
Pharmaceutical Product Development inc
of Wilmington, N.C., which coordinates dreg
tests, needed a way to speed up enrollment c
a study of a drug developed by the Zamboc
Corporation in East Rutherford, N.J.
So the company sent a fax to medical sodf
members who were screening panerrs
around the country, offering them bonuses
for fast enrollment.
"EVERY study coordinator has the
chance to receive $750 just by reaching tne
enrollment goal of 30 evaluable patients," me
fax said. "So GET BUSY!”
The stepped-up competition among dreg
companies for the services of doctors led to
the development of cash bonuses for there
one of the most controversial incentives now
offered. But even companies that were un
comfortable with the idea found it hard e
resist.
"It’s a tough issue," said Dr. Cynthia M.
Dunn, the director of the Clinical Research
Institute at the University of Rochester and a
former drug industry executive. "On one
hand, many companies recognize It’s pan of
what we have to do to be competitive. On the
other hand, they recognize they are seraag
up potential conflicts of interest” for doctors.
Some large drug companies have refused
to offer bonuses out of ethical concerns. "Yai
don’t want to provide an advantage that can
be misinterpreted,” said Dr. Joseph Ca
mardo, the senior vice president of clinical
research and development for Wye th-Averst
Research in Radnor, Pa
The bonuses all reward the same behav
ior: enrolling patients fast For example, a
coz*Lr<B^t
by Zbnh Inc., a
company owned by Omnicare Inc., provided
a $750 bonus for each patient enrolled by
June 15 or $500 for those enrolled between
June 15 and July 16 — upping the ante for
doctors whose enrollments were lagging.
Such incentives outrage some experts. Bo
nuses in clinical research are “inappropri
ate, potentially illegal and certainly unethi
cal,” Dr. Robert Tenery, a Dallas doctor who
is the chairman of the council on ethical and
judicial affairs for the American Medical
Association, said of such payments in gen
eral. "Why would you get an extra $500? How
can you explain the rationale? Maybe you
took a patient who really didn’t need to be
enrolled."
If something goes wrong, doctors might
never be able to escape the nagging doubt
that the bonus program was to blame. “How
would you like to confront the family when a
family member got hurt, and you got a bonus
for enrolling?" asked Michael Leahey, the
director of the office of clinical trials at
Columbia-Presbyterian Medical Center in
New York.
A system that offers so much cash and so
many benefits for quick recruitment as
sumes that doctors would never allow money
to distort their judgment — in this case by
raising them to put undue pressure on reluc
tant patients or to include patients who do hot
quality But the assumption that doctors can
resist financial temptations has been proved
wrong repeatedly in other situations.
For example, throughout much of the
19S0’s, doctors could refer patients to treat
ment centers — such as physical or radiation
therapy sites — in which they had a stake.
The practice was outlawed after studies
found that doctors were overusing treat
ments and tests when they had financial
interests in the centers that provided them. A
1992 study published in The New England
Journal of Medicine found that doctors with
mvestments in radiation sites prescribed
such treatment as much as 60 percent more
often than those without the financial con
flict.
With such studies demonstrating the ef
fects of financial incentives on doctors, ex
perts who have studied these conflicts said
they were troubled by the emergence of
research for hire.
"You have a recipe for trouble or abuse,”
said Marc A. Rodwin, an associate professor
of law and public policy at the School of
Public and Environmental Affairs at Indi
an* University and the author of a’ book on
financial conflicts in medicine. “The risk is
that the doctor will subconsciously down
play the risks or overplay the benefits" of a
particular study in order to persuade a
pauent to participate.
Complicating matters, companies some
times fail to consider how difficult it will be
to find patients to meet the requirements
they set for admission into a study. Then,
when recruitment falls short of expecta
tions, they offer to pay more to meet an
unrealistic goal — looking, for example, for
patients with a disease that their drug can
treat but who have no other health problems
that could affect the study.
"The simplest solution that inexperienced
people think of first is to increase the num
ber of sites or to increase the amount of
money you're offering." said Dr. Bert
Spilker. the senior vice president of scientif
ic and regulatory affairs at the Pharmaceu
tical Research and Manufacturers of Amerjea, the trade group for large drug compa
nies. "You can offer to triple the amount of
money and it will make zero difference If
the doctors are doing everything they can
do. it may be that the patients don't exist."
But, with so much money dangling in
trnnt of them, doctors could be tempted to
bend, the rules to get patients into studies,
and could get away with it, according to Dr.
Martha L. Elks, an associate dean at More
house-School of Medicine in Atlanta. "Let’s
say you’re dealing with an angina study
where the requirement for entry is a certain
level of pain on a certain number of days of
the week," Dr. Elks said. And "suppose the
patient's history is not quite that but is
borderline.”
Dr. Elks said sne overheard two doctors
talking recently about bonuses. One was
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Since the beginning of the 1990's.
• there has been a surge in drug trials
i by private doctors.
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Number o< new drufl
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16;OOO
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telling the other that be would get $500 if be
could-stgn up some patients in the next 24
hours.
"I knew this guy.” Dr. Elks said. "He is a
practitioner of the highest ethics.” But, she
said, '.‘he was talking about how to massage
entry criteria.”
Dr. £lks said she then noisily cleared her
throat. “I sort of a-hummed,” she said, ax
which point the doctors "stepped back for a
minute." suddenly realizing what one of
them bad been saying.
What happened next, she said, she was not
privy to know.
The Doctors
Drug Trials Provide
New Source of Income
j
The year was 1989. and Dr. Stuart R. Wess
was bored with private practice.
To liven up his work, the San Diego endo
crinologist tned his hand at drug studies. It
was an audacious idea — at the ume mas:
trials were conducted by university scien
tists. But Dr. Weiss worked hard to convince
a skeptical drug industry to take a chance on
someone with his background.
beat the bushes." he said. “I lobbied
long and hard with several organizatjoos to
give rhe a shot"
Eventually, he focused on a Merck study of
a new drug to treat osteoporosis, a degenera
tive bone disease. To show his eagerness, be
offered to fly to New Jersey to meet with
Merck executives ax their world beadquar
ters. Then Dr. Weiss went further, spendmg
his own money to buy an expensive piece of
equipment that measures bone densry
Merck finally gave m, asking him to find 2fl
patients.
He came up with 40.
And there, in the entrepreneurial spinx
displayed by Dr. Weiss, lay the solution to a
problem that was suddenly dogging the phar
maceutical industry — the slow pace a!
research m university laboratories.
For decades, drug companies had been
able to increase their prices almost at will,
and thus had little incentive to develop new
products. For the comparatively small num
ber of drugs the companies did test, they
turned to a trusted group of medical school
researchers who dictated bow trials were
conducted. And the drug companies had to
wait in line: Research financed by Govern
ment grants was far more prestigious; in the
eyes of many academics, drug-company
trials were to research what McDonald's
hamburgers were to food.
Ln those days, researchers were reim
bursed much differently than they are today.
Payments went to the university, not to the
investigator. The university doctors were
often paid a flat fee for their work, no matter
how many patients they actually enrolled.
Then, in the early 1990’s, the economics of
drug development changed. Managed care
put the squeeze on drug prices, leaving com
panies one option: increase the number of
drugs they were selling. As a result, the
companies began a rush to drug develop
ment, something that was aided by reforms
at the Food and Drug Administration that
speeded up the approval process for new
drugs.
Companies at first turned to their coterie
of medical school researchers, but found the
academic world was incapable of adapting
rapidly to the increasingly intense competi
tion.
"We had concretized bureaucracies," Dr.
David R. Bickers, chairman of the dermatol
ogy department at Columbia University's
College of Physicians and Surgeons, said of
the academic response. “And for companies,
time is money. Companies figure that out"
Quickly, the drug companies began re
cruiting a new breed of private-practice doc
tors like Dr. Weiss, willing to mine their
patient base for research subjects.
The transformation Is evident in a Times
computer analysis of thousands of forms
submitted each year to the Food and Drug
Administration from doctors wanting to con
duct research. According to the analysis,
11.662 private doctors conducted drug stud
ies in 1997, almost three times the number in
1990, when 4307 doctors conducted such stud
ies. And while the number of researchers and
medical schools also grew in that period — to
4,431 from 2.7^' — their share of the business
dropped from a third, to a quarter of the
total, according to the analysis.
Private-practice doctors in research said
the change was for the better, because the
doctor was not simply tending to the pa
tient's needs for the few weeks of a study, but
often for a lifetime. "Even though the physi
cian may want to make money, the moment
be sits across from the patient, he is not only
responsible to himself, he is responsible to
that patient," said Dr. Norman Zinner, a Los
Angeles docxor who in 1994 formed Affiliated
Research Centers, an organization of pri
vate-practice urologists who conduct drug
studies. “I have got to look you in the eye. 1
have got to see you again."
Not only that, these doctors said, but par
ticiparion in research allows them to know
the Latest ideas for treatment “I really feel I
can offer my patients more,” said Dr. Gross
man of Vivra Asthma and Allergy. “1 know
more what the cutting edge is. I know what
will be the recommended therapy two years
from now.”
Because anyone licensed to practice medione is eligible to be a researcher, medical
communities have been transformed in
towns where the onslaught of managed care
spawned legions of doctors scrambling to
replace lost income. In 1980, when clinical
■ ■ Ip .
” ’W"’
research was the fief of medical schools,
there were only eight projects in Tucson,
An?, and all but two were at hospitals
affiliated with the University of Arizona
Today, researchers are scattered in offices
dotting the city — in places like the sun
baked bames and the homely strip malls —
conducting 157 studies in 1997 alone. Drug
studies, and with them the competition for
patients, have become as common in Tucson
as the towering saguaro cactus.
Now, with federally financed research on
the wane, it is the academic researchers who
are banging on the doors of the drug compa
nies, asking for a second chance. But '-hey
are finding it hard to keep up with the private
doctors, who have shown themselves more
willing to sign contracts overnight, advertise
widely, offer financial incentives for patients
and open their offices at unusual times :o
accommodate patient schedules.
"It’s very difficult to conduct drug studies
at the medical school because of the competi
tion" from private doctors, said Dr. Marx a
Brown, a pediatric asthma specialist at the
University of Arizona. "It’s difficult to find
patients."
To keep up with the compeution from
private doctors, some academic medmal
centers have recently began setting up re
search divisions to draw on their own private
patients for drug studies. But it is a fledgung
effort, limited to a handful of universities.
Still, some junior faculty members are
now abandoning academia to get into the
drug-suxly uuSiucSS. Dr. Andrew Cutler, a
psychiatrist, left the faculty at the Universir;
of Chicago to join the Psychiatric Insumte c:
Florida In Orlando, a private practice with a
research business. Then last year, he formed
his own company. Coordinated Researcn cf
Florida, to perform drug studies full time.
Without a patient base to draw from for
studies, Dr. Cutler found other ways to re
cruit subjects, including serving as a nursing
home consultant
"I will strategically pick a nursing home
that has a large population that meets the
criteria for a study," he said. "If there is a
large community practice in town. I may
work out a referral arrangement, or make
them a co-investlgator, and the arrangement
is that they would be providing the patients
But the industry is not passively waittng
for doctors to knock on its door. Instead, ever
the last few years It has been aggressive;y
recruiting doctors with the lure of cash.
Every day, in hundreds of medical offices
around the country, blandishments amir bv
fax. mail and E-mail, encouraging doctors to
grab their piece of the research pie.
‘‘Discover the secret for obcauung more
funded studies," says a 1992 letter to doctors
from Research Investigator's Source, which
charges $275 to place doctors' profiles on
lists of researchers consulted bv drug com
panies.
A 1998 letter from Clinmark Dotcom, an
on-line listing service for researchers based
in Irvine, Calif., offered to Lis: doctors for
$350 the first year and $195 in the second But
the letter made no secret about the reasons
to join. ■
“Investigator grants average $43,000 per
study." it said.
Then there are the ubiquitous seminars,
sponsored by the industry, with enticing ti
tles to attract doctors, both fledgling and
experienced in studies. Some teach the bas
ics. with such titles as "How to Find Clinical
Trials: A Physician’s Perspective" and
“How to Develop or Evaluate a Patient
Recruitment Media Plan."
But nothing captured the transformation
of research more than a seminar on clinical
trials tn Nashville, sponsored tn 1996 by
Associates of Clinical Pharmacology, a pro
fessional association.
The title? “Successful Patient Recruit
ment: The Heart and Soul of Your Busi
ness."
Quality Questions
Testing Puts Value
On Speed Above All
Doctors and drug company executives
milled around a racing car parked on the
floor of the John B. Hynes Veterans Memori
al Convention Center in Boston last year,
waiting their turn to be photographed at the
wheel. Nearby, other images of speed dotted
the exhibit hall at the annual meeting of the
Drug Information Association, an industry
trade group. Checkered flags appeared on
corporate booths and T-shirts. One exhibit
featured a giant photograph of a cheetah;
another showed a mural at a horse race.
To some at the meeting on drug develop
ment in the global marketplace, the images
were a perfect metaphor for the industry
today: The push to finish trials quickly and
move the drugs onto the market has over
shadowed every other goal
"A few years ago'ft was 'better, faster,
cheaper.' " said M. Jane Ganter, the editor in
chief of Applied Clinical Trials, an industry
publication. "Nobody is saying ’better' or
•cheaper' anymore. The big emphasis is on
speed."
■
The driving forces behind the desire for
faster studies are the industry's financial
stakes With the clock ticking on a new drug's
patent even as it is being tested, every day's
delay is revenue that will never be earned.
"Time is money," said James PatriceUi, an
analyst of the drug-testing industry with
Dam Rauscher Wessels. "Speed is the key."
But some in the industry worry that such
smglemindedness has led testing companies
to tap an increasing number of doctors with
little or no experience in drug testing and
only a fuzzy understanding of the rules.
The Times analysis showed that during the
1990's, 70 percent of the doctors conducting
human experiments had been involved in
three or fewer previous drug studies, a num
ber unlikely to give them mastery over the
process. A quarter of all doctors who did
human experiments in 1997, the last year for
which complete data are available, conduct
ed only one experiment
"Some of the companies would be embar
rassed if they »aw the quality of the people
doing the research,” said Dr. Angela Bowen,
the president of the Western Institutional
Review Board, a private ethics board based
in Olympia, Wash, that reviews proposed
research on human subjects. “1 call them
clueless.”
One reason may be the predominance of
generalists taking part tn the studies. The
studies test drugs for particular diseases,
like asthma, in which a doctor's experience
and specialized training are crucial in mak
ing assessments such as distinguishing be
tween drug reactions and disease symptoms.
But doctors conducting clinical trials often
have no particular expertise in the disease
they are treating. The Times computer anal
ysis showed that the largest single group of
doctors conducting investigations was gen
eral internists; one in five was either a
"/0
general internist or a famiy practitioner.
These, of course, are the docun most Ameu|
leans see for checkups ant are thus the
industry's most efficient i su-ixters.
But some doctors who de rrmra! research
say that they often are offer-l srudies that
would require them to sc-r. a far beyond
their areas of medical expertse.
.. ,
"I wouldn’t do studies Irr aematoiogy o; ;
neurology or lung disease er epdepsy,” said .
Dr. Roy Fleischmann, the caief executive of,
Rheumatology Researct. izrenaaxal, a na.;.
tional network of clinical research sites thjit,
specialize in arthritis and strittal diseases, j
But, he said, “We get calls 100a them all the.
time."
-, i
Not every doctor has the power to refuse.
"There was a lot of pressure tor roe to dq.
things I did not feel comforzabie doing." said (
Dr. Claudia Baldassano, a psycfuainst and
neurologist who worked tor a commercial'
research center on the East Coast. "Th£f
thought because I have ax MJX I should 6^.
comfortable doing all studies."
’
She said, for example, ttur she was asked
to do Pap smears as part of a study pf .
hormone replacement and was asked to'
treat patients with diabetes.
t
"I said I hadn't done a Pap smear since
medical school, and I dxkiT fed comfort
able.” she said.
For the diabetes study. "1 said bow cou)d ,
you expect a physician who b net trained” a$ .
a diabetes specialist to rm the trials, she.
said. "1 was told by a nee president o!
operations that I could do Aabmc studies
with my eyes closed”
In the end. Dr. Baldassano stood her
ground on the diabetes study, bur participat
ed in the one on hormone replacement She.
resigned from the business after just a fe^wmonths, and now works n academic re-,
search.
,
Why would drug compasaes accept re-,
search even from doctors who doubt their
own expertise? Because, experts said, th?'
industry has grown so qmddy that no ode
has yet developed a good measurement of.
quality. Drug companies are teft to review
two factors: speed and cost Systems of
measurement for quality “haven't been tt-tablished to differentiate these companiely.
said Mr. PatriceUi of Dain Rauscher.
ti,
In an attempt to protect the quality of dA>_
and patients, the Government and mdus^l
have put into effect some means o( oversigtt^
The first line of defense for the integrityJj*
the data is the dispatch at study morutrffV
employed by the testing companies to
doctors’ offices to pore over the test resume
But the explosive growth cd the industfy^
has left experienced roontars in short sig
The monitors' sole task is protectir
not patients. That job falls largely
patchwork system of ethics boards, .
that are required by Federal law to approve,
research proposals involving humans. The
mam responsibility of these panels is to
insure that test candidates are fully in
formed of the benefits and risks of a particu
lar study and that they are not coerced to
participate.
But the review boards last year fell under
criticism from Government officials for re
viewing too many studies too quickly and for
larking expertise. And while these boards
will get involved in deciding the appropriate
language to be used for an advertisement for
patients, they do not consider whether pabents should be told of their doctors' finan
cial stake.
Dr. Shimm of Porter Adventist Hospital in
Denver recalled that when he served on an
ethics board at a university medical school, a
good deal of time was spent discussing
whether payments to patient volunteerswere coercive. The concern was that patientsmight enter studies for the money rather
than out of altruism, the ideal that is sought
But, immediately after such a discussion at.
one meeting, another proposal came up in
which a doctor stood to receive thousands of
dollars from the drug company for each,
panent recruited.
"1 said, 'Wait a minute.’ ” Dr. Shimm said.
"If it is coercive to pay a pauent $500, why is
it not coercive to pay the clinical investigator
$5,000?”
v v
1
A
I
j
But other members of the research board
were not interested in the topic.
"1 was told,” Dr. Shimm said, "to sit down
and shut up.”
