institutional conflicts of interest: protecting human subjects, scientific integrity, and...

Institutional Conflicts Of Interest: Protecting Human Subjects, Scientific Integrity, And Institutional Accountability Gordon DuVal

If clinical trials become a commercial venture in which self-interest overrules public interest and desire overrules science, then the social contract which allows research on human subjects in return for medical advances is broken.1

Background n the past two decades, the involvement of non- academic sponsors of biomedical research, partic- I ularly clinical trial research, has increased expo-

nentially. The value of such sponsored research is difficult to ascertain. However, it is estimated that, between 1980 and 2003, overall research and development expenditures by US pharmaceutical companies increased from $2 billion to $33 billion2 and that, in 2001, clinical trial research expenditures in Canada totaled $800 million to $1 billion.3

The source of funding for biomedical research has shifted significantly from predominantly government and private foundations to industry. By 2002,70% of funding for clinical trials came from industry.4 These factors have affected the conduct of research, particularly clinical trial research, in a variety of ways. There has been a significant shift away from academic research centers to non-academic research organizations for the performance of clinical trials. There has also been a reduction in the free flow of research information as researchers, particularly those receiving funding from industry, are more likely to restrict communica- tions with their colleagues: and there has been a shift toward a more entrepreneurial ethos in academic research.

Legal provisions permit researchers and research institutions to hold patents on scientific discoveries, even if the funding for initial stages of such discoveries had come from government sources, such as the NIH or CIHR.6 The policy rationale for permitting researchers to exploit government funded research, and the reason why commercial involvement in research is encouraged, is to facilitate technology transfer from academic and research centers to the commercial marketplace in the belief that such transfer permits the public more efficiently to benefit from scientific advances. It is also hoped that biomedical research can be harnessed as an economic driver, creating jobs and stimulating economic activity. These policies have the effect of increasing independent sponsorship and partnership of research. Since outside sponsors and partners have, to varying degrees, interests that do not fully align with those of funding agencies and academic health centers,

Gordon DuVal is at the University of Toronto Joint Centre for Bioethics, Department of Psychiatry and Faculty of Law; Centre fordddiction and Mental Health.

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their increasing involvement in academic research has had the effect of creating or exacerbating the conflicts of interest experienced by researchers and academic institutions.

Public trust in universities and other academic research institutions, and indeed in the entire biomedical research endeavor, relies on the broad belief that science is conducted with intellectual integrity and independence. It is crucial that these virtues are protected in an environment that values intellectual freedom, the

their patients’ health, whether these interests are self- regarding (such as financial gain or reputation) or other regarding (for example, the health interests of other patients). Researchers have an obligation to the integrity of their research and to the protection of human subjects. IRB (in Canada, generally referred to as Re- search Ethics Board) members are charged with overseeing the design and conduct of human subjects research to protect subjects and encourage research integrity. Institutional managers, officers, directors and

Neither financial nor non-financial interests are illegitimate in themselves and indeed the pursuit of such rewards may encourage greater production

and discovery. However, all of these interests may also have the effect of skewing the proper exercise of judgment.

unfettered exchange of information and ideas, and the pursuit of research ultimately for the public good. Out- side involvement in the sponsorship and funding of biomedical research threatens to blur the line between these research ideals and corporate or other funder interests, and to compromise the prompt dissemination of scientific knowledge.’ Van der Weyden asks, “Can [Universities and health care institutions] effectively oversee their investigators when both institutions and their investigators share parallel aspirations in acquir- ing industry funding, equity or royalties?”s

What is a Conjict of Interest? In his 1993 article on conflict of interest, Dennis Thompson defined conflict of interest as “... a set of conditions in which professional judgment concerning a primary interest (such as a patient’s welfare or the validity of research) tends to be unduly influenced by a secondary interest (such as financial gain).“9 The primary aims of conflict of interest rules are to ensure the integrity of professional or fiduciary judgment, to promote public confidence in professional judgment, and to minimize the conditions under which reasonable people may believe that judgment or decision-making has been improperly influenced, whether it has or not.’O

Physicians, researchers, institutional decision-makers, and others have professional and role-based obligations, commonly characterized as fiduciary or quasi- fiduciary in nature. Decision-making and judgment are entrusted to the fiduciary to be exercised for the benefit of others, not for personal benefit. For this reason, the exercise of professional or fiduciary judgment has a natural ethical priority over personal interests. For example, physicians and other clinicians have an obligation not to permit personal interests to compromise

other persons making decisions on behalf of a hospital or university are obliged to exercise judgment in the best interests of the institution, and its legitimate mis- sion and goals.

The specific interests and obligations of academic or healthcare research institutions include a commitment to advancing scientific knowledge, to protecting the safety of patients and research subjects under their care, to academic freedom, to open and timely dissemination of knowledge, to quality education, and to safe- guarding the integrity of research and teaching. The overarching goal of scientific progress should ultimately be to advance individuals’ health and well-being.” The public expects its universities and leading health science institutions to protect the larger public interest in the integrity of scientific research and its dedication to broad social benefit, not merely to enhance its own welfare. This paper addresses both financial and non-financial

institutional conflicts of interest. Financial interests include institutional or individual ownership of shares or other equity interests, and the right or opportunity to receive money or other things of value. Non-financial conflicts of interest also create powerful incentives that may affect appropriate decision-making by institutions, and institutional decision-makers.12 An institution may be strongly motivated to develop a strong research program, either generally or in a particular area. It may have an interest in attracting and retaining excellent scholars and scientists into its research program, to be the origin of numerous publications in prestigious jour- nals, and to be the recipient of large amounts of grant funding.

Neither financial nor non-financial interests are illegitimate in themselves and indeed the pursuit of such

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rewards may encourage greater production and discovery. However, all of these interests may also have the effect of skewing the proper exercise ofjudgment. Sec- ondary interests of whatever character can provide an incentive to act or make decisions at variance with primary professional, institutional or fiduciary obligations. Nevertheless, financial interests have a particular power. Money is a powerful motivator and professional judgment swayed by financial considerations is most alarming to the broad public. Further, the motivations of prestige and academic excellence are well-known and more or less shared by those in academia. However, an individual’s or institution’s undisclosed financial interests are typically less apparent to outside observers, and may give rise to greater mistrust.