Next: Inside a research fraud
I
iW
PtyAs a result, "They utilize some people wgt
fin
have very little experience in the disefWc
entity, or the drug, or tn pharmacology," s^T
Dr. Fleischmann of Rheumatokigy Resean^H
International. The monitors “don’t und^
stand what they are doing" •
"They are looking for boxes to fill in,” be
For trample, he said, the roost common
form of arthritis, osteoarthritis, is also called
"degenerative joint disease." A testing com
pany monitor who came to examine his data
announced that his patients were not quali
fied for the study because she dxi not know
the two terms meant the same thing, be said.
"If they don’t have that knowledge." Dr.
Fleischmann asked, "bow can they read a
chart and know what is real and what is not
real?"
Some experts said there was a decided
difference between the quality of monitors
who work for the drug industry and those
who work for the testing companies. Moth-,
tors sent by testing companies can be sounknowledgeable, said Margaret Chokreff.
the president of Margaret Chokreff 4 Associ
ates, which works with a network of private
doctors conducting research in Ohio, that she
and her nursing staff must sometimes tram
them about their own studies.
“You go to the trade
meetings on clinical
research, you go for two
entire days, and patients are
not mentioned.”
Dr. Robert M. Califf. the director of
the Duke Clinical Research institute, an
academic drug-testing center in
Durham. N.C., affiliated with
Duke Unrversrfy
ip'
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From Prospect to Prescription, How n Drug Comes to Market
From the Initial spark of an idea to the approval lor use by the public, the process of getting a new drug to the consumer
lakes an average ol 12 to 20 years. Here is a look at how that process works.
■
■;1
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I
Research and Development
Clinical Trials
Focuses on laboratory and animal testing.
Human test subjects become involved at this stage.
DISCOVERY
PRE-CLINICAL TESTING
Researchers
work through
thousands ol
compounds in
an effort to find
those with
some impact
on a disease
Hundreds ol potential drugs are pul
through laboratory and animal tests
to check the biological effect on the
disease, Those found to have
beneficial effects with reasonable
safety are proposed
lor clinical study.
•1
The proposal is submitted to the
Food and Drug Administration.
YEARS
:
■EmBBi
PHASE I
PATIENTS: 20 80
PHASE II
I
HI
Volunteers are
used to study the
sale dosage range
and how the drug
is absorbed and
metabolized by
the body.
Volunteer patients,
who have the
disease, are used
Io lest the drug’s
effectiveness and
side effects
PATIENTS IOO 3OO
| - 100 patient*
PHASE III
PATIENTS I.OOO-S.OOO
HHt iHHHtlHhH
HtH iiHI
The drug is studied in a larger,
more diverse group of patients.
Results are analyzed,
and if positive, a New
Drug Application is ••••
submitted for approval.
F.D.A.
Approval
The Food and
Drug Admin
istration
reviews the
application,
assessing the
quality of the
research and
wheiher the
drugs are sale
and effective.
Post-Market
Trials
PHASE IV
PATIENTS:
Number varies
Used to learn
more about
patients’
reactions to
the drug. Can
be mandated
by the F D A
i.
1
3
Sxxcn I'bIMA, Tults Ccnlni kx the Study 0/ frog Devekyimont
T?if Nr« York 1 lmr«
1
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Cost-Cutting Gives Rise to New Research Industry
Drug companies used to supervise all
their research, from the discovery of the
drugs to the animal tests to the prelimi
nary human tests to the large studies
involving hundreds or thousands of pa
tients.
No more. A multibillion-dollar industry
has sprung up to take care of all that and
more, including designing the studies,
finding doctors and patients, analyzing
the data, meeting with the Food and Drug
Administration, writing the scientific pa
pers and preparing the truckload of docu
ments that must be submitted before a
drug is approved.
These new companies have sliced the
drug-testing business in every possible
way. Some are little more than a Rolodex
of the names of doctors willing to help test
drugs. Others are major corporations, es
sentially drug companies without the
drugs.
It is an industry that arose to fill a
need: the enormous pressure that began
around 1992 from managed care compa
nies and health insurers on drug compa
nies to hold down prices, according to
industry analysts. Until then, the drug
companies had been profitable, making
money mostly by increasing prices, not by
developing new drugs.
The companies now had to find a new
way of generating profits. “Their vulnera
bility became transparent to the world,’’
said James Patricelli, an industry analyst
with Dain Rauscher Wessels in Minneapo
lis. “What you had was a drug industry
that suddenly had to make investments in
its future.'1
The companies' response was to search
for blockbusters — the Prozacs and Viagras hidden within the laboratory chemi- .
cals. The Food and Drug Administration
gave the companies another incentive by
speeding up its approval process, with the
median review time for new drug applica-
tions dropping from more thaz 22 months
in 1990 to just over 14 montzs in 1997,
according to the F.D.A.
“The industry has flip-floxed,” said
Kim Lamon, corporate senior nee presi
dent with Covance Inc., a g^ant drug
testing and development company.
“There is a push for novel, zmovative,
blockbuster drugs, and to be me first or
second to market”
Drug companies found they Lad to put
more effort and money into fizdmg drugs
while at the same time slashing their
Many companies are
ready to help take
care of the details.
development costs. For many, their solu
tion was to largely dismantle their divi
sions that ran clinical trials and to turn
the work over to smaller companies that
emerged to fill the need.
“Everyone had auditors, kids right out
of college, telling us how to do it cheaply,’’
said Dr. Cynthia M. Dunn, a former vice
president for medical affairs a: Fisons, a
British drug maker later acquired by
Rhone-Poulenc Rorer Inc., and now the
director of the Clinical Research Institute
at the University of Rochester. “They
really pushed the outsourcing.”
With the new companies came a variety
of new names. Contract research organi
zations were composed of companies that
ran parts or all of the clinical tnals. Site
management organizations — groups of
doctors willing to offer their services to
conduct trials — soon followed.
The growth in this sector has been
enormous. Roughly $3.2 billion wasjiaid to
the contract research organizations in
1997, up 52 percent from just two years
earlier, when payments were $2.1 billion.
Covance, one of the largest contract
research organizations, doubled its staff
and revenues from 1994 to 1998. Today, the
Princeton, N.J., company is an industry
giant, with 7,000 employees and more than
$700 million in revenues in 1998.
“It’s an industry that has been growing
and growing and growing,’’ said Ismail A.
Shalaby, the chief executive of Nema Re
search Inc., a clinical research network
based in Baltimore. “A drug company
doesn’t have to invest a lot of its own time
and money to develop a drug anymore.’’
In fact, some industry experts said, a
drug company barely even needs to be a
drug company any more. For example,
Neurobiological Technologies Inc. in
Richmond, Calif., has no factories, 11 em
ployees, 3 scientists and less than $1 mil
lion in cash. Yet it is using the new testing
industry to conduct huge clinical trials,
involving dozens of research sites and
doctors around the country.
“You could have a company of one
person, working out of their home, with no
office, develop a drug,” said Dr. Bert
Spilker, a senior vice president of scientif
ic and regulatory affairs with the Phar
maceutical Research and Manufacturers
of America, a trade association. “You
could have totally virtual companies.”
Longtime members of the industry
marvel at the change, which has occurred
in just a few years.
"One called me; they had two employ
ees,” said Dr. Leigh Thompson, a drug
industry consultant in Charleston, S.C.,
who is a former chief scientific officer at
Eli Lilly. "They have a molecule and hope
but nothing else.”
r
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THE NEW YORK TIMES NATIONAL SUNDAY, MAY 16.1999
^3j!NSSmM@raOT^?feS'1®!
51
Jill
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_____ ____
Of 2 patienfx atuhZ. E J
Price Tags on Patients
Incentive forms like the ones shown above encourage the enrollment of more patients in a
particular study. Below are the amounts paid to private doctors, which can vary from site
to site, who participated in specific studies.
SPONSOR
-
if
DRUG
DISEASE
PAYMENT
PER PATIENT'
SmithKline Beecham
Eprosartan
Diabetes
$4,410
Janssen Pharmaceutics
Alniditan
Migraine
$3,600
Merck
Losartan
Hypertension
$2,955
RhOne-Poulenc Rorer
Spariloxacin
Sinusitis
$2,67°
Glaxo Wellcome
..._C£ftin
Sinusitis
$1,730
SmithKline Beecham
_ SB 216469-S
Enlarged prostate
$1,610
Zambon Pharmaceutical
PH?.-J36
Osteoarthritis
$1,600
Bayer
Clotrimazole
Vaginitis
$1,200
Organon
CTR 99 & CTR 77
Birth control
$1,100
Bristol-Myers Squibb
Butorphanol Tartrate
Migraine
$1,000
'Amounts do not include bonuses paid foe performance.
The New York Tudcs
5^
^nation Sheets Page 2 - Updated 9/98
http://www.fda.goV/oc/oha/IRB/toc2.h
sS
FDA Home page | OHA Home | Table of Contents
U.S. Food and Druj Adminhhalion
|h
IEr?"*
PAGE 2
f’-
Food and Drug Administration
fe;'
1
I
INFORMATION SHEETS
Guidance for Institutional Review Boards and Clinical Investigators
1998 Update
_________________________________________________________________________________________________________________________________________________________________________________________________________________________________ ____________________________________________________________________ ■_____________________________________________________________________________________________________________________________________________________________ ~
FREQUENTLY ASKED QUESTIONS
Ke following is a compilation of answers to questions asked of FDA regarding the protection of human
Subjects of research. For ease of reference, the numbers assigned to the questions are consecutive
jfiroughout this section. These questions and answers are organized as follows.
W ■
EP-’
IRB Organization
IR.B Membership
IRB Procedures
IRB Records
fl
Informed Consent Process
aS
Informed Consent Document Content
Clinical Investigations
-
i
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■p
General Questions
IRB Organization
EWhat is an Institutional Review Board (IRB)?
wnder FDA regulations, an IRB is an appropriately constituted group that has been formally designated
P review and monitor biomedical research involving human subjects. In accordance with FDA
pgulations, an IRB has the authority to approve, require modifications in (to secure approval), or
^approve research. This group review serves an important role in the protection of the rights and
^uare of human research subjects.
purpose of IRB review is to assure, both in advance and by periodic review, that appropriate steps
g? taken to protect the rights and welfare of humans participating as subjects in the research. To
^uiplish this purpose, IRBs use a group process to review research protocols and related materials
■.J"3 lnformed consent documents and investigator brochures) to ensure protection of the rights and
: are of human subjects of research.
°
I
have to be formally called by that name?
^S')
6/1/99 9:11 P
■
http://www.fda.g0v/0c/0haAiR3/t
3 Iniomation Sheets Page 2 - Updated 9/98
,
n
•
<.
1
The K
toIRB
• j u travel <
■
No, "IRB" is a generic
tern, used by FDA (and HHS) to refer to a group whose fimction is to review
■' term
-term useo oyr
H J fare of the human subjects. Fach institution may
:arch to
assure the
Je chosen, the IRB. _
is subject
subject to
Agency’s IRB
IRB
research
to assure
the P
} r0tectl0^°^2^f
to the
the Agency's
use whatever name it chooses. ] igutod products arerr.~~<
reviewed and approved.
ret
3. Does an IRB need to register with FDA before approving studies?
i®
tf
...
/' 9.W
■
-x
Statement of Investigator” for a |
wuncuuj, FDA
FDa. does
d„_s not r£qyire IR?
^daddfesoftiie IRB that will be responsible for
Currently,
w
teld” ms.M
studies of FDA regtdated products must be established and
■
fl
operated in compliance with 21 CFR part 56.
•
FDA r
' . suits. I
regulat
I■
Thefu
„ subjec
provid
f) partici
has co
I®
4. What is an ’’assurance” or a ’’multiple project assurance?"
10. Is t
A„ "assurance," is a document negotiated?e™=»^
Human Services (HHS) in acc0{dance
by HHSAe HHS regulations require a written
conducted by HHS or supported in who!
Ration will comply with the HHS protection
assurance from the perfomance-si
assurance mechanism is described in 45 CFR
ssssasi-teStWSi ss^ aHI
11. D o
a resea
Iristitu
will be
treatm
Torres
anym<
infonr
BwaSa^*1-' *
sponsc
5. Is an "assurance" required by FDA?
Currently, FDA regulations do not require an(“^tads^d/OT Sp^onSnotnidttbe |
/■
Regulations for the protection of Human Subjects.
1
6 Must an institution establish its own IRB?
NO. ^ougi. institutions
—I
IRBs to oversee research conducted wthm the >ns
> "outside" IRB to be responsible for |
regulations permit an institution wi±ou
* ^^irb institution. Such arrangements should.
12. M:
BiSYes, h
KERB'S
BBrovid
^Winteres
Rftxroin c
■
' ttian o
■
Yes. r
7. May a hospital IRB review a study that will be conducted outside of the hospital?
Yes. IRBs may agree to review research_ from
|
conee
^there*
gL‘
capac
hialif
gende
appropriate knowledge about the study site(s).
8. May IRB members be paid for their services?
2ofl5
A
'-3
■
K-'
jLinaiioH
<!
IWB1 V
V
lay |
Sheets Page 2 - Updated 9/98
http://www.fda.gov/oc/oha/IRB/toc2
.
Th FDA regulations do not preclude a member from being compensated for services rendered. Payment
IRB members should not be related to or dependent upon a favorable decision. Expenses, such as
costs, may also be reimbursed.
is the FDA role in IRB liability in malpractice suits?
regulations do not address the question of IRB or institutional liability in the case of malpractice
^K'«]its. FDA does not have authority to limit liability of IRBs or their members. Compliance with FDA
MBi^jations may help minimize an IRB's exposure to liability.
. . .:
")ri ,‘5w
10 Is the purpose of the IRB review of informed consent to protect the institution or the subject?
®l '; .The fundamental purpose of IRB review of informed consent is to assure that the rights and welfare of
^^Bsubjects are protected. A signed informed consent document is evidence that the document has been
provided to a prospective subject (and presumably, explained) and that the subject has agreed to
participate in the research. IRB review of informed consent documents also ensures that the institution
||Iiihas complied with applicable regulations.
1’3
I |g||
HHKpDoes an IRB or institution have to compensate subjects if injury occurs as a result of participation in
research study?
n S
Institutional policy, not FDA regulation, determines whether compensation and medical treatment(s)
will be offered and the conditions that might be placed on subject eligibility for compensation or
Jreatment(s). The FDA informed consent regulation on compensation [21 CFR 50.25(a)(6)] requires that,
for research involving more than minimal risk, the subject must be told whether any compensation and
M«any medical treatment(s) are available if injury occurs and, if so, what they are, or where further
information may be obtained. Any statement that compensation is not offered must avoid waiving or
appearing to waive any of the subject's rights or releasing or appearing to release the investigator,
EH^sponsor, or institution from liability for negligence [21 CFR 50.20].
Dje-x.,
til
1,
■
■
IRB Membership
to
F
NRU. May a clinical investigator be an IRB member?
a/:
A
gYes, however, the IRB regulations [21 CFR 56.107(e)] prohibit any member from participating in the
initial or continuing review of any study in which the member has a conflicting interest, except to
'I ^^f'lRB's
Bprovide information requested by the IRB. When selecting IRB members, the potential for conflicts of
^interest should be considered. When members frequently have conflicts and must absent themselves
deliberation and abstain from voting, their contributions to the group review process may be
■Ronmnished and could hinder the review procedure. Eve n greater disruptions may result if this person is
MR^^person of the IRB.
vn
fo^
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. ' /
A
B
le y
H3- The IRB regulations require an IRB to have a diverse membership. May one member satisfy more
m^.-.than one membership category?
Yes. For example, one member could be otherwise unaffiliated with the institution and have a primary
! ■ Il ncern *n a n°n-scientific area. This individual would satisfy two of the membership requirements of
|. the regulations. IRBs should strive, however, for a membership that has a diversity of representative
I
and disciplines. In fact, the FDA regulations [21 CFR 56.107(a)] require that, as part of being
’i'L'. Rifled
as aiHRB
' ---------^J, the IRB must have ”... diversity of members, including consideration of race,
—i i____
^ gender, /%..u
cultural
backgrounds and sensitivity to such issues as community attitudes ...."
iI
i
^en IRB members cannot attend a convened meeting, may they send someone from their
^U^partment to vote for them?
I'W
_______
Alternates who are formally appointed and listed in the membership roster may substitute, but ad
»99:llp| '15
r
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-matron Sheets Page 2 - Updated 9/98
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--[ii
noc substitutes are not permissible as members of an IRB. However, a member who is unable to be
msSt at the convened meeting may participate by vtdeo-conierence or conference elephone call, when
K member hSreceived a copy of the documents that are to be reviewed at the meeting. Such members
«
1a;w^®sw,‘' '-V'’' a.
™v voTe and be counted as part of the quorum. If allowed by IRB procethires, ad hoc substitmes may
In i<-'
Zd i Consultants and gather information for the absent member, but they may not be counted toward
I;
sho*
*e ouomm or participate in either deliberation or voting with the board. The IRB may, of course, ask
&
pi
oieS of thfs representative just as they could of any non-member consultant Opinions of die absent J
i situa
SS Sat are transmitted by mail, telephone, telefax or e-mail may be considered by the attending
, »
:■ inapt
^ members but may not be counted as votes or the quorum for convened meetings.
I 1RB
/1
'-'W
15. May the IRB use alternate members?
i
The use of formally appointed alternate IRB members is acceptable to the FDA, provided that theHRB's
written procSes describe the appointment and function of alternate members. The IRB roster should
SWe Primary members) for whom each alternate member may subs itute. To ensure maintaining
mSopnfte quo mm, the alternate's qualifications should be compamble to the primary member to be
renEd The IRB minutes should document when an alternate member replaces a primary member.
^SiernateTfubstitute for a primary member, the alternate member should have received and
SSS material that Ike pSta^ member received or would have reeetved.
Ovi'/bec"
A.-/
K ■IRBf
0^56.1'
J
J
I s
Ii - z
|
16. Does a non-affiliated member need to attend every IRB meeting?
No Although 21 CFR 56.108(c) does not specifically require the presence of a member not otherwise
Sfilited wfih the institution to constitute a quorum, FDA considers the.presence: of sucht members an
i TRR'c diversity Therefore freauent absence of all non-affiliated members is
noucc?ptabl™o FD * Actoowledging their important role, many IRBs have appointed more than one
m2S X is not otherwise affiliated with the institution. FDA encourages IRBs to appoint members
in accordance with 21 CFR 56.107(a) who will be able to participate fully in the IRB process.
19./
.with*
botr-
a
,J
J.'
17. Which IRB members should be considered to be scientists and non-scientists?
21 CFR 56.107(c) rejmrcs .1
revic
'of th
Sd Ph D ‘SpTysicrd or blologtad scientists. Such membra satisfy the requirement for at least Me
Sn^'Xn InlRB enemmtem studies involving science teyond the expertise of foe members, the
IRB may use a consultant to assist in the review, as provided by 21 CFR 56.10/(1).
J
J
■‘T:.
"‘-S-'nao
concerns would be in non-scientific areas.
Some members have training in both scientific and non-scientific disciplines, such as a J.D., R.N. While J
S meSe^are of great vdue to an IRB, other members who are unambiguously non-scientific
should be appointed to satisfy the non-scientist requirement
jr The
HL IRB Procedures
t 5
K >wti
fci re*
review " What does the phrase "subsequent use" mean?
.
K
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IB
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'■■
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Sheets Page 2 - Updated 9/98
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otfrer subject
P^nmav occur where a second emergency use needs to be considered. FDA believes it is
date to deny emergency treatment to an individual when the only obstacle is lack of time for the
Sto^nvene, review the use and give approval.
fire there any regulations that require clinical investigators to report to the IRB when a study has
■ei
evaluation and approval of related studies.
What is expedited review?
reauire an IRB to review certain categories of research through an expedited procedure if the
^involves no more than minimal risk. A list of categones was last published m the Federal
fctcron January 27, 1981 [46 FR 8980]. The list is reproduced as Appendix D of this document.
IRB may also use the expedited review procedure to review minor changes in previously approved
arch during the period covered by the original approval. Under an expedited review procedure
ew of research may be carried out by the IRB chairperson or by one or more expenenced members
lie IRB designated by the chairperson. The reviewers) may exercise all the authorities of the IRB ,
^disapproval. Research may only be disapproved following review by the full committee. The IRB
squired to adopt a method of keeping all members advised of research studies that have been
roved by expedited review.
November 9, FDA published in the Federal Register concurrently with OPRR a new Expedited
few List. The entire Federal Register publication, including the FDA preamble, was published on
es 60353 - 60356 of the November 9, 1998 Federal Register and is available on the World Wide
b at the Dockets Management Page of the FDA home Page at
.
^.vw.fda.gov/ohrms/dockeis/98fr/l 10998b.txt (or use suffix ".pdf for Adobe Acrobat version) or
baatively at the Government Printing Office site at
access.gpo.gov/su docs/ledreg/a981109c.html and scroll down to Food and Drug
C
number of studies we review has increased, and the size of the package of review materials we
IRB members is becoming formidable. Must we send the full package to all IRB members?
ct
IK*-'
W'l
ftelRB system was designed to foster open discussion and debate at convened meetings of the full IRB
pbership. While it is preferable for every IRB member to have personal copies of all study materials,
b member must be provided with sufficient information to be able to actively and constructively
S^ipate. Some institutions have developed a "primary reviewer" system to promote a thorough
[pw. Under this system, studies are assigned to one or more IRB members for a full review oi all
&*als. Then, at the convened IRB meeting the study is presented by the primary reviewer(s) and,
5 discussion by IRB members, a vote for an action is taken.
Primary reviewer" procedure is acceptable to the FDA if each member receives, at a minimuml; a
* consent documents and a summary of the protocol in sufficient detail to determine the
’Priateness of the study-specific statements in the consent documents. In addition, the complete
iti
0.1 1
6
99 9<
<
■
‘
■
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51
1.
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. ;nf
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ormation Sheets Page 2 - Updated 9/98
M gs
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; both before and at the meeting. The
xi_. ~ J■.rr\f +!-»£» mPAfino tn
S”“st?°e
adVan“Of ,hC ",“""6 *
"
allow for adequate review of the materials.
__________
4
Some IRBs are also exploring lie use of electronic submissions
and computer
access for IRB. member.L • j
that each study receives an adequate review
Whatevw system the IRB develops and uses, it must ensure u---------,
. “atSights and welfare of the subjects are protected.
-i^HO'7
-f
'
The FDA regulations do not retjnimSttadonX'e'ubfeh t^"/
*y.
22. Are sponsors allowed access to IRB written procedums, minutes and membership rosters?
fc
i a policy on I
prohibit
the
sponsor
requesting
Ke“
Ses
or'afrom
pertSt
portL of the minutes am pmvided to sponsors.
■* .
.
•
__ —
^/-.rtinonf rtnrtir
h IRB also needs to be aware of State and local laws regarding access to IRB ■<
Because of variability, ead
records.
-■ M
23. Must an investigator's brochure be included in the documentation when an IRB reviews an
investigational drug study?
For studies
Y<
de
1R
m
re
an
?r
27
„
(jt
£
28
de
Yt
<
'
- •wi
HI
312B23(a°(5 "Sd
clearly required to be reviewed by the IRBt g
research. 21 CFR 56.1 ll«(l)^u‘«
r‘“>
CFR 56.111 (a)(2) requires the IRB to assure thaVU>'
e
SSoTg^TcFTp^ 56 does not AH™
part does not
such brochures
is ‘ m
mation cdfttameu m such
usuvuluvS-w
outline the criteria for IRB approval of
risks to the subjects are minimized. 21 '»
....
subjects are reasonable inrelatio n to Ute |
u, „view of
results of previous S
<
29
FE
i
h
30
'
There is no specific regulatory requir™“^»^
It
K^j.tht
sei
d|
-d-
XiSSS
“
of
24. To what extent is the IRB expected to. actively audit and monitor the performance of the mvesh^
with respect to human subject protection issues.
FDA does not expect IRBs to
n
SI
rec
glvS AeS^aSrity^observe, or have a thin
plXbSZconsenTprocess ^dthe^es^^^^
m
as part of providing
part of providing |
25. How can a sponsor know whether an IRB has been inspected by FDA, and the results of the
inspection?
The Division of Scientific Investigations,
|| 31
-
S^ctionaod dassification. The ...jj
inventory of the IRBs that have been insPe
infections assigned by the Center for Biologies
Division recently began including the resultsLofinsp
Radiological Health. This information is
,
Tt
•'.. on
'
nu
-g
Eh
available under FOI.
.
l
26 If an IRB disapproves a study submitted to i^and it is subsequently sent to another IRB for revie
should the second IRB be told of the disapproval?
6/l/’|
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I|"32
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■5/'
iation Sheets Page 2 - Updated 9/98
http://www.fda.gov/oc/oha/IRB/toc2.
*
1
Yes When an IRB disapproves a study, it must provide a written statement of the reasons for its
d^ision t01116 investi?ator 2X1(11116 institution [21 CFR 56.109(e)]. If the study is submitted to a second
a copy of this written statement should be included with the study documentation so that it can
^O^nSe an informed decision about the study. 21 CFR 56.109(a) requires an IRB to "... review ... all
itsearch activities [emphasis added]The FDA regulations do not prohibit submission of a study to
another IRB following disapproval. However, all pertinent information about the study should be
^vided to the second IRB.
0
b
■
n
C'
^w27- May
independent IRB review a study to be conducted in an institution with an IRB?
;’4-a Generally, no. Most institutional IRB have jurisdiction over all studies conducted within that institution,
b' ■ An independent IRB may become the IRB of record for such studies only upon written agreement with
the administration of the institution or the in-house IRB.
,n
■’IH^^mS^liheration
Could an ERB lose its quorum when members with a conflict of interest leave the room for
^Hfijcliberation and voting on a study?
Ml
t
'
■i Id
P9. Does FDA expect the IRB chair to sign the approval letters?
11 of W
2
|fes. "The quorum is the count of the number of members present. If the number present falls below a
/majority, the quorum fails. The regulations only require that a member who is conflicted not participate
|m the deliberations and voting on a study on which he or she is conflicted. The IRB may decide whether
S'an individual should remain in the room."
■
[*FDA does not specify the procedure that IRBs must use regarding signature of the IRB approval letter.
fThe written operating procedures for the IRB should outline the procedure that is followed.
1 • ;:S
zious
<
bl
; •;
|30. Does FDA prohibit direct communication between sponsors and IRBs?
B.
.
'b
_
i ggwlt is important that a formal line of communication be established between the clinical investigator and
i ■
CIinical investigators should report adverse events directly to the responsible IRB, and should
progress
Upafl ;|g!
ProSress reports
reP°rts directly to that IRB. However, FDA does not prohibit direct communication
<0
between the sponsor and the IRB, and recognizes that doing so c<
‘ * result
*. in
* more efficient resolution
could
some problems.
t it®
A does require direct communication betv.’een the sponsors and the IRBs for certain studies of
devices and when the 21 CFR 50.24 informed consent waiver has been invoked. Sponsors and
OIRBsi316 require^ t0 communicate directly for medical device studies under 21 CFR 812.2^812.66 and
K or
a diird |
g|?12.150(b). For informed consent waiver studies, direct communication between sponsors and IRBs is
■,ondu$j|
21 CFR 50-24(e). 56.109(e), 56.109(g), 312.54(b), 312.130(d), 812.38(b)(4) and
1'
B
’7,b)
TffrJRB Records
SB
30__Are annual IRB reviews required when all studies are reviewed by the IRB each quarter?
1
5
a
s
e
one JR^\r------ecorcis f°r each oiuuj
study’Os 11initial
and UAJULiiiuill^
continuing 1CVICW
review bliuuiu
should I1UIC
note the
'V On
11uai O11U
LIB frequency (not to exceed
ranmiK?
1
r°
r
^
e
next
contlnu
i
n
g
review
in
either
months
or
other
conditions,
1v
;or
continuing
such as after a particular
number of subjects are enrolled.
•’ ■
€en
'
may decide, to review all studies on a quarterly basis. If every quarterly report contains
llibat Clent
f°r an adequate continuing review and is reviewed by the IRB under procedures
review Gt FDA rec!!nrements f°r continuing review, FDA would not require an additional "annual"
gi s-A
iHfe
6/^4 *
bwssW'
‘L
' CFR 56-115(a)(1) requires that the IRB maintain copies of "research proposals reviewed." Is the
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•?'. Sb.ee’.-' '•
- cried 9 '98
. r
ctnHvmW -p- the investigator receives from the sponsor
■research propose'.' the same as the formal stud} protoco--------of the research?
out
M
Yes. The IRB should receive and reviewsuch as the
#>>1 :■ enh
ire the investigator to suomn mi
’ all documentation reviewed is to be
^it^t^nailv.ap.velooed protocol summary torm. a copy ___
;earch at that institution T91
[21 CFR
CFR 56.
56.115(b)].
inn of the informed consent document, only
Howevert when *e IRB makes ctatjes. ^h^ in the
x>rds.
>py needs to be retained in the IRB records.
.
the finally approved coi,
-•ed but never started?
33. What IRB records are required for studies that are approved
^ P“tev= study-bjeo^e
When an IRB approves a smdy, “fhnuing
con, wil-
Iteas-
S
starts All
on the
date of ||
lew should be ^SShTh^S
performed at least annually.
of the
records listed in 21 CFR 56-115(a)(1)-W are req^
progress reports should be received from
approval, whether or not subj ects have bee^prior to the date of expiration of IRB g
’. H
the clinical investigator for all studres that ar i
^.^gator's progress report would be brief. Such
mtuite for o. least three years after eaneellatio. 121
a
No. The consent document is a written
I ■ •' '■
Bfte No.
iiifc
;,y
Tht
■:w
W:for
subject. Many clinical investigators use Hocumentation of agreement to participate in a study, but is j
the study. The subject's signature pr°Y>
informed consent process involves giving a subject
;|
35SESSSS!SSS study, prouidtng adequate opportumty for the subject to cons.der
35. Ma, informed consent be obtamed by telephone horn a legally authorized representahve?
clir
the
J‘c^™iTgSdteSfonhebveI’bal explanation or a|
information, obtaining the subject's ““’J' 8^““effMhS’SrploSsslhS”d“ ra^de ™Ple
clir
St
CFR 56.115(b)].
V. Informed Consent Process
34, Is getting the subject to sign a consent
document all
ail that
that is
is re<
required by the regulat.ons,
:nt document
Yes
rele
stuc
H3
11: tot
1RI
?.'? res
h FE
JM
fe-',
qu'
p 'the
A verbal approval does not satisfy the 21 CFIC
f., del
»g40
Wi rei
Ct'' to
K "sl
. tn
f ZS Se^±^^e„oe for items
3S5*
“ i |ftvuan
such as seheduhng of . ■«
procedures and emergency contacts.
.
37. If m. IRB uses a standard "fill-in-the-blank" consent format, does the IRB need to review the 1
V'
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3/- out form for each study?
‘ I
I ’ a fill in the-blank format provides only some standard wording and a framework for organizing the
sYes- A im- infonnation -phg IRb should review a completed sample form, individualized for each
ensure that the consent document, in its entirety, contains all the information required by 21
sfwyP0Jr, • language the subject can understand. The completed sample form should be typed to
50 its readability by the subjects. The form finally approved by the IRB should be an exact copy of
that will be presented to the research subjects. The IRB should also review the "process" for
^iduriing the consent interviews, i.e., the circumstances under which consent will be obtained, who
obtain consent, and so forth.
iRlhe informed consent regulations [21 CFR 50.25 (a)(5)] require the consent document to include a
?''■
: s^cn'W
-•>«■■.I
s«'iy|
aS
itaJment that notes the possibility that FDA may inspect the records. Is this statement a waiver of the
Subject's legal right to privacy?
lt_ Jf
?Tom
I
-W
1
:h >
EFfDA does not require any subject to "waive" a legal right. Rather, FDA requires that subjects be
•Tinned that complete privacy does not apply in the context of research involving FDA regulated
i^Xcts. Under the authority of the Federal Food, Drug, and Cosmetic Act, FD A may inspect and copy
rihiical records to verify information submitted by a sponsor. FDA generally will not copy a subject s
name during the inspection unless a more detailed study of the case is required or there is reason to
Sieve that the records do not represent the actual cases studied or results obtained.
eled 9
raa
W‘
■»
■XaI
rA"* ■
*
The consent document should not state or imply that FDA needs clearance or permission from the
Bnical investigator, the subject or the IRB for such access. When clinical investigators conduct studies
for submission to FDA, they agree to allow FDA access to the study records, as outlined in 21 CFR
12.68 and 812.145. Informed consent documents should make it clear that, by participating in research,
subject's records automatically become part of the research database. Subjects do not have the option
\ to keep their records from being audited/reviewed by FDA.
•»
■pO
IH
i f1 krKH
■! When an individually identifiable medical record (usually kept by the clinical investigator, not by the
9Utis'-f|
is copied and reviewed by the Agency, proper confidentiality procedures are followed wnthin FDA.
c+
|r
’ Consistent with laws relating to public disclosure of information and the law enforcement
s erO| ^^responsibilities of the Agency, however, absolute confidentiality cannot be guaranteed.
’
p3d
I HI 39. Who should be present when the informed consent interview is conducted?
■
■
FDA does not require a third person to witness the consent interview unless the subject or representative
is not given the opportunity to read the consent document before it is signed, see 21 CFR 50.27(b). The
■ T. person who conducts the consent interview should be knowledgeable about the study and able to answer
^ questions. FDA does not specify who this individual should be. Some sponsors and some IRBs require
nent, ■' -'fl
the clinical investigator to personally conduct the consent interview. However, if someone other than the
o fhe
clinical investigator conducts the interview and obtains consent, this responsibility should be formally
1 ie» 7; ^legated by the clinical investigator and the person so delegated should have received appropriate
is^atana .
training to perform this activity.
;
I
g
v 40. How do you obtain informed consent from someone who speaks and understands English but cannot
read?
niiterate persons who understand English mav have the consent read to them and make their mark, if
M .appropriate under applicable state law. The 21 CFR 50.27(b)(2) requirements for signature of a witness
01 the
! ^7
consent process and signature of the person conducting consent interview must be followed, if a
CFR » 7"short form" is used. Clinical investigators should be cautious when enrolling subjects who may not
c ium601]
Understand what they have agreed to do. The IRB should consider illiterate persons as likely to be
onto
to coercion and undue influence and should determine that appropriate additional safeguards
• I ’ ' 216 hi place when enrollment of such persons is anticipated, see 21 CFR 56.111(b).
-
t
41. Must a witness observe the entire consent interview or only the signature of the subject?
iefined
' 7 is'
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B Information Sheets Page 2 - Updated 9/98
I
1I
•
-^oturAnf A witness when the subject reads and is capable of understanding
FDA does not require the signal
27tbYl' The intended purpose is to have the witness
• ■ ,|
the consent document, as outline m 21 CFR 50-27(bXy
.
P rp^
||
only to*attest to the validity of :.
te/
Bl'
wfe-'
Mfes.
42. Should the sponsor prepare a model informed consez: document?
IND regulations, the sponsor provides a service to the clinical investigator 9
Although not required by the 1------- „B . ■ wording for the scientific and techmeal content of q||
■ .
■'and appropriateness
all
'ording in the consent, see 21 CFR 56.109(a), 111(a)(4) and 111(a)(5).
the _nnn<,orCcannot
annot accept
uv conduct the
* study
accept, me
the sponsoi
sponsor may
may uc<au&
decide nw
no^to
i
Ig
®
25.W“p-must
--%sl
ibjects to obtain informed consent
be submitted to FDA y JI
informational materials to be provided to sul
s
as part of the IDE, see 21 CFR 812.25(g).
43 .Is the sponsor required to review the consent fomt appraved by the IRB to moke sone all FDA
;i
requirements are met?
_____
.• I
For investigational devices, the informed consent is a required_ part
of the IDE submission. It is,
XIV VUUUUVM^. —
.
-----------
J
rr. .
‘ jssa
B
When an IRB makes substantive changes in . |
involved in this p^eese.
KStf
‘V
acceptable to the sponsor.
44. Ar e there alternatives to obtaining informed consent from a subject?
The regulations generallynrqnire.that,subject
hwestigators also may obtam
as identifying a legally authorized
some suXd 1Kal
defers to state and local laws regarding who is a legal y
who require health care decisions."
Xney a®
p
Ji
including assurance that the
^dlnSilTo^:I
IBfc
45. When should study subjects be informed of changes in the study?
|
Protocol amendments must receive IRB review and approval before they are implemented, unless an tp30o)| bH: .*
fcfe
f®
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i
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-
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Infortnation Sheets Page 2 - Updated 9/98
1
I
,s.
.-.J
By
http://www.fda.gov/oc/oha/IRB/toc
affect their participation, for example when the change will be implemented only for subsequently
enrolled subjects.
VI. Informed Consent Document Content
/'O’'
HE
f <1
iKt
Yes. The FDA requirements for informed consent are the minimum basic elements of informed consent
that must be presented to a research subject [21 CFR 50.25]. An IRB may require inclusion of any
additional information which it considers important to a subject’s decision to participate in a research
study [21 CFR 56.109(b)].