Conflict of interest, then, is conceived as a state of affairs in which the performance of the primary obligation is, or is perceived to be, in conflict with the satis- faction of secondary interests. Conflict of interest rules seek to prevent secondary factors from dominating or appearing to dominate the relevant primary obligations to exercise judgement appropriately based on professional, fiduciary, or organizational considerations. The existence of a conflict of interest does not in itself indicate wrongdoing or unprofessional behaviour. Con- flict of interest regulation assumes only that it is often difficult or impossible for others to distinguish cases in which personal interests give rise to improper influence, from those in which it does not.13

Institutional Conflicts of Interest The American Association of Medical Colleges (AAMC) Task Force, in its 2002 Report on institutional conflict of interest in research, characterized institutional conflicts of interest as follows: ‘‘An institution may have a conflict of interest in human subject research whenever the financial interests of the institution, or of an institutional official acting within his or her authority, might affect - or reasonably appear to affect - institutional processes for the conduct, review, or oversight of human subject research.”*4 The concern is that institutional conflicts may compromise, or appear to compromise, the institution’s review, approval, or monitoring of research studies or the institution’s allocation of resources or facilities for use in research. Institutional conflicts of interest may be held by the institution itself, or through its officials or managers having relevant personal interests.15 For the purposes of this paper, institutional conflicts of interest will include also individual conflicts of those exercising decision-making authority on behalf of the institution, including IRB members.I6

Values Threatened by Institutional Conflicts of Interest O v e w i m Research is sponsored by a variety of organizations aside from commercial pharmaceutical and biotechnology companies. These include government and private granting agencies, foundations, non-governmental organizations, and others. Non-commercial sponsors also have mandates and agendas that may conflict with the obligations of scientific integrity or excellence. Whatever the source of funding, to the extent that universities and other research institutions rely upon outside sponsors to fund research activities, and particularly where such outside sponsors play a primary role in the design, methodology, and statistical analysis of research, academic and scientific interests are likely to come into conflict with the interests and agendas of funders.

Recent academic discussion however has focused primarily on the commercial motivation of industrial sponsors. While the interests of other research funders also may give rise to conflicts, the financial motivation of industrial sponsors is the most far-reaching and poses the greatest threat to scientific integrity and the protection of human subjects. The extent of commercially motivated clinical trial research funding and activity is much greater than that undertaken by governments, foundations and other non-commercial research funders. Further, industry sponsors are primarily concerned with research that promotes the development and marketing of new medications and devices, and this research generally poses the greatest risks to subjects and has the greatest potential to affect the safety of patients and the overall social cost of health care. In principle however, many of the conflicts iden- tified in this paper may also arise from the interests and agendas of other kinds of research sponsors.

The focus on commercial research funders, primarily pharmaceutical and biotechnology companies, does not imply that such companies, or the people that manage and work at these companies, are ill-intentioned. It is only to point out that the primary interests of commercial funders of research can be significantly at odds with the social goals of scientific research. To the extent that circumstances align the interests of institutions and institutional decision makers with those of the sponsors of research, those institutional interests may likewise conflict with the ideals of scientific advance and human subject protection. It is significant also to note that the advance of science may also at times conflict with the protection of human subjects. Sometimes the most efficient way to answer an important scientific question involves methods that are simply too risky or disrespectful to human subjects. Financial and non-fi-

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nancial interests however can threaten either or both of scientific integrity and human subjects. As sponsored research activity increases, the conflict

between the interests of institutions and research sponsors and the scientific interest in the unbiased advance of biomedical knowledge is becoming increasingly acute. The most pressing concern is that the profit- driven ambitions of industry, and the conflicting interests of other classes of research sponsors, may inap- propriately affect the clinical research environment and threaten to compromise the protection of human subjects and the scientific integrity of clinical trial research. Clinical trials, which may include research sites in a number of countries, can be a valuable source of scientific knowledge. Protecting the quality and integrity of this research is of paramount importance. However, the recent history of commercially motivated and industry-sponsored research gives ample reason to be concerned that important elements of research integrity are not being assured. Academic health science centers have not been immune to these forces?’ In con- trast to the scientific paradigm of disinterested pursuit of knowledge, commercial sponsors of biomedical research have a powerful financial interest in the success of the research.18 In particular, the sponsor seeks a positive outcome from the study, at acceptable cost, and to protect its intellectual property in the subject matter of the research?9 In themselves, these objectives are neither surprising nor objectionable. Pharmaceutical and biotechnology companies exist to maximize value to shareholders, and indeed it is their primary legal obligation to do so. Developing new medications can be an expensive and risky venture, and undoubtedly drug development is a key component of our advancing re- sponse to illness and disability. This is also not to say that pharmaceutical and biotechnology companies are necessarily indifferent to the integrity of research or the protection of human subjects. It is simplyto say that the profit motive often conflicts with these values and supplies an incentive to make decisions at odds with them.

To the extent that an institution, or an institutional official, has a financial interest in the outcome or findings of research, their interests are substantially aligned with those of the industry sponsor, and those interests are sometimes incongruent with the relevant primary obligation. Similarly, when any of these parties receives benefits from the industry sponsor, particularly if it is hoped that such benefits will continue, the worry is that decisions will be affected by feelings of gratitude, goodwill, or a desire to please, or not to displease, the industry sponsor.20

An institution may benefit in a variety of ways when its investigators undertake sponsored research. Spon-

sors commonly pay overhead to institutions, typically to their research programs, and such sums can be substantial. This money helps to defray the overhead costs of maintaining the physical space used in the research, and everyday expenses consumed in the conduct of the research that are not directly accounted for in the study budget. These amounts, however, also support other research activities of the institution, including research that is of scientific interest but does not have commercial potential. Payments by commercial sponsors may be an important source of revenue for the university or academic health center research program. In addition to overhead payments, research institutions are commonly compensated for performing research on a per- subject, or per-procedure basis. By operating efficiently, research institutions can show a surplus and return leftover funds to either the researcher’s or the department’s research budget. These excess funds can be used to fund or expand other research programs. Institu- tions may also have an equity interest (e.g. stock or options) in a corporate sponsor of research being conducted at the institution.21 Where such equity interest is of significant value, and particularly where the interest is in a non-publicly traded sponsor, the concern is heightened.

Institutions can benefit in other ways from the conduct of research, especially if it is successful. They may be entitled to receive royalties from the sale or license of technologies developed by their researchers22 or own shares in start-up companies established to finance the development of such research. Institutions and key researchers will commonly take an equity position in the start up company and benefit from the success of the venture, which in turn depends on the success of the research. Universities and hospitals may accept cash com- pensation for granting industry partners a first right of refusal to develop and market its discoveries.23 Aca- demic research institutions may also enter into part- nerships with drug companies to set up research centers and teaching pr0grams.2~ In some cases, institutions may develop their own products for marketing and sale. Institutions may also be the beneficia- ries of grants or donations from pharmaceutical or biotechnology companies that sponsor research or may be the recipients of donations or endowments from potential commercial sponsors of human subjects research,% and funding for drug development programs and educational activities.

Deans, chairs, department heads, trustees and other senior officers of universities and health research institutions are charged with making decisions in the best interests of the institution. Personal interests and financial holdings may give rise to conflicts with these institutional responsibilities. Senior management per-


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sonnel and key researchers may be appointed as officers or directors of start-up companies in which the institution maintains an ongoing equity interest and may receive remuneration, stock or stock options in com- pensation. Under such arrangements, institutional personnel may have a conflict arising not only from their personal financial interests, but also from their fiduciary obligations as directors or officers of the start-up company, which may be at odds with obligations owed to the institution itself.

Institutional Review Board (or Research Ethics Board) members also exercise authority on behalf of the institution in the review of proposed research involving human subjects. These individuals may also have financial ties to industry sponsors of research undertaken at their institution. They may own stock in drug or device manufacturing companies, have an interest in royalty payments derived from industry products tested or developed at the institution, participate in clinical trials, or otherwise receive industry support for their research.26 In a study published in 2003, Campbell et al surveyed 2,989 faculty members from 121 U.S. medical schools. Of those who served on IRBs during the pre- vious three years, 71% had conducted clinical research and 47% had served as paid consultants to industry.27

Institutional conflicts, which include conflicts of institutional officials and IRB members overseeing sponsored research, threaten appropriate decision-making with respect to the conduct of research in a variety of ways. If the success of the proposed research would benefit either the institution or a responsible official, then decision-making about the research may be improperly influenced. An institutional decision maker may, subtly or otherwise, encourage or permit research that fails to meet standards of research validity or integrity, or that threatens the safety or respectfid treatment of human subjects. They may pressure the IRB to approve deficient studies or to attach less onerous conditions. They may preferentially allocate institutional resources, such as funding, equipment, personnel, or lab space to industry sponsored or potentially commercially viable projects. Through its officials, the institution may exert pressure to delay publication or otherwise restrict the communication of findings that are unhelpful to its financial position.28 I R B members may be less skeptical and more inclined to approve such research, or to monitor its progress less rigorously. They may be more hesitant to suspend or terminate a study knowing that its continuation is of benefit to the institution or to the member him or herself.29

These conflicts, and the pressures that may arise from inappropriate managerial or professional decision- making by the institution and those acting on its behalf, threaten the integrity of the research agenda broadly,

the integrity of the conduct of particular research projects, and the protection of human subjects. Again, it is not argued that such misconduct would occur frequently, and certainly at most rarely would it occur consciously. Nevertheless maintaining public trust and scientific integrity requires that relationships be closely monitored. To the extent that institutions and institutional officials feel obliged to sponsors, or have interests aligned with those of sponsors, such as an interest in the research showing positive results, the risk that decision-making may be affected must be taken seriously.

l3reats to the Institutional Research Agenda Commercial pharmaceutical and biotechnology companies dominate the development and marketing of new drugs and devices. With only modest exceptions, governments are unwilling or unable to commit the necessary resources to develop, test and market new drugs. While drug companies are adept at responding to market demands for new pharmaceutical products, development focuses on those drugs and devices for which there is a market, or for which a market can be created, not necessarily those drugs for which there is the greatest need. Sometimes there is an satisfactory market for what is most needed, but not always. Drug development resources may be steered away from illnesses and conditions whose sufferers can ill afford to purchase these products.30 For example, orphan dis- eases and those that persist primarily in less-developed countries, with populations that have limited ability to pay for new drugs, tend to be neglected. On the other hand, pharmaceutical companies have spent enormous resources developing cosmetic, or so-called “me-too” drugs, for common conditions and illnesses, that offer little or no benefit when compared with existing drugs marketed by competitors.3’

Undertaking privately sponsored clinical trials can be of significant benefit to research institutions and researchers. So, institutions may be hesitant to refuse the offer of research funding or the terms under which it is offered. While payments to institutions by industrial sponsors may have positive benefits, they may also have the effect of skewing the institutional research agenda by providing an incentive to focus its resources, and the talents of its researchers, on studies with commercial applications, and away from other important research avenues. The amount of funding accepted for industry research may also affect public perceptions of conflict within the institution.

Threats to Trainees Emanuel and Steiner worry that graduate students and post-doctoral fellows “might be encouraged to conduct


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Emanuel and Steiner worry that graduate students and research in which the institution has a financial interest even if that research was not the most post-doctoral fellows “might be encouraged to conduct beneficial tothe person’s educa- research in which the institution has a financial interest

even if that research was not the most beneficial to the tion or career development.”32 The research opportunities af- fordedto students and junior re- person’s education or career development.’’ - searchers may be limited in an environment where there is a strong focus on commercial viability. Graduate students and fellows should not participate in research projects that involve requirements that would constrain the right to publish or communicate freely, or with conditions attached that would compromise the opportunity to promptly finalize degree requirements.

Threats to Human Subjects Protection Financial and non-financial interests can affect the way clinical research is undertaken by creating incentives for institutions that are adverse to the interests of subjects or that create additional risks for them. Recruit- ing appropriate subjects can be a major concern for the sponsors of clinical trials, particularly where large numbers are required. Depending upon the nature of the study, and the size of the disease group, recruitment can be an on-going challenge. To establish efficacy and safety of experimental new drugs, clinical trials commonly are large, and conducted at multiple sites to recruit enough subjects to ensure statistical validity. In- dustry sponsors of research may be under intense pressure to recruit and complete clinical trials quickly. In part, this is because delays increase the cost of conducting funded trials. Further, patents on new investigational drugs have a fixed period (typically 20 years), commencing upon registration of the patent. Since patents are generally filed prior to starting clinical test- ing, the patent period continues to run while clinical trials are proceeding. Once the patent expires, other drug manufacturers are at liberty to copy the drug and sell it at a lower price. So, the faster the clinical trials can be finished, the longer will be the period during which the original patent holder can market the drug exclusively, and at premium prices.

For these reasons, the industrial sponsor may put considerable pressure, and provide considerable incentives, for clinical trial sites to recruit quickly. Com- pensation for conducting trials is typically calculated on a per-subject basis, and sites with low recruitment may be terminated. So-called “competitive recruitment” provisions may provide incentives for clinical sites to recruit quickly. Cash bonuses may be paid for subject accrual above set recruitment thresholds and institutions and investigators may be paid a higher per-subject amount for subjects recruited above that threshold.

These techniques can create powerful incentives for institutions and individuals to ensure that accrual goals are met or exceeded.33 The difficulty is that they may also create incentives to recruit inappropriate subjects,3* recruit in ethically inappropriate ways, or steer available research subjects toward commercial research, depriving other research projects of sufficient enrolment.