MEy
47 £)Oes FDA require the informed consent document to contain a space for assent by children?
'
.
1-^1
46 May an IRB require that the sponsor of the study and/or the clinical investigator be identified on the
study's consent document?
■
■
•
No, however, many investigators and IRBs consider it standard practice to obtain the agreement of older
children who can understand the circum stances before enrolling them in research. While the FDA
regulations do not specifically address enrollment of children (other than to include them as a class of
| vulnerable subjects), |he basic requirement of 21 CFR 50.20 applies, i.e., the legally effective informed
consent of the subject or the subject's legally authorized representative must be obtained before
enrollment. Parents, legal guardians and/or others may have the ability to give permission to enroll
H■?•• . children in research, depending on applicable state and local law of the jurisdiction in which the research
l I is conducted. (Note: permission to enroll in research is not the same as permission to provide medical
K ? treatment.) IRBs generally require investigators to obtain the permission of one or both of the parents or
??
guardian (as appropriate) and the assent of children who possess the intellectual and emotional ability to
comprehend the concepts involved. Some ERBs require two documents, a fully detailed explanation for
parents and older children to read and sign, and a shorter, simpler one for younger children. [For
ft research supported by DHHS, the additional protections at 45 CFR 46 Subpart D are also required. The
■ Subpart D regulations provide appropriate guidance for all other pediatric studies.]
-' r
in
i
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1
48. Does FDA require the signature of children on informed consent documents?
As indicated above, researchers may seek assent of children of various ages. Older children may be well
acquainted with signing documents through prior experience with testing, licensing and/or other
E procedures normally encountered in their lives. Signing a form to give their assent for research would
not be perceived as unusual and would be reasonable. Younger children, however, may never have had
the experience of signing a document For these children requiring a signature may not be appropriate,
and some other technique to verify assent could be used. For example, a third party may verify, by
K;; signature, that the assent of the child was obtained.
■
49. Who should be listed on the consent as the contact to answer questions?
-
I,
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21 CFR 50.25(a)(7) requires contacts for questions about the research, the research subject's rights and
in case of a research-related injury. It does not specify whom to contact The same person may be listed
for all three. However, FDA and most IRBs believe it is better to name a knowledgeable person other
than the clinical investigator as the contact for study subject rights. Having the clinical investigator as
t^le °nly contact may inhibit subjects from reporting concerns and/or possible abuses.
50. May the "compensation" for participation in a trial offered by a sponsor include a coupon good for a
discount on the purchase price of the product once it has been approved for marketing?
No. This presumes, and inappropriately conveys to the subjects, a certainty of favorable outcome of the
study and prompt approval for marketing. Also, if the product is approved, the coupon may financially
coerce the subject to insist on that product, even though it may not be the most appropriate medically.
51. Must informed consent documents be Translated into the written language native to study subjects
who do not understand English?
3 ?/
6/1/99 9;
I
B
httpz/Zwww.fda.gov/oc/oha/IRB/toc^ j '
formation Sheets Page 2 - Updated 9/98
I.?.
i
|
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The signed informed consent document is the written record of the consent interview. Study subjects are
given a copy of the consent to be used as a reference document to reinforce their understanding of the
study and, if desired, to consult with their physician or family members about the study.
</ V
■
•' :
■■
:
In order to meet the requirements of 21 CFR 50.20, the consent document must be in language
understandable to the subject. When the prospective subject is fluent in English, and the consent
interview is conducted in English, the consent document should be in English. However, when the study
subject population includes non-English speaking people so that the clinical investigator or the IRB
anticipates that the consent interviews are likely to be conducted in a language other than English, the
IRB should assure that a translated consent form is prepared and that the translation is accurate.
:11/ ■
A consultant may be utilized to assure that the translation is correct. A copy of the translated consent
document must be given to each appropriate subject While a translator may be used to facilitate
conversation with the subject, routine ad hoc translation of the consent document may not be substituted
for a written translation.
•5WB
lib
.|i I
i
Also see FDA Information Sheets: "A Guide to Informed Consent Documents” and "Informed Consent
and the Clinical Investigator"
■fl
52. Is it acceptable for the consent document to say specimens are "donated"?
What about a separate donation statement? It would be acceptable for the consent to say that specimens
are to be used for research purposes. However, the word "donation” implies abandonment of rights to the
"property"
"property". 21 CFR 50.20 prohibits requiring subjects to waive or appear to waive any rights as a
condition for participation in the study. Whether or not the wordingjs contained^in "the actual consent
fom" "is ii^atCTi^TAifstiidy-relateci documents must be submitted to the IRB for review. Any separate
"donation" agreement is regarded to be part of the informed consent documentation, and must be in
compliance with 21 CFR 50.
*
•
•
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•
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53. Do informed consent forms have to justify fees charged to study subjects?
'W
FDA does not require the consent to contain justification of charges.
VII. Clinical Investigations
■^w
54. Does a physician, in private practice, conducting research with an FDA regulated product, need to
obtain IRB approval?
Yes. The FDA regulations require IRB review and approval of regulated clinical investigations, whether
or not the study involves inctitntinnalkpd
institutionalized cnhkrtQ
subjects. FDA has included non-institutionalized subiects
subjects
because it is inappropriate to apply a double standard for the protection of research subjects based on
whether or not they are institutionalized.
An investigator may be able to obtain IRB review by submitting the research proposal to a community
hospital, a university/medical school, an independent IRB, a local or state government health agency or
uuxvx vx^oxxlzzxuuiK,.
cannot be accomplished by one of these means, investigators may
contact the FDA for assistance (Health AsscdSizxni ?-~dicy Staff 301-827-1685).
B
1
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55. Does a clinical investigation involving a marketed product require IRB review and approval?
if the investigation is governed by FDA regulations [see 21 CFR 56.101, 56.102(c), 312.2(bXl),
361.1, 601.2, axx2
2] Ako. see the information sheet entitled " ’Off-label' and Investigational Use ol
Marketed Drugs and Biologies" ror mure
^rrr<tion.
VIII. General Questions
3'S
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6/1/999:11^
f
of 15
■-K .
■
n Sheets Page 2 - Updated 9/98
http -JAvww.fda.gov/oc/oha/IRB/to
^RB/t
til
56. Which FDA office may an IRB contact to determine whether an investigational new drug application
(IND) or investigational device exemption (IDE) is required for a study of a test article?
‘e .0
For drugs, the IRB may contact the Drug Information Branch, Center for Drug Evaluation and Research
B
For a biological blood product, contact the Office of Blood Research and Review, Center for Biologies
Evaluation and Research (CBER), at 301 -827-3518. For a biological vaccine product, contact the Office
of Vaccines Research and Reviews 301 -827-0648. For a biological Therapeutic product, contact the
Office of Therapeutics Research and Review, CBER, at 301-594-2860.
h
fe'
g|
For a medical device, contact the Program Operation Staff; Office Of Device Evaluation, Center for
Devices and Radiological Health (CDRH), at (301) 594-1190.
it
b
If the IRB is unsure about whether a test article is a "drug," a "biologic" or a "device," the IRB may
■ contact the Health Assessment Policy Staff; Office of Health Affairs, at (301) 827-1685.
1:
57. What happens during an FDA inspection of an IRB?
K
Study
■I
tuted B
FDA field investigators interview institutional officials and examine the IRB records to determine
compliance with FDA regulations. Also, see the information sheet entitled "FDA Institutional Review
Board Inspections" for a co mplete description of the inspection process.
se~.
58. Does a treatment IND/IDE [21 CFR 312.34/812.36 ] require prior ERB approval?
R’'
ie
; Test articles given to human subjects under a treatment IND/IDE require prior IRB approval with two
B exceptions. If a life-threatening emergency exists, as defined by 21 CFR 56.102(d), the procedures
described in 56.104(c) ("Exemptions from IRB Requirement") may be followed? In addition, FDA may
grant the sponsor or sponsor/investigator a waiver of the IRB requirement in accord with 2F
FR
21 c
CFR
56.105. An IRB may still choose to review a study even if FDA has granted a waiver. For further
information see the information sheets entitled "Emergency Use of an Investigational Drug or Biologic,"
Biologic,”
’Ttmorrmr-ir-if T Ina zx-P T
J 1
J.’
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fl fill
•
T~» T~» _ _
•
n
"Emergency Use of Unapproved
Medical
Devices,"
"Waiver
of TT»
IRB
Requirements"
andi r.^r'
"Treatment use
of Investigational Drugs and Biologies."
tc
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ent
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ill
tc
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-
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-
.
On December 13, 1994, FDA published a final rule on the labeling of prescription drugs for pediatric
populations [59 FR 64240]. The rule [21 CFR 201.57] encourages sponsors to include pediatric subjects
m clinical trials
so that more
complete information
the
and biological
------------------------------------...................... .... ............... about
....
XXAW use
u^v of
vx drugs
U1 U&J U11U
M1V/1VK,»kXXl products
LUVUUbU in
111 the
U1V
pediatric population can be developed.
/-':-
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60. What is a medical device?
lit.
y or
y
6/1/99 9:11
•— C/"
On July 22, 1993, the FDA published the Guideline for the Study and Evaluation of Gender Differences
in the Clinical Evaluation of Drugs, in the Federal Register [58 FR 39406]. The guideline was developed
to ensure that the drug development process provides adequate information about the effects of drugs
and biological products in women. For further information, see the information sheet entitled
"Evaluation of Gender Differences in Clinical Investigations."
|
Mt
n
1
59. How have the FDA policies on enrollment of special populations changed?
i
etb<ar
*1
A medical device is any instrument, apparatus, or other similar or related article, including component,
part, or. accessory, which is: (a) recognized in the official National Formulary, or the United States
Fiiarmacopeia, or any supplement to them: (b) intended for use in the diagnosis of disease or other
conditions, or in the cure, mitigation, treannent, or prevention of disease, in humans or other animals; or
(c) intended to affect the structure or any function of the human body or in animals; and does not
achieve any of its principal intended purposes through chemical action within or on the human body or
pu^se '
nOt dePendent uPon being metabolized for the achievement of its principal intended
’I
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15
!
6/1/99 9:1
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h ttp 7/www. fda. go v/oc/oh a/I RB/toc2 .hi
3 Information Sheets Page 2 - Updated 9/98
Approximately 1 >700 Jpea
diverse, including bundngcs, tiiermoin
information sheets entitled "Medical Devices,"
md
”d
,
■W
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Nonsignificant Risk Medical Device Studies.
61. Are in vitro diagnostic products medical devices?
I
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62. W are Ore IRB’s senenal obligations towanls inmtoeniar lens (1OL) clbfal investigaions?
An IRB is responsible for the
io>- “’ssr™* ““id™s»“
“J™Se All IOL studies are also subject to FDA approval.
of
63. Considering the large number of IOL studies, how does an IRB approach the renew of a new IOL
■
style?
■■CM
Full IRB review is required for all new lOLs
changes to existing lenses may be. app
Dre^etennined classification scheme and advises the
investigational plan which
*e
||
ii.-I
proposed lens that describes its characteristics. It is
S”s~w ,od.“ ”ve ”a decis,“or “
■
mi rigoS its evaluadon thaA FDA considers mmtmally reqmred.
64. Must a manufacturer comply with 21 CFR SO and 56 when conducting trials within its own facility
using employees as subjects?
Yes. This situation represents a prime example of a vulnerable subject population.
i
mnurvi
65. Do Radioactive Drug Kesearcn
--------- have authority to approve initial clinical
studies in lieu of an IND?
No. Ao IND is required when the purpose of the smdy“
SSStXdbg
particular organ or fluid space and to desoibe the
'
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considered to be basic research within
studies must be conducted under the conditions set
1a
'1
I
forth in 21 CFR 361.1(b).
All RDRC approved studies must also be approved by an IRB prior to initiation of the studies.
■via
I
66. Does FDA approve RDRCs?
f
6/1/99 9:1
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http7/www.fda.gov/oc/oha/IRB/toc.
-nfoimation Sheets Page 2 - Updated 9/98
p
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21 CFpRJa,ci(CHFD 1601^Center forDrug Evaluation and Research, FDA, 5600 Fishers L^ne,
R^k^e NtoyEd 20857. The FDA contact for compliance issu^is; the; Human Subject Protection
^^(HFD-343), CDER, FDA, 7520 Standish Place, Rockville, MD 20855.
■fi
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Return to Top
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6/1/99 1
:T5
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in.
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Editorials
’0|
li 1
5
'O
o
00
R'
K Thyroid Storm
BHgty To stiMy, to finish, to publish.
> 3 'JI
—Benjamin Franklin
BMOv' T stopped a flawed study, that would have put millions of
'I patients at risk.
« Tjll
.
—Carter Eckert
? an
f In this issue of THE JOURNAL, we are publishing a report1 of
W
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"'
work that started 9 years ago, was concluded in December 1990,
Z 8 g
and the data from which were published in another journal in
KO? '
1995* Glveri thatwe at JAMA like to keep up-to-date and
7
c 85 i
‘
we try never to republish what others have already put in
- 8 gg
print, the reader might well ask what is going on. The story
wJ necessary to answer this question provides a cautionary tale
"5 . that illustrates the sharply differing views of research taken by
fWS-th
e uraversity researcher and the company sponsoring that
S
• -o
research, if the company’s product is at stake. At a time when
fe^9 'x an increasing proportion of research funding is provided by
Jw
5 .
1r private companies,2 the story holds lessons for both, as well as
. f°r university faculties, administrators, regulatory agencies,
,
and for physicians who prescribe on the basis of evidence.
>
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See also pp 1199,1205 and 1224.
In this Editorial, I shall be discussing events that took
place at the University of California, San Francisco (UCSF),
which is where the West Coast office of JAMA is situated. I
should make it plain that until JAMA became involved, I did
not know, and had never had contact with, any of the research
workers involved.
«-»<au*yround
Background
s IBW..
L
S-.
The issue of the potency,
reliability,
-. and bioequivalence of
levothyroxine preparations has continued to raise controVersv ®
nrnvM vmnn
ver
sy.3 Natural thyroid extracts were
marketed before the
^gulations of
of 1938
1938 and
and so
so were
were exempted
exempted fro;
from amendments
regulations
tothe
theFood,
Food, Drug,
Drug,and
and Cosmetic
CosmeticAct
Actrequiring
requiringthat
thatdrugs
dru£ be
to
2. 1KvA -■ Proved safe and effective. Synthroid, the first synthetic ver._
^5 A.
K. .
ssi°ion,
n’ had
had come
come to
to dominate
dominate aa $600
$600million
millionaayear
yearmarket
market44that
that
fj (2
Pnnd and
ond Fh-ncr
Ad_
. Was
was eSSentiallv
essentially unpopulated
unregulated heeanee
because tho
the Food
Drug Ad_'
v
ministration (FDA) had no approved standards for bioavail0• r
ability and bioequivalence and no mechanism to evathate
|||£ them, and there were no adequate well-controlled trials. Such
S 2i
dominance was unusual, given that other competing formu
c’
lations of levothyroxine had been available for years, and it
o|; L
Si
was greatly assisted by the manufacturer’s claims that other
preparations were not bioequivalent.
r1, ■
g .£
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s
Editorials represent the opinions of the authors and The Journal and not those of the American Medical Association
is
on
GO o:
K
IM
the institute of Health Policy Research. Umversity’ofCa
Francisco. Dr Rennie is also Deputy Ed.ter (West). JAMA.
Reprints Drummond Rennie.
JAMA. 515 N State St. Chicac? _
1238
:
In 1987, to establish that Synthroid was truly more effec
tive than competing preparations, Flmt Laboratories, then
the manufacturers of Synthroid, approached Betty J. Dong, r
PharmD, at UCSF. This seemed a good choice because in
1986, Dong et al5 had published a letter showing that the
levothyroxine content of different thyroid products, 2 brand
name products and 7 generic, differed widely. They noted
that the 2 brand-name preparations, 1 of them Synthroid,
were the preparations of choice. Flint and Dong signed a
lengthy protocol/contract to finance comparative studies of
the bioequivalence of Synthroid and 3 other preparations, and
both sides expected the study to show that Synthroid was
superior Getter from B. J. Dong to N. M. Kurtz, March 31,
1994). The contract detailed the experimental design and
analysis of the data. Representatives of Flint, and after their
takeover, Boots Pharmaceuticals Inc, made regular site vis
its, about 3 a year, to satisfy themselves that the work was
being.done properly. During these visits small problems were
ironed out, but there was no hint of any bigger cloud.
In January 1989, at a time when there was a move to add a
competitors preparation to the Massachusetts formulary/ Boots,
in the first of their site visits, began asking for the preliminary
results of a parallel in vitro study in which tablets were com
pared, and because this would have.meant breaking the mask
ing code and therefore invalidating that particular study, Dong
et al refused to comply. By the end of 1990, the major in vivo
study was finished, and Dong sent all the results to Boots: it was
clear that all 4 preparations were bioequivalent.
Over the next 4 years, Boots waged an energetic campaign
to discredit the study and prevent publication of the drafts
Dong and her colleagues sent to them for comment, claiming
that the study was seriously flawed. Boots cited scores of
purported deficiencies, including failure to carry out proce
dures not called for in the protocol. They alleged deficiencies
with patient selection criteria and compliance, with assay
reliability, with study administration, with measuring bio
equivalence, and with the statistical analysis. Boots also cited
unspecified ethical problems and demanded disclosure of any
financial conflicts of interest, past, present, or future. Dong
answered the catalog of complaints in a detailed letter (to N.
M. Kurtz, March 31,1994), noting her “serious objections to
the allegations made” by Boots and agreeing to meet.
Boots also sent their complaint to the chancellor, all the
vice chancellors, and several department heads at UCSF.
Two investigations by the university found nothing but the
most minor and easily correctible problems Getter from J. E.
Goyan to N. M. Kurtz, June 5, 1992; memo from S. Fields to
B.- J. Dong, June 2, 1992). The company’s interactions with
Dr Dong were considered “harassment” to prevent publica
tion of results the company did not like (memo from L. Z.
Benet to J. E. Goyan, September 9, 1992). Dr Le-iie Benet,
then chairman of the Department of Biorharm .
S.i-
JAMA.Apr:! 16. 1937—.: 277.':^ : =
M
-----w . J---- —
' win*'1
ences, characterized the company’s representatives as “de
ceptive and self-serving.”6 UCSF found the study to be rig
orously conducted in a way that complied fully with the
contract. Minor deviations, made with the full knowledge of
Boots, met clinical and ethical standards, and there were no
violations of human subjects’ procedures. Furthermore, the
statistical procedures Boots criticized had been agreed on by
Boots and had been performed well.