This was the situation in the Gelsinger case where the academic institution, the University of Pennsylvania, itself held shares in Genovo, the biotechnology firm sponsoring the research. A detailed description of the Gelsinger case is instructive as the structure of the university’s involvement in Genovo’s research is not un- common. In that case, Dr. James Wilson was a promi- nent researcher at the University of Pennsylvania Medical Center. In 1992 he founded Genovo, a private biotech start-up company. In 1995, the University of Pennsylvania struck a deal with Genovo, that in return for a $2.8 million per year investment in Penn, it would have exclusive rights to commercialize any gene therapy discoveries made in Dr. Wilson’s lab. Both Wilson (30%) and the University (3.2%) became shareholders of Genovo and stood to profit should any of its research be developed into commercially viable technology. Wil- son was interested in the use of gene therapy techniques in the treatment of disorders including OTCD, a rare genetic metabolic disorder, using an adenovirus. Jesse Gelsinger, an 18-year-old student, with a mild form of OTCD, was recruited into the study. In 1999, Jesse was brought to the Penn Medical Center and infused with the experimental virus. During the days following his treatment on the study, Gelsinger’s condition steadily deteriorated and he died four days after the infusion. A subsequent investigation by the Food and Drug Ad- ministration found numerous breaches of federal research rules, including failing to advise Gelsinger of known risks, and exaggerating the potential benefits of study participation. Further, at the time he was given the experimental virus, Gelsinger’s blood ammonia lev- els were too high to meet inclusion criteria.35 In 2000, Targeted Genetics Corp. acquired Genovo. In the takeover, Wilson reportedly earned $13.5 million in Targeted Genetics stock and Penn $1.4 million. Had the research been more successful, it may be predicted that


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the profits would have been higher, perhaps substantially so. While it is unclear whether the potential for profit, either by the University or by Wilson, motivated any of the reported research lapses, or whether Gelsinger would have died anyway, the existence of the profit potential, tied substantially to the success of the research, is extraordinarily worrying.

Obtaining valid informed consent to research participation is a core requirement of ethical research and respect for human subjects. Valid informed consent requires adequate information, a capable subject, and agreement to participate that is voluntary and free of coercion and undue inducement.36 The existence of an institutional conflict, and the imperative to recruit quickly and show positive results, may create subtle or overt pressures on employed or affiliated researchers to misrepresent the true nature of the trial, neglect a description of alternatives to research, underestimate risks or overstate benefits of research participation. Conflict may cause a researcher to be insufficiently cautious in assessing the decision-making capacity of a prospective research subject or cause researchers to exert subtle pressures to help ensure that the prospective subject gives consent. Researchers may also be tempted to include subjects that are inappropriate for the study, either because of inclusion or exclusion criteria, or simply because it is clinically unwise for them to participate. In the on-going conduct of the study, because of these institutional pressures, researchers may fail to report adverse events as required, ensure that the protocol is strictly followed, or fail to disclose new information that may be relevant to the subjects’ decision to continue.37

A further worry is that subtle or overt institutional pressures may lead Institutional Review Boards to approve research activities in which the institution has a financial stake or may be insufficiently rigorous in their review of such protocols.38 In discharging its obligation to monitor the ongoing conduct of research, and terminate research for safety reasons or significant misconduct, the IRB may be less willing to act in appropriate circumstances.39

Threats to Research Integrity In 2002, Davidoff wrote:

The primary motivation behind the pharmaceutical industry’s support of clinical research is, under- standably, to meet regulatory requirements; the discovery of scientific fact is only a part of its agenda. But, importantly, research pointing to a drug’s efficacy and safety is also used for marketing purposes, and the driving force behind marketing is persuasion rather than objectivity. For both of these reasons, commercial influence is inevitably one

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potential source of bias in clinical research.40 As Bodenheimer has shown, researchers with ties to

industry are more likely to report results favorable to the products of those companies than researchers without such ties. Other reviews have shown similar re- s u l t ~ . ~ ~ Multicenter clinical trial research raises particular worries about scientific accountability. The principal investigator carrying on research at a single site must meet certain standards of research practice. He or she is obliged to ensure that there is an important research question, sound methodology, thorough and objective analysis of the data and that findings are reported fairly and disseminated to the scientific community at large. These are obligations also of the institution hosting the study and of those responsible decision-makers exercising the authority of the institution. In multicenter, industry-sponsored clinical trials, these obligations are no less important, but it is less clear how they are maintained. Overt or subtle pressures may be felt that affect the integrity of research in the formulation of the research question and methodology, that is, bias may be introduced.42 With respect to these issues, conflicting interests may compromise the judgment of institutions, institutional decision makers, and IRB members, as well as individual investigators.

In clinical trials, sponsors often employ their own staff to design the trial protocol, which is subsequently carried on at academic or hospital research centers, or in the community. This may be problematic since the company has an inherent interest in designing a trial that will have the greatest likelihood of a positive result for their investigational drug, in order to establish a competitive advantage over its rivals. Sponsoring companies have in past employed a variety of methods to influence aspects of the trial design in order to make it more likely that research yields desired results.w A trial may be designed to answer a sub-optimal research question or one that is too narrowly focused and does not provide relevant information.

Even assuming a scientifically important and appropriately framed research question, the methodology employed may introduce bias in study findings in a number of ways. The subject population to be used in the study may not be representative of the patient group likely to receive the drug.& For example, older subjects tend to be included less frequently as research subjects, presumably because of their lower health status as a group. Rochon et al demonstrated that although the el- derly population is a frequent user of non-steroidal anti-inflammatory drugs (NSAIDs) for musculoskele- tal problems, only 2.1% of subjects used in NSAID research were over age 65. The effectiveness of experimental drugs may be exaggerated if conclusions are

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based on data drawn from a healthier population.M The use of inappropriate comparator drugs:6 inappropriate dosing:’ inappropriate measurement scales:e selecting major endpoints post h o ~ , ~ 9 reporting results selec- tively,50 and a range of other techniques may also be employed.51

Further, industry sponsored trials may measure for numerous outcomes and endpoints, but only publish those indicating positive outcomes. Lauritsen et a1 de- scribe a case in which favorable data from a single site was published separately, while more ambivalent data from others was suppressed.52 Surrogate endpoints may be measured that are at best weak predictors of the relevant health outcome.53 Manipulating endpoints and outcomes measured in a clinical trial can result in the appearance that the sponsor’s product is superior to others, when a more cautious conclusion is warranted. In these situations, and myriad others, trial design and methodology can compromise the quality and integrity of research.