Boots had alleged numerous breaches of research ethics,
but when asked by UCSF to make specific allegations that
UCSF could formally investigate, Boots did not respond.
Noting that all records and data had been open to Boots, who
had monitored the study closely, UCSF told Boots, in August
1994, that there was no reason to suppress the manuscript
and to do so would be an unprecedented intrusion upon aca
demic freedom Getter from P. Lurie and S. M. Wolfe to D. A.
Kessler, May 29, 1996). Later, they agreed to meet again
with Boots, but suggested that this time it should be in the
presence of officials from the FDA. That meeting never
took place. Dong et al made numerous changes in their manu
script to accommodate Boots, but finally decided they would
publish.
JAMA Becomes Involved
We at JAMA knew none of this when, in April 1994, JAMA
received a manuscript, “Bioequivalence of Generic and Brand
Levothjmoxine Products,” by Dong and 6 other coworkers at
JCSF. The paper reported a 4-way crossover trial comparing
1 generic (Geneva Generics and Rugby) and 2 brand-name
levothyroxine preparations, Synthroid (Boots) and Levoxine
renamed Levoxyl, Daniels Pharmaceuticals Inc, now Jones
dedical Industries) in hypothyroid patients. The patients
i-eceived the 4 preparations in a random sequence to ensure
that potential carryover effects from the previous formula
ion would introduce no systematic bias. Each preparation
vas given for at least 6 weeks, and the primary investigators,
including the statisticians, were blinded to the preparation,
^hey looked at 3 aspects of bioequivalence (area under the
urve, peak serum concentration, and time to peak concenration), measured for 3 indexes of thyroid function (thyrox
ine [T4], triiodothyronine [TJ, and free T4 index), and conluded that for these patients with primaiy hyothyroidism
,_ J
-
1
t •
•
.
*
general criteria for oral preparations and were therefore
interchangeable. The authors calculated that if the generit
generics
- the other brand-name preparation were substituted for
ynthroid, $356 million might be saved annually.
With the manuscript came a letter explaining that the work
Hd been funded by Boots. It went on: “Boots Pharmaceutical
ompany has been very critical of this study despite our
- umerous meetings with them.... we have sent them all the
data, including a copy of this manuscript” The letter also
entioned individuals who were paid consultants to Boots,
id asked that they not be reviewers, and some who the
authors thought, not always correctly, were free of such ties.
The manuscript was sent out to 5 expert reviewers, some
vealing themselves as consultants to Boots. It was revised
id was accepted for publication under a revised title in
November 1994. Proofs were circulated and a publication
"te set for January 25,1995, when, on Januaiy 13,1995, we‘.
ceived a letter from Dr Dong abruptly withdrawing the
...anusenpt from publication. She gave as their reason “im-
penizig legal action by Boots Pharmaceuticals, Inc against
the University of California, San Francisco and the investi
gators. When I inquired, Dr Dong explained to me that in the
proLxoUcontract she had signed back in May 1988, there was
a rescnctn e covenant which read: “All information contained
in ths protocol is confidential and is to be used by the investigaior only for the conduct of this study. Data obtained
by the investigator while carrying out this study is also con
sidered confidential and is not to be published or otherwise
released without written consent from Flint Laboratories,
Inc. They did not have this permission, and she had just been
told by a UCSF attorney that because of this clause, the
universty advised her to withdraw the paper, saying it would
not defend the authors if a suit was brought by Boots.
Knowing that the University of California forbids such
restrictions on the right to publish, I asked how she had
managed to sign such an agreement. She said that she had
assumed the clause to be routine. It was in fact common,
partly because until 1993, there was no general requirement
for centralized review of such contracts, and the university
attorney was told only after the fact. Dr Dong had not pre
viously informed JAMA because she had been reassured by
the university lawyers that such contracts had never before
prevented publication, and she had repeatedly informed the
company that she intended to publish. UCSF was now con
vinced that the company would forbid publication. The senior
author claimed to have been twice threatened with the pos
sibility of lawsuit should sales of Synthroid suffer as a con
sequence of publication. The company has vigorously denied
4 making such threats.4
The Position at the University
At the University of California, “Freedom to publish is
fundamental to the university and is a major criterion of the
appropriateness of a research project.”7 At the most, the
sponsor could be allowed 30 days for comment and, where a
patent application was to be filed, an extra 60 days. Dong had
in 1fact
signed
a »clause
giving
a sponsor
vetothe°requisite
rights
over
publication,
which
somehow
failed
to receive
j
T*
a•
t
w
°
administrative review. Despite this, the university counsel
whom she consulted advised her that, though it was improper
of Dong to have signed a contract with this restrictive clause,
the university which states that “the University will undertake research or studies only if the scientific results can be
published or otherwise promptly disseminated,”8 there was
uniikeiy to be a problem.
When Dong and her colleagues finally decided that the
company’s saentific concerns were spurious delaying tactics
and that they should publish, the university, now with a new
lawyer, was faced with a difficult choice. The university knew
the financial stakes had risen because of an impending takeover of Boots, and they had to consider “the possibility of
significant damages the company might claim by virtue of
publication of the article.”9 Extensive negotiation failed to
change the university’s opinion that the contract superseded
any general right of a member of the faculty to publish, or
considerations of science or the public health.
Boots/Knoll
At this time the pharmaceutical manu facturing arm of Boots
was indeed being considered for purchase, and information on
April 16. 1997—Vol 277. No. 15
Editorials
1239
t; study for sue!
Bnumber of sp
B^At the sam
Ifcjologizing fc
E jecting to its c
|.aLa*5;Piyen 1
^preemptive st
I study by Doni
K Utter would n
^requires more
SWhat Are the
For Resean
Kbeen approach
Bjsume that the
Ivorable result.'
| Dir Dong was i
hfenseagains
^leagues deserx
lights.
Given that th
Fthe reaction of
|to.have consid
Ibrought this u
Uigningthe cont
■ But I believe-1
|Some faculty, p
^iave imagined t
>aig,-sympathiz€
Worried lest Do
Save spoiled thi
pany’sponsorsh
bexiriven to fri
testing shops.
H The answer s
■ging.like this h
1 |.«ponsor, to pati
Kfeculty and the u
ER be bullied a
1 | versity has faile
j gversit/s rep,
Loutcry, the facu)
| B For the Univ
^*Rld forbid sue
I??611 had
Up '
fc^Awil 16, 1997
... r...
---------
.
W - w
HI
ur
«r?RiVersity, r
’ ^^nctiveclaust
!
researchers,
l^wedbythe
I |!Bp> tbe univer
Marchers t
^®y Were to publ
j
I ^bere are 2 vic
veto po\
J
’
permissi.
; EJy» ^gned her
^fetter of the
j rRo have been 1
j '^^viseagai
L gainst its
-..... -.-..-.JSS
the comparative bioequivalence of its'most important drug,
stimulating hormone.” The Knoll letter further stated that B
Synthroid, might affect its price. In March 1995, the company
Knoll can state unequivocally that it is aware of no study that j
was bought by BASF AG, for $1.4 billion, and is now part of
nas been published or even conducted that satisfies these J
ti
their Knoll Pharmaceutical subsidiary. In May 1995, JAMA
criteria, though the Berg and Mayor article cited 4 published ' I La
c<
and a number of other journals received a letter from Dr
ones the authors considered to be deficient. For the first time t| B ■
in
Gilbert Mayor at Boots/Knoll, who had been monitoring the
the company mentioned the unpublished work done by Dong |
in
work of Dong et al, disparaging both the study and Dr Dong,
et al, which Mayor and the company had known about for 3
and saying that the journals should “be concerned about
years before the Berg and Mayor article came out. The letter
■'
publishing [the paper].” Meanwhile, Boots/Knoll had hired
“ 016 “uPcoming” PaPer by Mayor et al,10 and dis-'
firms of investigators to look, among other things, into pos
missed the work on which it was based as worthless.
th*
sible conflicts of interest on the part of the UCSF researchers
Despite this, on November 7,1996, the FDA wrote to Knoll I■A w:.: sit
(of which they had none).:
concluding that Knoll had violated the Federal Food, Drug I I
Iti
Unable to publish their paper and receiving calls from their
and Cosmetic Act, 21 USC 5331(a) by misbranding Synthroid S14 .iy be
acquaintances asking about the firms’ inquiries, Dong and her
(letter from M. Baylor-Henry to R. Ashworth). The FDA II M M. ela.
colleagues were further mortified when Mayor et al,10 em
letter continues: “[Tjhe endpoints evaluated were the rate dI
dan
ployees of Boots/Knoll, not only published the results of the
the
and extent of absorption over a relatively short period of time - I
I
;
study by Dong et al in a 16-page article without any acknowl
(less than one half-life) following supra-therapeutic doses of II '••• ■' ■ in bF
edgment to the people who did the study, but did so in a
levothyroxine sodium [in normal volunteers].... [T]he au--I
reanalysis that reached the opposite conclusion and threw
dem
thors noted that to show similarity, ‘a more complex design WI
doubt on the work at UCSF. Indeed, the article contains a
5
reqi
involving chronic administration in a well-controlled, hypo- flI
table showing 18 “major study limitations.” Using the UCSF
thyroid population with the measurement of several end-fl
with
data, Mayor et al agreed that bioequivalence of all the prepa
duce
points’ [n] would be required.”
|I
rations was the same, but if correction was made for baseline
latioi
The letter noted that Knoll was in possession of the results -I!
values (something Dong et al did not do because they thought
of the study by Dong et al, which the company had not 8
it inappropriate, partly as it produced negative values for
disclosed. The FDA wrote that the article by Dong et al was
I ' ? taken
levothyroxine), the preparations were “therapeutically in
“a study with just such a more complex design involving
equivalent.” The effect would, of course, be at the same time
administration of thyroid replacement products in a hypo-ffl
- pheny
to strengthen the position of Synthroid and make it impos
thyroid population with the measurement of several end-fl
sible for any journal to publish Dong’s paper. The article by
points, including thyroid stimulating hormone.” And, of course,flL . .^.thati
Mayor et al was published in a new journal, the Avierican
the manuscript written by Dong et al reached opposite con-fBk^tequir
.
Journal of Therapeutics, of which Mayor was an associate
elusions:
namely,
that
Synthroid
was
bioequivalent
with
thefl
.
;
- y
editor.
_I
_
: fore g
other preparations.
Publicity
j " public
KnoU Changes Its Mind
:■ E
I',;.' . issue
IIsLwoaw
if.
The issue came to the attention of the public when, on April
25, 1996, the Wall Street Journal published a meticulously
researched account of the story, written by Ralph King. The
Boots/Knoll position was best summarized by Carter Eckert,
president of Boots/Knoll, who was quoted as saying: “I stopped
a flawed study that would have put millions of patients at
risk.
Food and Drug Administration
On August 26,1994, the FDA wrote to Boots (letter from
A. M. Reb to R. F. King) saying that an article published in
1992 by 2 Boots researchers, Berg and Mayor,11 on work done
at inr Research Corporation, Scarborough, Ontario, to sup
port the position that Synthroid was pharmacokinetically
superior to other preparations was misleading and should not
be disseminated by Boots. This article showed that in normal
volunteers studied over 48 hours (the half-life of levothyrox
ine is 7.6 days), there was a difference in absorption between
Levoxme (now Levoxyl) and Synthroid
Boots replied (letter from K. F. King to A. M. Reb, Sep
tember 20,1994), arguing that the study by Berg and Mayor11
was designed not to test bioequivalence but to identify bio!nequiyaIen“- And a later letter from Knoll Getter from B.
A. Buhler to P. C. O’Brien, July 12,1995) quoted the Berg and
Mayor article as saying that to determine bioequivalence
u ould require a more complex design involving chronic ad
ministration in-a well-controlled hypothyroid population with
measurement of several endpoints, including thyroid1240
JAMA, April 16, 1997—Vol 277. No. 15
Under pressure from the FDA, and perhaps realizing that^K
was
aP
wasap
the public perception was so negative, Knoll began negotia-|B " presen'
tions with the university. Eventually, this resulted in theW;
If *route u
0111
of Knoll,
Carter
and a™
board menwifl-----------president
-----------------xjvuci L,
auu a Eckert,
uuaru memar
ber, Louis Sullivan, MD (former secretary of the US De-® '/Q? A
partment of Health and Human Services), meeting with the s
chancellor of UCSF on November 25,1996. Knoll agreed not®
1
p:'expertis
to block publication of the manuscript by Dong et al, whild
B J’harmac
still insisting that its conclusions were not supported by the!
data.
j
i^Pharmac
^Assodat
JAMA is now publishing the manuscript set into proof 2]
the
years ago1: none of the content has been
^PorPr
mission is the public health, and we try hard to select the bestf
Atting p
papers we are sent We do not claim that we are publishing] i
tcame
evi.
a perfect study, just one of the best, made as good as expert
review can make it. Experience has taught us that there are;^E; I^perts t
^i^dth Boot
very few studies in which some reviewers cannot find flaws^
^Jy&or
d may
and so it may be here. For example, though mean values rf
&
fc^th
thi.^
thyrotropin (TSH), the important long-term measure, werel
| ^ grants gi?
similar, individual values differed. Because this may make
|
*hich is d
difference to individual patients when switching therapy^
E
.^id A
some clinicians may feel that bioequivalence might not be th®j L- ^^ercu
clinically relevant parameter when switching, as opposed
whet}
starting, therapy. However, it is our belief that this is a go<^| b/:
^Per.Obv
study carried out by highly competent workers following
. ^unpt
sensible design that tried to answer an important question I tKl^Donget
It is hard to believe that the sponsors would have made suck|
extraordinary efforts to delay and block publication of th«1
l-'l
J-
Editorial
®. Z242 jama.
, T/ ----- -
I'1
I
ic ‘ , Inc against! L for such a very long time and for such an extraordinary
) < I the investfl iL of specious reasons if the results had shown Synto be better.
d to me that in th3
y 1988, there was! t the same time, we are publishing a letter from Knoll
m on contained Lgizing for blocking the manuscript,12 and another obto its conclusions,13 as well as rebuttals from Dong et
2 1 :d by the iifl
(y. Data obtained! Given that Knoll has already made an extraordinary
st’^y is also coni Ejptjve strike by publishing its lengthy criticisms of the
h( or otherwise l Dong et al at a time when it looked as though the
in ^aboratoriesS £ would never see the light of day, we do not think Knoll
she had just beefl jres more space.
f 1 ‘ ; clause, the! J Are the Lessons?
tr, ying it would!
ht uy Boots. .’1 L Researchers and Faculty.—Even if researchers have
by sponsors, investigators should not as•nia forbids such] ^approached
®
< it
will
pf unfa.
low she hatfl
sa that she had] We results and should never allow sponsors veto power.
in fact common! Jong was naive, but faculty members are the last line of
er-1 requirement pse against industry interference, and she and her colid ic university! nes deserve credit for standing up for their academic
*oi.6 had not pre!
een reassured bj$ ren that this is an issue basic to their freedom to publish,
hi never before! faction of faculty at UCSF has been mixed. Many seem
informed
theWve considered, reasonably enough, that Dr Dong had
;d L__
______
Sh was now coni ;ht this upon herself and her colleagues by foolishly
zation. The senior igthe contract and did not realize it could be challenged,
ic vith the pos- believe that other considerations have been at work.
1! 5fer as a con- 5 faculty, perhaps hoping for commercial success, might
rigorously denied imagined the view from the commercial side of the fence
-j empathized with the company. Or perhaps they were
: ied lest Dong and her coworkers might, by their stance,
spoiled things for others hoping for pharmaceutical comom to publish is sponsorship and fearing that potential sponsors would
>r terion of the ■ iven to friendlier universities or to commercial drug>£ shopsic most, the]
1
ient and, where a ( e answer starts with the realization that when some»0 days. Dong had like this happens, everyone loses, from researcher, to
vt rights over »r, to patient But none stands to lose more than the
t^ie university. When it is revealed that its faculty
iy Jie°requisite
_
1
e
bullied
and kept quiet by their sponsor, yet the uniniversity counsel
h’' /as improper y ^ias fmled to back them fully on this basic issue, the
...................................
’ suffers. ”
”
”
* > no
inevitably
When
there
is
•e: ictive clause, ^/s reputation
jr,
the
faculty
is
seen
as
willing
to
cede
its
freedoms.
ieix contract with
srsity will under- • the University.—All academic research institutions
fic ■suits can be 1 forbid such clauses. But the problem would never have
at< ”* there was i had the university set up a system to screen them out
niversity, handicapped by its faculty’s signature on this
deeded that the ctive clause, investigated charges against, and cleared,
s < aying tactics Jsearchers, while encouraging them to publish. Then,
v with a new
by the amount of money they thought might be at
j university knew ' ,th,
’ t^le diversity suddenly switched its position and told
ii on/iipg
ending taketake- ' isearchers they would be at great personal jeopardy if
ability
of ' Fere publish because the university would not defend
th xjssi
XL11A1
aim by
MJ virtue
VllbUC WA
of |
otiation failed to ’
2 views of the clause in the contract giving the
superseded :
veto power. One, the narrower, holds that Dr Dong,
itr
Permission of the university and against its regulaIt’ 3 publish, or i
signed her publication rights away. She was bound by
1th.
tter of the contract, and any attempt to get out of it
have been legally doomed. In this view, the university
iri „ arm of Boots advise against
_
.publication. If the researchers had gone
nd information on aSainst its advice, the university would be freed from
ditorials 1239
Apnl 16. 1997—Voi 277. No. 15
its statutory duty to indemnify and defend its faculty, and the
researchers would have been on their own. This is the view
that prevailed.
The other view, and that taken by the UCSF attorney who
originally advised Dr Dong, was that when the company
approached her they knew she did not work at a commercial
drug-testing laboratory, but at a university, where she had
a duty to publish, and where a high premium was placed on
publication. The restrictive clause was incompatible with uni
versity regulations and the purpose of university research
and was at odds with the purpose of the_rest of this research
contract
The university, well aware of the importance of publication
and the refusal of Boots/Knoll to consent to it, could have
taken the case to court by filing for a motion for declaratory
judgment, whereby a judge would be asked to rule on the
meaning of the contract, particularly the reasonableness of
the restrictive clause. With a ruling in their favor, Dong et al
would have been free to publish. However, UCSF apparently
failed to threaten to do so to Knoll’s legal counsel, and when
UCSF put this idea to the researchers, the plan died because
the faculty was under the impression that this would require
them to engage in a lengthy court battle and because the
faculty was still afraid of being left to fend for themselves in
any suit after publication.
In my view, an academic principle of the highest priority
was at stake and recognized as such in the university's poli
cies, and this principle should have been immediately and
staunchly defended, notwithstanding the language of the con
tract If the university had advised publication and stood
behind its faculty, I doubt whether any suit would have
resulted, if only because of the consequent adverse publicity
to the company.
A university must above all things support the rights of its
faculty. Indeed, California law requires UCSF to defend its
employees, of whom Dong was one. The failure to do so
seriously threatens academic freedom by creating an impres
sion that the university will not back its faculty’s right to
publish or even to use results for other purposes, for example,
teaching? This should be pondered by all segments of the
institution if it is intent on encouraging academic-industry
partnerships. Pharmaceutical companies come to researchers
because they wish to form mutually beneficial cooperative
relationships in developing and testing their products. And
they come to places like UCSF because of its extraordinarily
high reputation, hoping that some of the prestige of the
university and its researchers will carry through to influence
the FDA and the prescribers. Commercial sponsors are most
likely to take their business elsewhere when the best people
leave. And if the university, lawyers, and faculty cannot be
trusted to defend faculty on such a key issue, why should they
feel confident about staying?
For the Company.—I am relieved that the company presi
dent has said, in response to a highly critical editorial in
Science,16 that Knoll is “committed to strong industry aca
demic partnerships.”17 A skeptic might ask whether the com
pany’s change of heart came in order to appease the FDA
after the company had successfully delayed the bad news
several years to maintain the market position of Synthroid
and to increase the purchase price of Boots. Nevertheless, I
congratulate them on belatedly seeing that neither academics
nor the public are likely to commend their heavy-handed
Editorials
1241
77
I
q|
' i
tod thaq
r oixi
no study th^
it es thes^
tactics. I suggest that it is in the long-term interests of
companies intending to sponsor research to be careful not to
d mblishm
include such restrictive clauses if they wish to attract the best
the first time I
| investigators.
lo"Q by Dot
7
Companies should realize that even if, as in the present
n out for
3W'fS-’ c instance, they select researchers whose results have favored
ut helett
I; 5. the
thecompany*s
compan/sproduct
productininthe
thepast,
past,the
theresults
resultsmay
maygo
goagainst
against
al,10 and diSK'XJ'. them. Sponsors must understand that researchers at univer11 ss.
|i’ sities
sities have
have aa duty
duty to
to publish
publish and
and a
a self-interest
self-interest in
in publication.
publication.
zr sto
r It may seem that the short-term interests of a company will
hood, ]
Ibe served by suppression of the results, but the public revngSynt
elation ofbullying tactics and spurious charges will uftimately
i)
he FD4
Idamage the name of the sponsor in the eyes of the profession,
ze the ra
■«
TXT\ A
. J Al. —. —_
■ ’ the FDA, and the public.
period oftw
For the FDA.—Thyroid preparations were grandfathered
doses
|hi by the 1938 Food, Drug,
ug, and
and Cosmetic
Cosmetic Act,
Act, which
which required
required
,e M
'■■■ demonstration of safety,r. and the 1962 amendment, which
required that drugs be shown to be effective. As is the case
H11
ro
’
with ^er preparations of levothyroxine, Synthroid, introS
G 4
0 ‘ duced in 1958, could reasonably be regarded as a reformu-
_r—--------------------- ..J
i ? $ lation. The FDA has the authority to designate important
of the result!
pre-1938 drugs that have been reformulated as “new* drugs
ianv had nd§ 11 - and require a New Drug Application (NDA). The FDA has
o etal wasS
'
taken this course in the cases of, for example, theophylline,
ig involvinjiS
phenytoin, quinidine, and digoxin. With levothyroxine, the
ts in a hypoH J ' issue is not so much safety and efficacy, but the requirement
s iral end8 w E
ft8 bioavailability be demonstrated. This itself would
it
of course 11 | ’ require specific standards to be set for levothyroxine, which
opposite con
would then allow bioequivalence to be measured and there
Jent with the
fore generic substitution. One advantage of pursuing the
NDA route is that it would finally let the practitioner and the
public know whether substitution with cheaper formulations
was appropriate and would dispel the confusion surrounding
re^l’zingtha 7
'
present claims of bioequivalence. It is, however, an arduous
e£
negotu
|
route to take merely to straighten this out for a drug that is
si id in th
good and one relied upon by millions. .
a board meml
A simpler and possibly more fruitful approach to setting
T US DO
standards for both bioequivalance and clinical interchangeti with the,
- ability might be for scientific organizations with the best
oh agreed not.
'■
expertise in this area, such as the American Association of
g et al, whilej
,7 Pharmaceutical Scientists, the American Society for Qinical
p< id by thei 5 f * Pharmacology and Therapeutics, and the American Thyroid
|| ‘ “• Association, to establish guidelines by consensus, winch they
t into proof £
could then publish for the benefit of all.
ge^
• -. 4 ‘
For Professional Societies.—The research comnsniity is
;el .thebe^
getting progressively more entangled with industry, as bere ,
031116 ev^^en^
me when I found it hard to find thyroid
ood as expert^
experts to review the paper who did not have finandal ties
,h: .here are',
.^.with Boots/Knoll. This is a ireflection, perhaps, of the
____
exio' nd flaws,’
traordmary market dominance of Synthroid and, associated
iean values of r
with this, the munificent scale of research and educational
iensure, were
grants given by Boots/Knoll. But there is an inverse side
s i y make« ;
dependence. Recently, for example, the American
iii therapy.
Thyroid Association, which receives more than 60% of its
ght not be the •
commercial sponsorship from Knoll, had the courage to de
as^nposedto
ate whether to write to Knoll to allow publication of the
.t] is a good
/ paP61*- Obviously, the members could not debate its merits as
rs Jlowing*.
Jt was unpublished, and the senior author of the manuscript
.ant question-,
y Dong et al, Dr Greenspan, did not attend the meeting,
,v< lade such
Partly because the gag clause in the contract forbade him
ic on of the
from discussing it. The motion to write the letter was narb
rowly defeated. At stake was the crucial ethical issne of
I
I
Editorial g.
1242 JAMA, April 16. 1997—Vol 277, No. 15
suppression of a manuscript coauthored by one of its most
distinguished members. An outsider is left with the sad impression that the ability of the association to influence these
events by speaking with moral authority was weakened by its
heavy dependence on money from Knoll.
Having said this, I would point out that other specialty
r
W
W
«
|
societies supported by Knoll have failed to address the issue j
at all. And the AmericaiAThyroid/Association, at the same i
meeting, voted to write to phanhaceutical companies to in- >
dicate that clauses restricting publication be removed from J
contracts; to write to their members advising them to avoid
such clauses; and to write to the FDA requesting appropriate -1
guidelines for bioequivalence studies. The association has
also taken steps to make itself more independent of corporate
sponsorship: an essential prerequisite for maintaining the
public trusu
w-d
But the fact is that though all of us believe we are per *
sonally uninfluenced by money or gifts, that is not how others
*
see it. If academic societies wish to retain any credibility, they
*
should consider making sure that no individual sponsor can
contribute, for example, more than 5% of the total, and, for
example, rely more on charging their members realistic dues.
Meanwhile, if academics wish to be credible as objective
authorities, they should be cautious when they accept speakeris fees and travel advances from individual companies, lest
they be accused of conflict.
Institutions and researchers worry that research money
will go to more compliant places in a race for the ethical
bottom. The answer to this is for prestigious societies such as
the Association of American Medical Colleges and the As
sociation of American Universities, which work by moral
persuasion, to set up standards for such contracts. I strongly
recommend that they do this, and soon.
For Joumals.—This has been an awkward time for JAMA.
We put in a lot of work on the paper, only to see it suddenly
withdrawn at the last moment But when the news broke, we
were constrained from discussing it because of the rules
against discussing unpublished papers. We were then shocked
when the reanalysis of “our” paper appeared in print10 A
journal’s job is to select the best, publish it, and then let the
criticism come in, but certainly not to publish results hijacked
from those who did the work. I believe that editors of the
journal publishing the paper by Mayor et al should examine
their policies carefully.
Is This Common?
The Synthroid case, where publication was delayed about
7 years, seems an extreme case. However, in this issue of The
Journal, we publish a paper from Blumenthal et al18 on
withholding of research results by researchers. These au
thors found that almost 20% of 2100 life science faculty re
ported delay of over 6 months in the publication of their
research results. Of 410 respondents to their survey who
reported such delay, in 28% it was “to slow dissemination of
undesired results.” It is not clear whether such an unaccept
able delay came from the scientists themselves or from in
dustry sponsors. Blumenthal et al conclude that withholding
is not widespread. Perhaps. But if “undesired results” are
withheld by only about 5% of all researchers, the fears in
duced by the increased part industry is playing in the funding
of research are not dispelled. And before we decide the dan
ger is past, workers at Carnegie-Mellon University reported
Editcriais
7^
f
1'
I
I
|
i
I
that m their sample of university-industry research centers
oo ,a of the signed agreements allowed the sponsor to delete
information from publication, 53% allowed publication to be
delayed, and 30% allowed both.19
The ethical dilemma in which researchers may put themselves is also not trivial. In 1995, Dr Nancy Olivieri published
an oprirnist.c article on the effects of an oral iron-chelation
agent - As her trials proceeded, however, she became disur ed by increasing evidence of the agent’s lack of effec
tiveness. She found an increase in hepatic iron in those on the
ora herapy, despite good compliance over 2 years, and she
was concerned about possible danger to patients. She had
signed a confidentiality agreement with her sponsors the
im^ert°f tHe drUg‘ She decided she had to break confiden
tiality by reporting her results at a meeting.^ The manu.
facturers disagreed with her int^pretation of the results and
tried unsuccessfully to block her presentation. Because she
now feels that she risks Utigation for having made her prewdth me"’
W°Uld nOt’ °n tHe adViCe °fher attorney> SP^
Rosenberg,2* sounding the alarm, makes the point that
secrecy m research is increasing and gives 4 examples from
his personal experience. He writes: “The goals of medical
research are clear to prevent human suffering and prema
ture death from disease.... Deliberately withholding useful
information .. is a violation of this principle.” As I have
pointed out before,25 a major problem in medicine is failure to
publish the results of studies that show no advantage to the
intervention understudy, so that treatments tend to be based
on biases in favor of the new. I take Chalmers’ position2^ that
it is unethical not to publish such negative results. The Ol
ivier case, hinging as it does on the interpretation of data
about the safety of a therapy, shows that this is not just a
theoretical position.
J
Rosenberg24 concludes, as do I, that scientists should never
sign any agreements that give their sponsors veto power over
publication.
Marshall27 has recently described the battle in genome re
search between those who wish to lock up results by delaying
publication and those, mcluding sponsors both governmental
and commercial, who see a wider societal good in putting gene
sequences prompUy into the public domain. Marshall notes
that, for example, withholding DNA sequence data on pathogens could cost human lives, but is “commonplace.” It is too
early to see who will win, but unless the scientific community
gives its strong support and approval to sponsors who forbid
secrecy, we will all suffer the consequences.
was discredited. Now that the thyroid storm has passed 1
cmicians and third-party payers finally have the information I
they need to best serve their patients.
|
Coda
1I
There is nothing new about commercial sponsorship of f
resych a fact brought home to me when I was privileged Ir
’
t°-tftenrMhei:IU?e 1996 meetln8 of the International Com- i*
mritee of Medical Journal Editors (the Vancouver Group)
I
,
the Council Room in the Trent Building of the University of I
Nottmgham in England. As we editors discussed the impH- I -1
cations
of the su;
canonsof
suppression of the paper by Dong et al, we did ■
I
so
°?hu man who would become Baron 1
n -iTd who° had given the land
Iand and the niuue
™ney
y s*
for the
the Trent
Building to
to be
be built
built in
in 1928.
1928. Lord
Lord Trent.
wlJ I1
for
Trent Building
Trent, who
founded the chain of retail chemists (pharmacies) that have I
3 household word in
United Kingdom, ]
start«l off life as Jesse Boot. I wondered whether Boot would
°f the research his company had spon
sored or of the skill with which his company had protected the I
interests of its shareholders.
J tr.
II. '
isl
■BH
IwMfi
.....
..__
, ,
Drummond Rennie, MD I
“ TX'!
cornmente of a score of coi- 4 r;
the
leagues, 12 of w hom criticized an earlier draft of the manuscript
kI^J„;H,aUCk
JG. Gee L, White JR, Bubp JL Greens^.
t
I
*’
I
• ■ ■*5^ \?.*'
iwlr'
f •■ .
19t®JSL26S4-2695T°'d ht’rTnooe U^tmenL new insights into an old therapy. JAMA. ‘1
for univen’ity ““dy’
I
6. Benet LZ. Morality play. Science. 1996^73:1782.
9 kS^g'Cmtraa
ManuaL
Manual 11-110.
t
■
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■
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.
I
•
■
1
I
:
I
1
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199G^:1784.
I
Conclusion
We are proud to publish the article by Dong and her col
eagues. We beheve it is good work, not merely because it
P^od peer review by more than the usual number of ex
perts, but because it has also passed carefid and prolonged
by
Umve5sity In response to widely disseminated
allegations of scientific defects and ethical violations. We are
also confident in the work because of the university’s finding
that none of the allegations had the slightest merit and bl
cause they came from those who had most to gain if the work
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JAMA. April 16. 1997—Vol 277. No. 15
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Editorials
1243 q
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international guidelines
FOR ETHICAL REVIEW
OF EPEDEMIOLOGICAL STUDIES
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INTRODUCTION
I
These Guidelines are iintendedTot,investigators, health policy-makers,
Ir3}.3”?6 7 epidemiology. They may also assist in
the establishment of standards, for ethical review of epidemiological
.
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.Jhe Guidelines are an expression of concern to ensure that
epidemiological studies observe ethical standards. These standards apply
nv«H^
°f thetypeS of actiW covered by the Guidelhes
of the ® studi”^
-be-held responsible for the ethical integrity
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?efTd “ the Study of the distribution and deterT i- f fheallhlre‘ated states or events in specified populations, and
the apphcation of this study to control of health problems
sent cent^ Th
™prOved the huraan condition in the pre
sen century It has clarified our -Understanding of many physical
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obSdah^b"behaV1rTI’d?nSerS t0 health- Some of 1116 knowledge
threes to
D apPhed t0 the contro1 of environmental and biological
hreats to health such as diseases due to drinking polluted water Other
to chaXd0 val
ha5 b£C°me Part °f popular culturc> ieading
examntc d 7 ^“
behaviour, and thus has led to improved health
3 S'
S t0Wa[dS PerS°naI hygiene-tobacco smoking,
A d ex"ras.e,ln re!2tI0n to heart disease, and the use of seat-belts
to reduce the risk of traffic injury and death.
tion aS™02ICal PraCtiCe and research are based mostly on observaand caiT'7
mterven,tlon more invasive than asking questions
may oJX °Utfr0Utlnc m,edlcal ^aminations. Practice and research
^nd oriS’
f0rkexamPle- when both routine surveillance of cancer
of a D0DubiirnSehrCh40n cancer are conducted by professional staff
oi a population-based cancer registry.
experimema°l:0SiCal
“ °f two main tyP«: observational and
ed-I3
of .obse7ational epidemiological research are distinguishand cX/(alS0 kn07n 33 SUrVey^’ case-controls^es,
subjects Th?v -
Oi.l.studxcarry minimal risk ro study
J^te^entiQn o^eFtEan asking questipns. g^
——is normally re-
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auired although there are some exceptions — fgr_example, very large
rnhA7r~e77?iTri conducted exclusively by_£xanuning medical-records.
A Cr^^Kiional study (survey) is commonly done on a random sample
of a population. Study subjects are asked questions, medically examin
ed or asked to submit to laboratory tests. Its aim is to assess aspects
of the health of a population, or to test hypotheses about possible causes
of disease or suspected risk factors.
A case-control study compares the past history of exposure to nsx
among patients who have a specified condition (cases) with the past
history of exposure to this risk among persons who resemble the cases
in such respects as age and sex, but do not have the specified condition
(controls). Differing frequency of past exposure among cases and controls can be statistically analysed to test hypotheses about causes or
risk factors. Case-control studies are the method of choice for testing
hypotheses about rare conditions, because they can be done with small
numbers of cases. They generally do not involve invasion of privacy
or violation of confidentiality. If a case-control study requires direct
contact between research workers and study subjects, informed consent
to participation in the study is required; if it entails only a review of
medical records, informed consent may not be required and indeed may
n° In a JXrtstudy, also known as a longitudinal or prospective study,
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individuals with differing exposure levels to suspected risk factors ye
identified and observed over a period, commonly years, and the rates
of occurrence of the condition of interest are measured and compyed
in relation to exposure levels. This is a more robust research method
than a cross-sectional or case-control study, but it requires study of
large numbers for a long time and is costly. Usually it requires only
asking questions and routine medical examinations; sometimes it re
quires laboratory tests. Informed consent is normaliy required but an
exception to this requirement is a retrospective cohort study that uses
linked medical records. In a retrospective cohort study, the imtial or
base-line observations may relate to exposure many years earlier to a
potentially harmful agent, such as x-rays, a presenbed drug or an oc
cupation^ hazard, about which details are known; the final or end
point observations are often obtained from death certificates. Numbers
of subjects maybe very large, perhaps millions, so it would be imprac
ticable to obtain their informed consent. It is essential to identify precisely
every individual studied; this is achieved by methods of matching that
are built into record linkage systems. After identities have been est^^
to compile the statistical tables, all personal identifying information
' is obliterated, and therefore privacy and confidentiality are safeguarded
An experiment is a study in which the investigator intentionally alters
one or more factors under controlled conditions to study the effects
of doing so. The usual form of epidemiological experiment is the ran
domized controlled trial, which is done to test a preventive or therapeutic
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oy researgh^
'------------------------——-______________ -_____ '^UsuSfiyin this form of experiment, subjects are allocated at random
groups, one group to receive, the other group not to receive, the
experimental regimen or procedure. The experiment compares the out
comes m the two groups. Random allocation removes the effects of
bias, which would destroy the validity of comparisons between the groups
nfVh 11 1S, a!ways P?ss.lble that ha™ may be caused to at least some
of the subjects, their informed consent is essential.
pidemiology is facing new challenges and opportunities. The ap
plication-of information technology to large data-files has expanded
mnnAHer“d capac‘ty of eP>denuological studies. The acquired imXen
Synd[°medAIDS) epidemic and its management have
Se usined l^?’C^ StUd‘-eS neW urSency; Public health authorities
are using population-screening studies to establish prevalence levels of
h™ unmunodeficiency virus (HIV) infection for purposes of monitor‘"o and restneting the spread of infection. Ahead lie entirely new
2d noDul’atlon
ar’SmS fr°m the conjunction of molecular
ana population genetics.