Institutions, institutional decision-makers, IRBs, and the researchers they oversee all have responsibility to ensure that research conducted within their walls con- forms to strict standards of scientific integrity. Even assuming that most sponsored clinical trials do not suf- fer from methodological and design flaws, it is incum- bent on the institution to ensure that inappropriate influences do not affect the research carried out under its authority. Institutions and institutional decision-makers with conflicting interests may be insufficiently at- tentive to these matters.

Access to Data The analysis of data in industry-sponsored studies is of particular concern. In multicenter trials, data is commonly retained by the sponsor, who oversees its analysis and interpretation. Problems can arise when clinical data is not released to the investigators for independent analysis and publication. In their 2000 publication of a clinical trial evaluating an HIV immunogen, Khan et al report that because of a disagree- ment between the study team and the commercial sponsor, the sponsor withheld a significant portion of the collected data and refused to disclose the full list of site co-investigators participating in the multicenter trial. The sponsor’s proprietary immunogen failed to show better effect than placebo.54

In order to ensure the integrity of the analysis, investigators independent of the commercial or other interests of the sponsor should analyze and interpret study results. In doing so, it is crucial that investigators, or at least a committee of investigators, have access to all the data from all study sites to ensure a scientifically valid statistical analysis. If institutions or institutional

decision-makers are too reliant on sponsored research, or themselves have an interest in positive research results, they may fail to ensure proper access to study data.

Suppressing Results and Restricting Publication A key requirement of ethical research is that it be scientifically important; that is, the research has social value by seeking to answer an important question. Re- searchers should not squander resources or expose research subjects to risks and inconvenience by pursuing questions without social value. By failing to report research findings in a fair and scientifically valid way, or by not reporting such findings at all, the researcher or research sponsor undermines the social value of the research. Scarce research funds are wasted, and more importantly, research subjects are exposed to the risks and inconveniences of research without a reasonable possibility of corresponding scientific advance - the social value of the study is lost and the subject is be- tra~ed.~5 As discussed earlier, industry and other sponsors of

research, including clinical trials, may have interests in the outcome and findings of research at odds with the disinterested pursuit of objective scientific knowledge. Pharmaceutical and biotechnology companies are ultimately interested in profit and to maximize shareholder value. Government departments, foundations, voluntary and other non-governmental organizations may not be concerned with turning a profit, but may have goals or interests of other kinds. While government granting agencies and most foundation or other non- government funders do not impose publication restrictions or require prior review of manuscripts, provincial and federal government departments con- tracting for research may seek to impose such conditions due to potential political sensitivity, intellectual property concerns of partner organizations, or for other reasons relating to their particular mandate and agenda. All these factors can affect the dissemination of research findings if the institution, or institutional officials, seek to maintain a beneficial relationship with the sponsor, or have interests aligned with those of the research sponsor.

Sponsors have sought to restrict the investigators’ freedom to communicate findings and publish manuscripts reporting results. They may do so for a number of reasons: to protect their intellectual property in the therapy being tested, to keep negative findings from becoming widely known, and to control the dissemination of information to their benefit. However, the broad dissemination of research findings, both positive and negative, allows others to integrate evidence- based knowledge into clinical care, to subject findings


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to critical analysis, and to build upon findings to further advance scientific kn0wledge.~6 Clinical data must be widely available and subject to independent analysis and critique, ultimately for the benefit of patients.57 Suppressing reports of research findings skews the lit- erature and can result in clinicians making inappropriate treatment decisions - using either unsafe or less

~~

ment for iron overload in pediatric patients with tha- lassemia major. By 1996, Olivieri became concerned that the drug may worsen hepatic fibrosis (hardening of the liver). When advised of these concerns, the hospital’s Research Ethics Board (IRB) ordered that the informed consent form be amended to warn of these added safety concerns. When Apotex was sent a copy of

the revised consent form, it re-

effective medications or other treatment approaches.58 This is particularly true of clinical trials involving drugs and devices intended to be marketed.

In an analysis of 30 studies of drug-related research, Lexchin et al have shown that research funded by drug companies is less likely to be published than other studies.59 Similar findings have also been reported else- where.60 Chalmers concludes that large numbers of studies are never published at all, which he character- izes as scientific misconduct.m Institutional and individual interests in technology transfer also threaten the open sharing of new discoveries both to the public and within the scientific community. If a discovery or study finding has commercial potential, researchers may be hesitant to share relevant information with colleagues or the broader scientific community for fear that such commercial potential may be compromised or usurped.62

These worries are not idle.63 In a 1997 study, Blu- menthal et a1 found that 19.8% of a random sample of academic life scientists from major research institutions had delayed publication of findings for longer than six months at the request of the sponsor.64 In 1990, a group of researchers at the University of California at San Francisco completed a study funded by Boots Phar- maceuticals Inc. (after its takeover of the original sponsor, Flint Laboratories) comparing the efficacy of the sponsor’s synthetic thyroid, Synthroid, to three rival preparations. Both the sponsor and the researchers had expected to show that Synthroid was superior. However, the research found Synthroid to be no more effective than the others. Because of restrictions provided in the research agreement signed by the investigators, Boots was successful in blocking publication of this significant finding for almost seven years.65

In 1993, Dr. Nancy Olivieri, of the Hospital for Sick Children, which is affiliated with the University of Toronto, signed a contract with Apotex Research Inc. to undertake a study to evaluate deferiprone as a treat-

waslater reported by a panel appointed by the Canadian As-

sociation of University Teachers that the University was at the time in the process of negotiating a large dona- tion from A~otex.~’

What can be Done? Institutions Because academic research institutions can use excess resources derived from commercialization activities to meet other socially valuable research and clinical goals, it may not be appropriate to prohibit institutions from engaging in such activities, even though they may create financial conflicts. However, research institutions should establish administrative processes to assess and manage institutional conflicts. Cooperation between academic research institutions and outside sponsors should remain at arm’s length. The incentives of the marketplace create serious difficulties when they become integral to the culture of academic medicine.68

Openness and honesty are indicators of responsibility and integrity - characteristics that promote good quality research. Accordingly, financial conflicts of institutions and institutional decision-makers should be routinely disclosed, as should non-financial conflicts where they are not apparent. The obligation of disclosure should be clearly set forth in publicly available policies addressing institutional conflicts of interest. Policies should provide who is to make disclosures, of what, and to whom. Reports of conflicting institutional interests should be made to the IRB reviewing proposed research and disclosure should also be made in all publications resulting from the research.69 Subjects should be apprised of the source of funding and the institution’s financial interest in the research as a routine part of the informed consent process.70

Circumstances under which disclosure is inadequate should be plainly set forth, and policies should be re- viewed and updated at regular intervals to ensure that they remain suitable and responsive. Policies should

INTERNATIONAL AND COMPARATIVE HEALTH LAW AND ETHICS: A 25-Y&Ut RETROSPECTIVE WINTER 2004 621

SY M POSl U M

provide clear standards that define conflict of interest, identify relevant financial interests, establish criteria for disclosure, management, or elimination of conflicts, and provide clear and effective sanctions for viola- tions.71 In a 2000 study, Van McCrary et al concluded that there is substantial variation among conflict of interest policies at American medical schools and other research institutions and concluded that current standards may not be sufficient to maintain scientific integrity.72 Lo et al reached a similar conclusion based on a survey of large academic research centres.73

It may be helpful for institutions to establish com- mittees charged with reviewing and monitoring conflicts of interest.74 An Institutional Conflict of Interest Committee could oversee disclosure and other conflict management techniques and make conflict management decisions in difficult cases. Such committee should be composed of members with sufficient expertise, seniority and independence to provide effective and authoritative oversight in the management of institutional conflicts. Members of the COI Committee should be outside the line of authority for overseeing research within the institution.75 Such committee should also have community and other membership for trans- parency in its operation and decision-making. A committee of this kind could review conflicts of the institution and senior personnel making decisions on its behalf, and review and oversee business agreements relating to the institution’s financial stake in research and its commercial interests in the development of technology.

Where an institution stands to gain significantly, as a direct result of the outcome of research, it should consider carefully whether that research should be conducted within its walls.76 The integrity of the research and the protection of human subjects may be best pro- moted by having the research designed, conducted and evaluated by independent investigators at another institution or institutions.77 As shown by the Gelsinger case described earlier, public confidence may be pro- foundly affected if things go badly. The AAMC Task Force Report proposes a rebuttable presumption that such research should not take place within the institution.78 In extraordinary circumstances, for example, where the expertise to perform the study resides exclusively or primarily within that institution, it may be acceptable to conduct the research there. The decision to undertake such research should be made by an independent body, such as an Institutional COI Committee, and only after careful consideration of the scientific context, the extent and nature of the conflicting interests, how closely the interest is related to the research, the degree of risk that the research poses to human subjects, and the degree to which the interests in ques-

tion may be affected by the outcome of the research.79 Emanuel and Steiner make a similar recommendation, pointing to four considerations that must be addressed in order to justify such research within an institution: “The relation between an institution’s primary missions and its financial interest, the size of the financial interest, the degree of discretion involved in achieving the primary missions, and the seriousness of the harms that might result from the institutional conflict of interest.”80

However, even in such circumstances, special proce- dures should be developed to effectively manage such conflicts, including independent oversight of recruitment, informed consent, adverse events, data analysis, and reporting and publication of findings.81 These pro- cedures could also include inviting independent review of the research design, plan for statistical analysis, the development of research findings, and the preparation of the manuscript for publication. The institution could also invite an independent IRB to review the proposed protocol, including the balance of risks and benefits, plan for recruiting subjects, informed consent, treatment and reporting of adverse events and other matters relating to safety. An independent Data and Safety Monitoring Board, consent monitoring and independent review of decisions made by interested persons participating in research may also be of assistance.82

Institutions should erect effective “firewalls” between the overall management of investment activities and its academic and research affairs, possibly by using professional investment managers. The purpose of raising organizational barriers is to seek to prevent institutional financial considerations from influencing academic decisions. The AAMC Report also recommends that “...institutions should ensure that in practice, the functions and administrative responsibilities related to human subjects research are separate from those related to investment management and technology li- censing.”83 Universities and other health-care research institutions commonly have offices or departments de- voted to managing their intellectual property and commercial interests relating to technology transfer. It is important that these units are not under the direct control of institutional personnel primarily responsible for research, such as deans, chairs, or vice-presidents of research. Institutional policy should affirm that the welfare of human subjects and the integrity of research will not be compromised by competing institutional interests. At a minimum, institutions should ensure that those bodies responsible for the protection of human subjects and for setting the institutional research agenda are separated from the management of financial interests. In some circumstances however such separation will be insufficient to avoid the ap-


Gordon DuVal

pearance or the fact of improper influence. Policies relating to institution-related start-up companies should ensure a strict separation from research affairs. Insti- tutions may also wish to limit the proportion of ownership that it takes in any investment, including its share in a start-up or spin-off company, and place decisions relating to selling institutional investments in outside hands.

To help ensure that research is properly designed, that data is appropriately analyzed, and that findings are validly reported and published, institutions may consider requiring that multicenter clinical trials be placed under the authority of a Steering Committee comprised primarily of individual site investigators. Such Steering Committee would have the authority to review the study question, design and methodology, have access to all data, and be primarily responsible for reviewing data analysis, reporting findings and prepar- ing manuscript(s) for publication of the study.84 In addition, an adequately constituted and resourced Data and Safety Monitoring Board should be a routine part of most, if not all, clinical trials.85

Institutional Oficials Institutional officials should be required to disclose all relevant conflicts to a superior and recuse him or herself from decision-making, where this is possible. It may be necessary that very senior officials make disclosure and annual reports of personal interests to an audit or other sub-committee of the Board of lhstees or Board of Governors as the appropriate oversight authority. When a conflicting interest has a value greater than a minimum threshold, senior officials may be required to divest such interests. In such circumstances, the conflict may be too great to manage effectively and others may not realistically be in a position to police the behavior of senior officials. If a senior official is also a researcher involved in a study creating such conflict, that official should not undertake the research in question, and as discussed above, it is likely that research should not be undertaken within the institution at all. Other means of managing such conflicts may include submitting the matter to an appropriate institutional committee, such as an Institutional COI Committee, to ensure appropriately independent review and oversight of research undertaken or supervised by that official.86

A senior official may have divided loyalties by reason of being an officer or director also of a start up biotechnology company, in which the institution has an equity stake. Indeed, the institution may have appointed the official as its representative on the Board of Directors or to senior management. The official will have a fiduciary obligation to act in the best interests of both en- tities, and in law it may not be possible to prefer the in-

terests of the academic health-care institution while appropriately discharging his or her duties as an officer or director of the spin-off company. This creates a difficult situation. In such circumstances, legal advice should be sought and the oversight of an independent Conflict of Interest Committee may be invaluable both for effective management and to safeguard public trust and confidence.