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PREAMBLE
The general conduct of biomedical studies is guided by statements of
m eraationafiy recognized principles of human rights, including the
Hel emvb-erg Code a"d the WorId Medical Association’s Declaration of
Helsinki as revised (Helsinki IV). These principles also underlie the
HumMSubTc?3-1011^^1^1^5 f°r Biomedical Research Involving
?SSieJ • ’ ISS-Ued by the Council for International Organizations
on t^ modH
‘•n 1,982-These and similar national codes are based
tients” a •
ln!ca medicine, and often address interests of “paJroLos of Jo i
n ?ubjects”’ Epidemiological research concerns
f-ftL^eS fp
tnr he ^0Ve C°deS do not adeciuately cover its special
denende’
p0SaItepidemiological studies should be reviewed in
dependently on ethical grounds.
ser^^V iSSUCS ?ften- arlSe aS 3 resultof conflict among competing
the rifhT111?’• SfChaS’ Jn the neld Of publichealth>theconflict between
hLeSfr *ndlV*duals andthe need5 of communities. Adherence to
sn^dief m hnCS WlU nOt aV01d 311 ethicaI Prisms in epidemiological
r>“n nnM^y sltuatI0rns. require careful discussion and informed judgeminisrraM h\PTi, °f InvestlSators> ethical review committees, ad™In,Practiti°ners, policy-makers, and community
in; countrieT'
sponsored epidemiological studies in developm= countries merit special attention. A framework for the application
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of these guidelines is set by the laws and practices in each jurisdiction
in which it is proposed to undertake studies.
The purpose of ethical review is to consider the features of a propos
ed study in the light of ethical principles, so as to ensure that investigators
have anticipated and satisfactorily resolved possible ethical objections,
and to assess their responses to ethical issues raised by the study. Not
all ethical principles weigh equally. A study may be assessed as ethical
even if a usual ethical expectation, such as confidentiality of data, has
not been comprehensively met, provided the potential benefits clearly
outweigh the risks and the investigators give assurances of minimizing
risks. It may even be unethical to reject such a study, if its rejection
would deny a community the benefits it offers. The challenge of ethical
review is to make assessments that take into account potential risks
and benefits, and to reach decisions on which members of ethical review
committees may reasonably differ.
Different conclusions may result from different ethical reviews of
the same issue or proposal, and each conclusion may be ethically reach
ed, given varying circumstances of place and time; a conclusion is ethical
not merely because of what has been decided but also owing to the
process of conscientious reflection and assessment by which it has been
reached.
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GENERAL ETHICAL PRINCIPLES
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All research involving human subjects should be conducted in accordance jvith four basic ethical principles, namely rejpecr for persons,
beneficence, non-maleflcence,
justice. It is usually assumedthat
these principles guide the conscientious preparation of proposals for
scientific studies. In varying circumstances, they may be expressed dif
ferently and given different weight, and their application, in all good
faith, may have different effects and lead to different decisions or courses
of action. These principles have been much discussed and clarified in
recent decades, and it is the aim of these Guidelines that they be applied
to epidemiology.
Respect for persons incorporates at least two other fundamental ethical
principles, namely:
a) autonomy, which requires that those who are capable of delibera
tion about their personal goals should be treated with respect for their
capacity for self-determination; and
b) protection of persons with impaired or diminished autonomy,
which requires that those who are dependent or vulnerable be afforded
security against harm or abuse.
Beneficence is the ethical obligation to maximize possible benefits and
to minimize possible harms and wrongs. This principle gives rise to
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norms requiring that the risks of research be reasonable in the light
of the expected benefits, that the research design be sound, and that
the investigators be competent both to conduct the research and to assure
the well-being of the research subjects.
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Non-maleficence (“Do no harm”) holds a central position in the tradi
tion of medical ethics, and guards against avoi-dable harm to research
subjects.
Justice requires that cases considered to be alike be treated alike, and
that cases considered to be different be treated in ways that acknowledge
the difference. When the principle of justice is applied to dependent
or vulnerable subjects, its main concern is with the rules of distributive
justice. Studies should be designed to obtain knowledge that benefits
the class of persons of which the subjects are representative: the class
of persons bearing the burden should receive an appropriate benefit,
and the class primarily intended to benefit should bear a fair propor
tion of the’risks and burdens of the study.
The rules of distributive justice are applicable within and among
communities. Weaker members of communities should not bear
disproportionate burdens of studies from which all members of the
community are intended to benefit, and more dependent communities
and countries should not bear disproportionate burdens of studies from
which all communities or countries are intended to benefit.
General ethical principles may be applied at individual and com
munity levels. At the level of the individual (microethics'), ethics governs
how one person should relate to another and the moral claims of each
member of a community. At the level of the community, ethics applies
to how one community relates to another, and to how a community
treats each of its members (including prospective members) and members
of other groups with different cultural values (macroethics). Procedures
that are unethical at one level cannot be justified merely because they
are considered .ethically acceptable at the other.
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ETHICAL PRINCIPLES
APPLIED TO EPIDEMIOLOGY
Informed Consent
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Individual consent
,
1. When individuals are to be subjects of epidemiological studies, their
informed consent will usually be sought. For epidemiological studies
that use personally identifiable private data, the rules for informed consent
vary, as discussed further below. Consent is informed when it is given
by a person who understands the purpose and nature of the study, what
participation in the study requires the person to do and to risk, and
what benefits are intended tq result from the study.
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2. An investigator who proposes not to seek informed cnn^nchas
die obligation to explain to anethical review committee how the study
\ypuld_be ethical in its absence: it may be impractical tn Inrsrr subjects
whose records are to be examined, or the purpose of some studies would
be frustrated — for example, prospective subjects on being informed
would change the behaviour that it is proposed to study, or might feel
needlessly anxious about why they were subjects or study. The investigator
will provide assurances that strict safeguards will be maintained to pro
tect confidentiality and that the study is aimed at protecting or advanc
ing health. Another justification for not seeking informed consent may
be that subjects are made aware through public announcements that
it is customary to make personal data available for epidemiological
studies.
3. Am ethical issue may arise when occupational records, medical
records, tissue samples, etc. are used for a purpose for which consent
was not given, although the study threatens no harm. Individuals or
their public representatives should normally be told that their data might
be used in epidemiological studies, and what means of protecting con
fidentiality are provided. Consent is not required for use of publicly
available information, although countries and commumties differ with
regard to the definition of what information about citizens is regarded
as public. However, when such information is to be used, it is understood
that investigators will minimize disclosure of personally sensitive infor
mation.
4. Some organizations and government agencies employ epidemiologists —
who may be permitted by legislation or employees’ contracts to have
access to data without subjects’ consent. These epidemiologists must
then consider whether it is ethical for them, in a given case, to use
this power of access to personal data. Ethically, they may still be ex
pected either to seek the consent of the individuals concerned, or to
justify their access without such consent. Access may be ethical on such
grounds as minimal risk of harm to individuals, public benefit, and
investigators’ protection of the confidentiality of the individuals whose
data they study.
Community agreement
5. When it is not possible to request informed consent from every
individual to be studied, the agreement of a representative of a com
munity or group may be sought, but the representative should be chosen
according to the nature, traditions and political philosophy of the com
munity or group. Approval given by a community representative should
be consistent with general.ethical principles.-When investigators work
. with commumties, they will consider communal rights and protection
as they would individual rights and protection. For communities in which
collective decision-making is customary, communal leaders can express
the collective will. However, the refusal of individuals to participate
12
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of Vcnm!aS>° bk respec.ted: a leader may express agreement on behalf
is bind!
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When people
AnTV"
P^°P? are aPP°inted fay agencies outside z croup, such as
a department of government, to speak for members of the iJrouD in
ves .gators and ethical review committees should co^J how authen
XfemenTofX'
f°r'the grouP> and if necessary seek also the
^reement of other representatives. Representatives of a communitv
fh/_\ ,p may sometimes be in a position to participate in designing
the study and in its ethical assessment.
resigning
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7. The definition of a community or group for nurnosec nf
of a C?m OglCal StUdy may be a matter Of ethical concem- vln memberSf
and feX^1™ y
naturaI1y conscious of its activities as a community
,rrin.
Interests With other members, the community exists
a com 1Ve.0f.the study Proposal. Investigators will be sensitive! how
of u^SegXX?- °r
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grounsrth^Pa°reeS Of ePidem*olo^caI study. investigators may define
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may not
ftl^able as leaders or representatives, and individuals
y ot be expected to nsk disadvantage for the ben-fit of others
anTah th! mo'
d‘ffiCUlt t0 £nSUre grouP representation,’
sent to pan7cipeatemPOrtant t0 °
S“bjeCtS’
and infonned con-
Undue influence
lOh!r°SpeCtiVe subjects rnay not feel free to refuse requests from those
who have power or influence over them. Therefore theTdentky of
_.V“bgatOr or other Person assigned to invite prospective subjects to
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Selective disclosure of information
dLomTl^f1027’ P11 aCCePtabIe study technique involves selectivTL
of info
lnforalallon- which seems to conflict with the principle
is ieSsibleOevent’
ePideraioloSical studies non-dfsclosme
condTt ndi even “sentlal- so as to not influence the spontaneous
respondent miXeSt'8atl°n’
t0 aV0‘d obtaining responses that the
disclosure
ln °rjler t0 P‘eaSe the ^estioner. Selective
does not ind,
bemgn and ethically permissible, provided that it
to do Teth!)SUb^CtS t0 d° What they Would not othe^e consent
o 00. An ethical review committee may permit disclosure of only selected!
information when this course is justified.
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such amamn? in n
COalmittee how they propose to neutralize
PP nt influence. It is ethically questionable whether subjects
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should be recruited from among groups that are unduly influenced by
persons in authority over them or by community leaders, if the study
can be done with subjects who are not in this category.
Inducement to participate
11. Individuals or communities should not be pressured to participate
in a study. However, it can be hard to draw the line between exerting
pressure or offering inappropriate inducements and creating legitimate
motivation. The benefits of a study, such as increased or new knowledge,
are proper inducements. However, when people or communities la°ck
basic health services or money, the prospect of being rewarded by goods,
services or cash payments can induce participation. To determine the
ethical propriety of such inducements, they must be assessed in the light
of the traditions of the culture.
12. Risks involved in participation should be acceptable to subjects
even in the absence of inducement. It is acceptable to repay incurred
expenses, such as for travel. Similarly, promises of compensation and
care for damage, injury or loss of income should not be considered
inducements.
Maximizing Benefit
Communication of study results
13. Part of the benefit that communities, groups and individuals may
reasonably expect from participating in studies is that they will be told
of findings that pertain to their health. Whenrfindings could-be applied
in public health measures to improve community health, they should
be communicated to the health authorities. In informing individuals
of the findings and their pertinence to health, their level of literacy
and comprehension must be considered. Research protocols should in
clude provision for communicating such information to communities
and individuals.
Research findings and advice to communities should be publicized by
whatever suitable means are available. When HIV-prevalence studies
are conducted by unlinked anonymous screening, there should be, where
feasible, provision for voluntary HIV-antibody testing under conditions
of informed consent, with pre- and post-test counselling, and assurance
of confidentiality.
Impossibility of communicating study results
14. Subjects of epidemiological studies should be advised that it may
not be possible to inform them about findings that pertain to their health,
but that they should not take this to mean that they are free of the
disease or condition under study. Often it may not be possible to ex
tract from pooled findings information pertaining to individuals and
their families, but when findings indicate a need of health care, those
concerned should be advised of means of obtaining personal diagnosis
and advice.
14
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nen epidemiological data are unlinked, a disadvantage to subjects
is that individuals at risk cannot be informed of useful findings perti
nent to their health. When subjects cannot ce advised individually to
seek medical attention, the ethical duty to co good can be served by
making pertinent health-care advice available to their communities.
Release of study results
15. Investigators may be unable to compel release of data held by govern
mental or commercial agencies, but as health professionals they have
ail ethical obligation to advocate the release of information that is in
the public interest.
Sponsors of studies may press investigators to present their findings
m ways that advance special interests, such as to show that a product
or procedure is or is not harmful to health. Soonsors must not present
interpretations or inferences, or theories and hypotheses, as if they were
proven truths.
Health care for the community under study
16. The undertaking of an epidemiological project in a developing coun
try may create the expectation in the community concerned that it will
e provided with health care, at least while the research workers are
present. Such an expectation should not be frustrated, and, where neo^l£n££j hgglth care, arrangejn^nts should be
to have them trerHrrl
the needed carei
----------------------------------- ----------- "
Training local health personnel
17. While studies are in progress, particularly in developing countries
the opportunity should be taken to train local health workers in skills
and techniques that can be used to improve health services. For in
stance, by training them in the operation of measuring devices and
calculating machines, when a study team departs it leaves something
or value, such as the ability to monitor disease or mortality rates.
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Minimizing Harm
Causing harm and doing wrong
18. Investigators planning studies will recognize the risk of causing harm,
in the sense of bringing disadvantage, and of doing wrong, in the sense
of transgressing values. Harm may occur, for instance, when scarce
health personnel are diverted from their routine duties to serve the needs
of a study, or when, unknown to a community, its health-carejjriorities
are changed. It is wrong to regard members of communities as only
impersonal material for study, even if they are not harmed.
19 Ethical review igust always asscssjhe risk of subjects or groups
1
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in a study, investigators wilT
inform ethical review committees ancTprospecti vesubj ects of perceived
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risks, and of proposals to prevent or mitigate them. Investigators must
be able to demonstrate that the benefits outweigh the risks for both
individuals and groups. There^should be a thorough analysis to deter
mine who would be at risk ancTwho would benefit from the study.
It is unethical to expose persons to avoidable risks disproportionate
to the expected benefits, or to permit a known risk to remain if it^can
~be avoided nr at hast minimised—
20. When a healthy person is a member of a population or sub-group
at raised risk and engages in high-risk activities, it is unethical not to
propose measures for protecting the population or sub-group.
Preventing harm to groups
21. Epidemiological studies may inadvertently expose groups as well
as individuals to harm, such as economic loss, stigmatization, blame,
or withdrawal of services. Investigators who find sensitive information
that may put a group at risk of adverse criticism or treatment should
be discreet in communicating and explaining their findings. When the
location or circumstances of a study are important to understanding
the results, the investigators will explain by what means they propose
to protect the group from harm or disadvantage; such means include
provisions for confidentiality and the use of language that does not
imply moral criticism of subjects’ behaviour.
Harmful publicity
x
22. Conflict may appear between^jon the one hand, doing no harm
and, on the other, telling the'truth and openly disclosing scientific fin
dings. Harm may be mitigated by interpreting data in a way that pro
tects the interests of those at risk, and is at the same time consistent
with scientific integrity. Investigators should, where possible, anticipate
and avoid misinterpretation that might cause harm.
Respect for social mores
23. Disruption of social mores is usually regarded as harmful. Although
cultural values and social mores must be respected, it may be a specific
aim of an epidemiological study to stimulate change in certain customs
or conventional behaviour to lead through change to healthful behaviour
— for instance, with regard to diet or a hazardous occupation.
24. Although members of communities have a right not to have others
impose an uninvited “good” on them, studies expected to result in health
benefits are usually considered ethically acceptable and not harmful.
Ethical review committees should consider a study’s potential for
beneficial change. However, investigators should not overstate such
benefits, in case a community’s agreement to participate is unduly in
fluenced by its expectation of better health services.
Sensitivity to different cultures
25. Epidemiologists often investigate cultural groups other than their
own, inside or outside their own countries, and undertake studies in-
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itiated from outside the culture, community or county in which the
study is to be conducted. Sponsoring and host counties may it er
in the ways in which, in their cultures, ethical values are understoo
and applied — for instance, with regard to autonomy ot individuals.
Investigators must respect the ethical standards of their own countries
and the cultural expectations of the societies in which epidemiological
studies are undertaken, unless thirimplies a violation of a transcending,
moral rule. Investigators risk harming their reputation by pursuing work
• that host countries find acceptable but their own countries consider
offensive. Similarly, they may transgress the cultural values of the host
countries by uncritically conforming to the expectations of their own.
Confidentiality
26. Research may involve collecting and storing data relating to in
dividuals and groups, and such data, if disclosed to third parties, may
cause harm or distress. Consequently, investigators should make ar
rangements for protecting the confidentiality of such data by, for ex
ample, omitting information that might lead to the identification of
individual subjects, or limiting access to the data, or by other means.
It is customary in epidemiology to aggregate numbers so that individual
identities are obscured. Where group confidentiality cannot be main
tained or is violated, the investigators should take steps to maintain
or restore a group’s good name and status. Information obtained about
subjects is generally divisible into:
Unlinked information, which cannot be linked, associated or connected
with the person to whom it refers; as this person is not known to the
investigator, confidentiality is not at stake and the question of consent
does not arise.
Linked information, which may be:
— anonymous, when the information cannot be linked to the person
to whom it refers except by a code or other means known only to
that person, and the investigator cannot know the identity of the
person;
— non-nominal, when the information can be linked to the person by
a code (not including personal identification) known to the person
and the investigator; or
— nominal or nominative, when the information is linked to the per
son by means of personal identification, usually the name.
Epidemiologists discard personal identifying information when con
solidating data for purposes of statistical analysis. Identifiable personal
data will not be used when a study can be done without personal iden
tification — for instance, in testing unlinked anonymous blood samples
for HIV infection. When personal identifiers remain on records used
for a study, investigators should explain to review committees why this
is necessary and how confidentiality wall be protected. If, with the con-
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sent of individual subjects, investigators link different sets of data regar
ding individuals, they normally preserve confidentiality by aggregating
individual data into tables or diagrams. In government service the obligationtcr protect confidentiality is frequently reinforced by the practice
of swearing employees to secrecy.
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Conflict of interest
Identification of conflict of interest
27. It is an ethical rule that investigators should have no undisclosed
conflict of interest with their study collaborators, sponsors or subjects.
Investigators should disclose to the ethical review committee any poten
tial conflict of interest. Conflict can arise when a commercial or other
sponsor may wish to use study results to promote a product or service,
or when it may not be politically convenient to disclose findings.
28. Epidemiological studies may be initiated, or financially or other
wise supported, by governmental or other agencies that employ in
vestigators. In the occupational and environmental health fields, several
well-defined special-interest groups may be in conflict: shareholders,
management, labour, government regulatory agencies, public interest
advocacy groups, and others. Epidemiological investigators may be
employed by any of these groups. It.can be difficult to avoid pressures
resulting from such conflict of interest, and consequent distorted inter
pretations of study findings. Similar conflict may arise in studies of
the effects of drugs and in testing medical devices.