IRBs and IRB Members IRB members may also have individual interests that affect their judgment in reviewing protocols and overseeing the conduct of research. These conflicts can be managed to some extent by ensuring that the IRB's reporting and funding relationships do not threaten its autonomy. For example, many institutions have trans- ferred reporting relationships and funding for its IRB from the research portfolio to some other institutional authority separate from the research office. In addition, it is helpful to ensure strong community membership, by experienced, independent persons having no interest in the outcome of the research or in the financial well-being of the institution. IRB members should be required to disclose, on an annual and ad hoc basis, their research activities and financial interests involving commercial sponsors and to disqualify themselves from deliberation and voting on protocols with which they have some involvement. The institution should develop clear policies with respect to disclosure and recusal of members, including the Chair, from de- liberating or voting on protocols for which there is a potential or actual financial or non-financial conflict of in- tere~t.~'

In order to ensure that there is no legal impediment to publication, or otherwise to conducting the study with integrity, the Institutional Review Board should review clinical trial agreements from sponsored clinical trials. In this way, the IRB can be satisfied that there are no unethical publication restrictions. At the same time, the IRB can satisfy itself about a number of other issues including the appropriateness of the budget, the adequacy of protection of confidentiality, and that the investigator is entitled to disclose sufficient information to subjects to obtain and maintain valid informed consent and to warn subjects, other site investigators, and IRBs of safety concerns.88

The institution should also establish educational programs on financial and other conflict of interest as part of their educational requirements for IRB members. Certainly these issues should form part of the initial ori- entation and education for new IRB members, and also be updated on a regular basis.89


SYMPOSIUM

Conclusion For individuals and for institutions, the opportunity to engage in research gives rise to important obligations and the public rightly expects that research will be carried out with integrity, for the broad social good, and in a way that adequately safeguards the rights and safety of the subjects enrolled. Conflicting financial and non- financial interests can compromise appropriate decision-making, and institutions and institutional decision-makers are also vulnerable. Vigilance is necessary to ensure that institutions, no less than individuals, meet the significant obligations they bear.

Acknowledgements This research was undertaken with the kind support of the Canadian Institutes for Health Research, Ottawa.

References 1. J. Quick, “Maintaining the Integrity ofthe Clinical Evidence Base,”

Bull World Health Organization 79, no.12 (2001): at 1093. 2. PhRMA, 2004 Pharmaceutical Industry Pro&, Washington DC:

Pharmaceutical Research and Manufacturers of America (2004). 3. M. Begin, J. Erola, G. Wells, J. Potworoski, AccelerathgAccess for

Patients to Best Medicine: The System and the Challenge (Ottawa: University of Ottawa, 2002).

4. T. Bodenheimer, “Uneasy Alliance - Clinical Investigators and the Pharmaceutical Industry,” New England JournalofMedicine 342, no. 20 (2000): 1539-1544.

5. D. Blumenthal, E. G. Campbell, M. S. Anderson, N. Causino, I<. S. Louis, Withholding Research Results in Academic Life Science: Evidence from a National Survey of Faculty,” Journal of thedmer- ican MedicalAssociation 277, n0.15 (1997): 1224-1228.

6. Bayh-Dole Act, 35 USC 200-212; (1980). 7. C. D. DeAngelis, “Conflict of Interest and the Public lhst,” Jour-

nal of the American Medical Association 284, no. 7 (2000): at 2237-2238; MAngell, “Is Academic Medicine For Sale?” New En- gland Journal ofMedicine 342, no. 20 (2000): 1516-1518.

8. M. B. Van Der Weyden, “Confronting Conflict of Interest in Re- search Organizations: Time for National Action,” Medical Journal ofAustralia 175, no. 8 (2001): 396-397.

9. D. F. Thompson, “Understanding Financial Conflicts of Interest,” New England Journal of Medicine 329, no. 8 (1993): 573-576.

10. See Thompson, supra note 9. 11. J. B. Martin, D. L. Kasper, “In Whose Best Interest? Breaching the

Academic-Industrial Wall,” New England Journal of Medicine 343, no. 22 (2000): 1646-1649.

12. N. G. Levinsky, “Nonfinancial Conflicts of Interest in Research,” New England J o u m l of Medicine 347, no. 10 (2002): 759-761.

13. See Thompson, supra note 9. 14. Task Force on Financial Conflicts of Interest in Clinical Research,

Protecting Subjects, Presedng W t , Promoting Progress 11: As- sociation of American Medical Colleges, ( M C : Washington, D.C., 2002).

15. Task Force on Research and Accountability, Report on Individuul and Institutional Financial CmJict oflnterest, Washington, DC: Association of American Universities (2001).

16. M. M. Johns, M. Barnes, P. S. Florencio, “Restoring Balance to In- dustry-Academia Relationships in an Era of Institutional Finan- cial Conflicts of Interest: Promoting Research While Maintaining ’hst,” Journal of the American Medical Association 289, no. 6 (2003): 741-746.-

17. E. Press, J.Washburn, “The Kept University,” Atlantic Monthly 285 (2000): at 39-54.

18. S. Lewis, P. Baird, R G. Evans, et al, “Dancingwith the Porcupine: Rules for Governingthe University-Industry Relationship,” Cana- dian Medical Association Journall65, no. 6 (2001): 783-785.

19. J. Collier, I. Iheanacho, “The Pharmaceutical Industry as an In-

20. See Angell, supra note 7. 21. OHRP, Financial Relationships in Clinical Research: Issues for

Institutions, Clinical Investigators, and IRBk to Consio!er when Dealing with Issues of Financial Interests and Human Subject Protection, Washington, D.C.: office of Human Research Protec- tions (2001).

formant,”lancet 360 no. 9343 (2002): 1405-1409.

22. See Martin, supra note 11. 23. See Press, supra note 17. 24. See Van Der Weyden, supra note 8. 25. See Task Force on Financial Conflicts, supra note 14 26. See Press, Washburn, supra note 17. 27. E. G. Campbell, J. S. Weissman, B. Clarridge, R Yucel, N. Causino,

D. Blumenthal, “Characteristics of Medical School Faculty Mem- bers Serving on Institutional Review Boards: Results of a National Survey,AcademicMedicine 78, no. 8, (2003): 831-836.

28. See Johns, Barnes, Floencio, supra note 16. 29. See OHRP, supra note 21. 30. M. N. Dukes, “Accountability of the Pharmaceutical Industry,”

Lancet 360, no. 9346 (2002): 1682-1684; B. Pecoul, P. Chirac, P. Trouiller, J. Pinel, Access to Essential Drugs in Poor Countries: a Lost Battle? Journal of theAmerican MedicalAssociation 281, no.

31. M. Angell, A. S. Relman, “Prescription for Profit,” Washington Post, June 20,2001, at A27.

32. E. J. Emanuel, D. Teiner, “Institutional Conflict of Interest,” New England JournalofMedicine 332, no. 4 (1995): 262-267.

33. D. Shalala, “Protecting Research Subjects-What Must Be Done,” New England Journal of Medicine 343, no.ll(2000): 808-810.