29. Investigators and ethical review committees will be sensitive to the
risk of conflict, and committees will not normally approve proposals
in which conflict of interest is inherent. If, exceptionally, such a pro
posal is approved, the conflict of interest should be disclosed to pro
spective subjects and their communities.
30. There may appear to be conflict when subjects do not want to change
their behaviour and investigators believe that they ought to do so for
the sake of their health. However, this may not be a true conflict of
interest, as the investigators are motivated by the subjects’ health interests.
Scientific objectivity and advocacy
31. Honesty and impartiality are essential in designing and conducting
studies, and presenting and interpreting findings. Data will not be
withheld, misrepresented or manipulated. Investigators may discover
health hazards that demand correction, and become advocates of means
to protect and restore health. In this event, their advocacy must be
. seen to rely on objective, scientific data. .
18
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ETHICAL REVIEW PROCEDURES
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Requirement of ethical review
32. The provisions for ethical review in a society are influenced by
economic and political considerations, the organization of health care
and research, and the degree of independence of investigators. Whatever
the ci re u mstances^Jhere_is-a-respo ns ibi 1 ity -to en-siue th?t the~Qeclaraiiori oTHelsihkTand the CIOMS International Guidelines fncBiamedical
Research Involying_jluman Subjects are taken into accojuxt in
epidemiological studies?^ ----------------------33. The requirement that proposals for epidemiological studies be sub
mitted to independent ethical review applies irrespective of the source
of the proposals — academic, governmental, health-care, commercial,
or other. Sponsors should recognize the necessity of ethical review and
facilitate the establishment of ethical review committees. Sponsors and
investigators are expected to submit their proposals to ethical review,
and this should not be overlooked even when sponsors have legal power
to permit investigators access to data. An exception is justified when
epidemiologists must investigate outbreaks of acute communicable
diseases. Then they must proceed without delay to identify and control
health risks. They cannot be expected to await the formal approval
of an ethical review committee. Nevertheless, in such circumstances II
the investigator will, as far as possible, respect the rights of individuals, \\
namely freedom, privacy, and confidentiality.
Ethical review committees
34. Ethical review committees may be created under the aegis of na
tional or local health administrations, national medical research coun
cils, or other nationally representative health-care bodies. The authority
of committees operating on a local basis may be confined to one institu
tion or extend to all biomedical studies undertaken in a defined political
jurisdiction. However committees are created, and however their jurisdic
tion is defined, they should establish working rules — regarding, for
instance, frequency of meetings, a quorum of members, decision-making
procedures, and review of decisions, and they should issue such rules
to prospective investigators.
35. In a highly centralized administration, a national review committee
may be constituted to review study protocols from both scientific and
ethical standpoints. In countries with a decentralized administration,
protocols are more effectively and conveniently reviewed at a local or
regional level. Local ethical review-committees have two responsibilities:
— to verify that all proposed interventions have been assessed for safe
ty by a competent expert body, and
— to ensure that all other ethical issues are satisfactorily resolved.
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36. Local review committees act as a panel of investigators’ peers, arid
their composition should be such as can ensure adequate review of the
study proposals referred to them.JThejr membership should include
epidemiologists, other health practitioners;-and lay^mons~quaHfied
to represent_aj^ig<^
cultural and morarvalues. Com
mittees should have diverse composition and includFrepresentatives
of any populations specially targeted for-study. The members should
change periodically to prevent individuals from becoming unduly in
fluential, and to widen the network involved in ethical review. In
dependence from the investigators is maintained by precluding any
member with a direct interest in a proposal from participating in its
assessment.
Ethical conduct of members of review committees
37. Ethical review committee members must carefully guard against
any tendencies to unethical conduct on their own part. In particular,
they should protect the confidentiality of review-committee documents
and discussions. Also, they should not compel investigators to submit
to unnecessary repetition of review.
Representation of the community
38. The community to be studied should be represented in the ethical
review process. This is consistent with respect for the culture, the digni
ty and self-reliance of the community, and the aim of achieving com
munity members’ full understanding of the study. It should not be
considered that lack of formal education disqualifies community members
from joining in constructive discussion on issues relating to the study
and the application of its findings.
Balancing personal and social perspectives
39. In performing renews, committees will consider both personal and
social perspectives. While, at the personal level, it is essential to ensure
individual informed and free consent, such consent alone may not be
sufficient to render a study ethical if the individual’s community finds
the study objectionable. Social values may raise broad issues that affect
future populations and the physical environment. For example, in pro
posals for the widespread application of measures to control intermediate
hosts of disease organisms, investigators will anticipate the effects of
those measures on communities and the environment, and review com
mittees will ensure that there is adequate provision for the investigators
to monitor the application of the measures so as to prevent unwanted
effects.
Assuring scientific soundness
40. The primary functions of ethical review are to protect human sub
jects against risks of harm or wrong, and to facilitate beneficial studies.
Scientific review and ethical review cannot be considered separately:
a jtudy that is scientifically unsound is unethical in exposing subjects
toTisk or Inconvenience and achieving no benefit in knowledge. Nor-
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mally therefore, ethical review committees consider both scientific andetmcal aspects^Anethical review committee may refer technical aspects I
scientific review-te a scientifically qualified person or committee, /
but will reach its own decision, based on such qualified advice, on scien- /
;‘C s°un^ness- If a review committee is satisfied that a proposal is /
c en ifically sound, it will then consider whether any risk to the subject <
tnivS '-Jh y
exPe!;ted benefit> and whether the proposal is satisfac
tory with regard to informed consent and other ethical requirements.
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Assessment of safety and quality
41 All drugs and devices under investigation must meet adequate stan
dards of safety. In this respect, many countries lack resources to underLa,m-alndefJendent assessment °f technical data. A governmental
multid^sciphnmy committee with authority to co-opt experts is the most
suitable body for assessing the safety and quality of medicines, devices
and procedures. Such a committee should include clinicians, phar
macologists, statisticians and epidemiologists, among others; for
epidemioJogmal studies,, epidemiologists occupy a position of obvious
2Ce‘ EthjCa- reVIeW Procedur« stlould provide for consultation
with such a committee.
Equity in the selection of subjects
42.. Epidemiological studies are intended to benefit populations, but
individual subjects.are expected to accept any risks associated with studies
When research liintended to benefit mostly the better off or healthier
™™,berS °-f/ P0PylatI0n. H is particularly important in selecting subn
aV°ld 1??quity on the ba5is °f age, socioeconomic status, disability
or other variables. Potential benefits and harm should be distributed
equitably within and among communities that differ on grounds of
aSe> gender, race, or culture, or other variables.
1
Vulnerable and dependent groups
43 ^Ethical review committees should be particularly vigilant in the case
of proposals involving populations primarily of children, pregnant and
nursing women, persons with mental illness or handicap, members of
eommunities unfamiliar with medical concepts, and persons with
nH
fr.ecd°m t0 m^ke truIy independent choices, such as prisoners
nd medical students. Similar vigilance is called for in the case of proposals for invasive research with no direct benefit to its subjects.
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Control groups
studies that require control (comparison) or placebon°51'treat=d) ?rouP.s are governed by the same ethical stan,
ose hat apply to clinical trials. Important principles are thath w-r
gr°Up in a study of a condition that can cause death
d^ahility or serious distress should receive the most appropriate
currently established therapy; and
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(ii) if a procedure being tested against controls is demonstrated to be
superior, it should be offered promptly to members of the control
group.
A study will be terminated prematurely if the outcome in one group
is clearly superior to that in the other, and all subjects will be offered
the better treatment. Research protocols should include “stopping rules”,
i.e., procedures to monitor for, and act upon, such an event. Investigators
must continually bear in mind the potential benefits of the study to
the control group, and the prospect of improved health care from ap
plying the findings to the control group.
Randomization
45. Trials in which the choice of regimen or procedure is determined
by random allocation should be conducted only when there is genuine
uncertainty about differences in outcome of two or more regimens or
procedures. Where randomization is to be used, all subjects will be
informed of the uncertainty about optimum regimens or procedures,
and that the reason for the trial is to determine which of two or more
is in the subjects’ best interests. Informing subjects about such uncer
tainty can in itself arouse anxiety among patients, who may already
be anxious for other reasons; therefore, tact and delicacy are required
in communicating the information. Ethical review committees should
ascertain whether investigators refer explicitly to informing subjects about
this uncertainty, and should enquire what will be done to allay subjects’
anxiety about it.
Random allocation also can cause anxiety: persons chosen for, or ex
cluded from, the experimental regimen or procedure may become
anxious or concerned about the reasons for their being chosen or ex
cluded. Investigators may have to communicate to members of the study
population some basic concepts about application of the laws of chance,
and reassure them that the process of random allocation is not
discriminatory.
Provision for multi-centre studies
46. When participation in a multi-centre study is proposed according
to a common protocol, a committee will respect different opinions of
other committees, while not compromising on the application of the
ethical standards that it expects investigators to observe; and it will
attempt to reconcile differences so as to preserve the benefits that only
a multi-centre study can achieve. One way of doing so could be to in
clude in the common protocol the necessary procedures. Another would
be for the several committees to delegate their review functions to a
joint committee of the centres collaborating in the study.
Compensation for accidental injury
47. Some epidemiological studies may inadvertently cause harm.
Monetary losses should be promptly repaid. Compensation is difficult
when it is not appropriate to make monetary payments. Breach of con22
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:.-e..jaJiy or insensitive publication of study findings, leading to loss
Oi group prestige, or to indignity, may be difficult to remedy. When
harm results from a study, the body that has sponsored or endorsed
the study should be prepared to make good the injury’, by public apology
or reparation.
Externally sponsored studies
48. Externally sponsored studies are studies undertaken in a host coun
try but initiated, financed, and sometimes wholly Or partly carried out
by an external international or national agency, Avith the collaboration
or agreement of the authorities or the host country.
Such a study implies two ethical obligations:
The initiating agency should submit’the study protocol to ethical
review, in which the ethical standards should be no less exacting
than they would be for a study carried out in the initiating country.
The ethical review committee in the host country should satisfy itself
that the proposed study meets its own ethical requirements.
49. It is in the interest of the host country to require that proposals
initiated and financed externally be submitted for ethical approval in
the initiating country, and for endorsement by a responsible authority
of the same country, such as a health administration, a research coun
cil, or an academy of medicine or science.
50. A secondary objective of externally sponsored studies should be
the training of health personnel of the host country to carry out similar
study projects independently.
51. Investigators must comply with the ethical rules of the funding coun
try and the host country. Therefore, they must be prepared to submit
study proposals to ethical review committees in each country. Alter
natively, there may be agreement to the decision of a single or joint
ethical review committee. Moreover, if an international agency spon
sors a study, its own ethical review requirements may have to be satisfied.
Distinguishing between research and programme evaluation
52. It may at times be difficult to decide whether a particular proposal
is for an epidemiological study or for evaluation of a programme on
the part of a health-care institution or department. The defining at
tribute of research is that it is designed to produce new, generalizable
knowledge, as distinct from knowledge pertaining only to a particular
individual or programme.
For instance, a governmental or hospital department may want to exam
ine patients’ records to determine the safety and efficacy of a facility,
umt or procedure. If the examination is for research purposes, the pro
posal should be submitted to the committee that considers the ethical
teatures of research proposals. However, if it is for rhe purpose of
programme evaluation, conducted perhapsbxjtaf^ePttarmstittrttott—
23
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to eygluste therapeutic programme fnr its effects, the proposal may
not need to be submitted to ethical review,-^ori the contrary, it could
be considered poor practice and unethicaTnot to undertake this type
of quality assurance. The prospect of benefit or avoidance of harm
to patients may constitute an ethical value that outweighs the risk of
breaching the confidentiality of former patients whose medical records
are liable to be inspected without their consent.
If if is not clear whether a proposal involves epidemiological study or
routine practice, it should be submitted to the ethical review committee
responsible for epidemiological protocols, for its opinion on whether
the proposal falls within its mandate.
Information to be provided by investigators
53. Whatever the pattern of the procedure of ethical review, the in
vestigator must submit a detailed protocol comprising:
— a clear statement of the objectives, having regard to the present
state of knowledge, and a justification for undertaking the investiga
tion in human subjects;
— a precise description of all proposed procedures and interventions,
including intended dosages of drugs and planned duration of
treatment;
— a statistical plan indicating the number of subjects to be involved;
— the criteria for terminating the study; and
— the criteria determining admission and withdrawal of individual sub
jects, including full details of the procedure for obtaining informed
consent.
Also, the protocol should:
A include information to establish the safety of each proposed procedure and intervention, and of any drug, vaccine or device to be
tested, including the results of relevant laboratory and animal research;
specify the presumed benefits to subjects, and the possible risks of
proposed procedures;
indicate the means and documents proposed to be used for eliciting
informed consent, or, when such consent cannot be requested, state
what approved alternative means of obtaining agreement will be
used, and how it is proposed to protect the rights and assure the
welfare of subjects;
-^provide evidence that the investigator is properly qualified and ex
perienced, or, when necessary, works under a competent supervisor,
and that the investigator has access to adequate facilities for the
safe and efficient conduct of the research;
-A describe the proposed means of protecting confidentiality during
Z the processing and publication of study results; and
—refer to any other ethical considerations that may be involved, and
indicate that the provisions of the Declaration of Helsinki will be
respected.
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' ^^?TlSsbciATI0N MEDICALE MONDIALE, INC
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ASOCIACION MEDICA MUNDIAL, INC
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THE WORLD MEDICAL ASSOCIATION, INC.
B. P. 65 - 01212 FERNEY-VOLTAIRE Cedex, France
28, avenue des Alpes • 01210 FERNEY-VOLTAIRE, France
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fephone: 50 40 75 75
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:50 40 59 37
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Cable Address:
WOMEDAS, Ferney-Voltaire
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WORLD MEDICALAS5QCJATI0N DECLARATION OF LISRorj
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Original: English
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THE RIGHTS OF THE PATIENT
Adopted by the 34th World Medical Assembly
Lisbon, Portugal, September/October 1981
and amended by the 47th General Assembly
Bali, Indonesia, September 1995
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O' PREAMBLE
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|g| The relationship between physicians, their patients and broader society has
^Tne>SIBn'/L.Cant chan9es in recent times. While a physician should always act
HB Srding t° his/her conscience, and always in the best interests of the patient equal
.effort must be made to guarantee patient autonomy and justice.
The following
SB ?rnfTa iOn rePreSentS 5°me of
PriHciP31 rights of the patient which the medical
Bi-' in th
endorses and promotes. Physicians and other persons or bodies involved
fc h th PTVISI?Ana.°f health care have a j°int responsibility to recognize and uphold
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tr'9htH’ W^never legislation, government action or any other administration or
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lnn^eUtlr b,omedlcaJ research - the subject is entitled to the same right? and
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Right to medical care of good quality
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Every person is entitled without discrimination to appropriate medical care.
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b. Every patient has the right to be cared for by a physician whom he/she
interfS t0
^ee t0 ma^e chnical anci ethical judgements without any outside
c The patient shall always be treated in accordance with his/her best interests.
The treatment applied shall be in accordance with generally approved medical
principles.
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d. Quality assurance always should be a part of health care Phv^iHane •
medicarseXiL^
responsibility for bein9 guardians of the7 quality’ of
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e. In circumstances where a choice must be made between potential oatientd
^for a particular treatment which is in limited supply, all such parents are entitled
a fair selection procedure for that treatment/That choice Xt be based on
medical criteria and made without discrimination.
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The patient has the right of continuity of health care. The physician has an
obligation to cooperate in the coordination of medically indicated care with othe?
th/± care providers treating the patient. The physician may not discontinue
niv^H^h1 ° a Pat'erit as lQng as further treatment is medically indicated without
9'V'?9 the Pat'ent reaso?abla assistance and sufficient opportunS to make
alternative arrangements for care.
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Right to freedom of choice
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j/ Jb7 pa-ieT aas the right to choose freely and change his/her physician and
prtate ofpSc sJcte8 lnstrtlJt,on ■ regardless of whether they are based in the
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b. The patient has the right to ask for the opinion of another physician at any
stage.
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Right to self-determination
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right to self-determination, to make free decisions
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ripaTT/3bon ne(/'ssary t0 make his/her decisions. The patient should understand
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Of mldicin?.ient haS the ri9ht t0 refUSe t0 ParticiPate in research or the teaching
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The unconscious patient
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P°SS“>le' *Om a le9a"y en“lad
k . „ni,!?sally ?nJtled representative is not available, but a medical intervention
Tn,ly - e°ded- consenl 0'the Patie« may be presumed unless It is obvious
™™ TOn.d>,aTy TT” on ,f,e basis °f ,ha palienfs pre™ut Trm explession of
conviction that he/she would refuse consent to the inteivention in that situation.
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the patient mnct6^re'Seniatl^e-' wbere legally relevant, is required. Nevertheless
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the le9a^y incompetent patient can make rational decisions hk/hOr
decisions must be respected, and he/she has the right to forbid the disciosnZPnf
information to his/her legally entitled representative.
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J?’ ;’t *h,e pa*iei?t,s Iegal|y entitled representative, or a person authorizArf hv tho
patient forbids treatment which is, in the opinion of the physician in the^natiAnt1!
best interest, the physician should challenge this decision> iri thS relevanS^^nr
?nteerestSt Utl°n’ 0 CaSe °f emer9encV'lhe Physician will act in the patient^beTt
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Procedures against the patient's will
Diagnostic procedures or treatment against the patient's will can be osrripH m.t
SPKifi^'y Permi,te5 by
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Right to information
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health status0 mcL^dfngerth^em^icafOfactsaaboutbhisU/hernc°orndef
h''S/her
confidential information in the patient's records about a third part?'shou7d°no/he
given to the patient without the consent of that third party.
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not be
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Right to confidentiality
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All identifiable information about a patient's health
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ldentlfiab.1 e Patient data must be protected. The protection of the data
Right to Health Education
The education should include imormation Jhnnt 1 ith3’
Ie.h.eaith services.
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Right to dignity
a. The patient's dignity and right to privacy shall be resoected At ah tfmo
meoical care and teaching, as shall his/her culture and values
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c. The patient is entitled to humane terminal rarp pnH
available assistance in making dying as dignified and comfortable as possible. a"
11.
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Right to religious assistance
The patient has the right to receive or to decline soiritual pnH m^roi
including the help of a minister of his/her chosen religion.
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comfort
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