34. See Martin, supra note 11. 35. Warning Letter from FDA, Center for Biologics Evaluation and

Research to Dr. James Wilson, dated March 3,2000, accessed at http: //www.fda.gov/foi/warning-letters/m3435n.pdf on No- vember 5,2004.

4 (1999): 361-367.

36. See Shalala, supra note 33. 37. See Johns, Barnes, Floencio, supra note 16. 38. See OHRP, supra note 21. 39. See Johns, Barnes, Floencio, supra note 16. 40. F. Davidoff, “Between the Lines: Navigating the Uncharted Ter-

ritory of Industry- Sponsored Research. A Former Medical Jour- nal Editor Describes How and Why Staff Changed Their Policy on Disclosing Conflicts of Interest,” HealthAfairs (Millwood) 21, no. 2 (2002): 235-242.

41. R A. Davidson, “Source of Funding and Outcome of Clinical M- ds,” Journal of GeneralInternalMedicine 1, no. 3 (l986): 155-158: M. Friedberg, B. S&an, T. J. Stinson, W. Nelson, C. L. Bennett, “Evaluation of Conflict of Interest in Economic Analyses of New Drugs Used in Oncology,” Journal of the A d c a n MedicalAsso- ciation 282, no. 15 (1999): 1453-1457; J. Lexchin, L. A. Bero, B. Djulbegovic, 0. Clark, “Pharmaceutical Industry Sponsorship and Research Outcome and Quality: Systematic Review,” British Med- ical Journal 326, no. 7400 (2003): 1167-1170; M. K. Cho, L. A. Bero, “The Quality of Drug Studies Published in Symposium Pro- ceedings,”AnnulsofInternalMedicim124, no. 5 (1996): 485-489; M. Bhandari, J.W. Busse, D. Jackowski, et al, “Association between Industry Funding and Statistically Significant Pro-Indus- try Findings in Medical and Surgical Randomized Mals,” Cana- dian MedicalAssociation Journal 170, no. 4 (2004): 477-480.

42. L. A, Bero, Rennie D. Influences on the Quality of Published Drug Studies, International Journal of Technob~Assessment in Health Care 12, no.2 (1996): 209-237.

43. See Bero, supra note 42. 44. D. J. Safer, “Design and Reporting Modifications in Industry-

Sponsored Comparative Psychopharmacology Mals,” Journal of Nmoua andMentalLXsease 190, no. 9 (2002): 583-592.

45. P. A. Rochon, J. H. Gunvitz, R. W. Simms, et al, “A Study of Man- ufacturer-Supported Mals of Nonsteroidal Anti-Inflammatory Drugs in the lkeatment of Arthritis,” Archives of Internal Medi- cine 154, no. 2 (1994): 157-163.

46. J.S. Montaner, M. V. OShaughnessy, M. T. Schechter, “Industry- Sponsored Clinical Research: a Double-Edged Sword,” Lancet


Gordon DuVal

358, no. 9296 (2001): 1893-1895. 47. W. A. Ray, M. R. Griffin, J. Avorn, “Evaluating Drugs after their

Approval for Clinical Use,” New England Journal of Medicine 329, no. 27 (1993): 2029-2032; see Rochon, Gurwitz, and Simms, supra note 45

48. M. Marshall, A. Lockwood, C. Bradley, C. Adams, C. Joy, M. Fen- ton, “Unpublished Rating Scales: a Major Source of Bias in Ran- domized Controlled Trials oflleatments for Schizophrenia,” Brit- ish Journal ofpsychiatry 176 (2000): 249-252.

49. W. Carpenter, “Industry Phase IVMals are of Little or No Value: Pro,” Journal ofPsychotic Disorders 5, no. 4 (2001): at 3 and 13.

50. M. H. Mvedi, A. J. Rush, T. J. Carmody, et al, “Do Bupropion SR and Sertraline Differ in their Effects on Anxiety in Depressed Pa- tients?” Journalof ClinicalPsychiatry 62, no. 10 (2001): 776-781; W. T. Carpenter, Jr. “From clinical trial to prescription,”Archives of General Psychiatry 59, no. 3 (2002): 282-285.

51. See Safer, supra note 44. 52. K. Lauritsen, T. Havelund, L. S. Laursen, J. Rask-Madsen, ”with-

holding Unfavorable Results in Drug Company Sponsored Clin- ical Mals,” Lancet 1, no. 8541(1987): at 1091.

53. See Ray, Griffin, supra note 47; B. M. Psaty, N. S. Weiss, C. D, Furberg, et al, “Surrogate End Points, Health Outcomes, and the Drug-Approval Process for the lleatment of Risk Factors for Car- diovascular Disease,” Journal of theAmerican MediculAssociatiOn 282, no. 8 (1999): 786-790.

54. J. 0. Kahn, D. W. Cherng, K. Mayer, H. Murray, S. Lagakos, “Eval- uation of HIV-1 Immunogen, an Immunologic Modifier, Admin- istered to Patients Infectedwith HIV Having300 to 549 x 10(6)/L CD4 Cell Counts: A randomized Controlled Mal,” J o u m l of the American Medical Association 284, no.17 (2000): 2193-2202.

55. E. J. Emanuel, D. Wendler, C. Grady, “what Makes Clinical Re- search Ethical?” Journal of the American Medical Association 283, no. 20 (2000): 2701-2711.

56. Editorial, “A Duty to Publish,” NatureMedicine (1998); 4(10): at 1089; A.J. Munro, “Publishing the Findings of Clinical Research,” British Medical Journal 307, no. 6915 (1993): 1340-1341.

57. S. A. Rosenberg, “Secrecy in Medical Research,” New England Journal of Medicine 334, no. 6 (1996): 392-394; S. Nadis, “US Concern Grows Over Secrecy Clauses,” Nature 398, no.6726 (1999): at 359.

58. I. Chalmers, “Underreporting Research is Scientific Misconduct,” Journal of theAmerican MedicalAssociation 263, no. 10 (1990): 1405-1408.

59. See Lexchin, supra note 41. 60. D. Rennie, “Thyroid storm,” Journal of theAmerican MedicalAs-

sociation 277, no. 15 (1997): 1238-1243; See Blumenthal, Champ- bell, Anderson, Causino, Louis, supra note 5.

61. See Chalmers, supra note 58. 62. R. P. Kelch, “Maintaining the Public Trust in Clinical Research,”

New England Journal of Medicine 346, no. 4 (2002): 285-287. 63. See Bodenheimer, supra note 4. 64. See Blumenthal, Champbell, Anderson, Causino, Louis, supra

note 5.

65. R J. Simonsen, “Corporate-Sponsored Research Contracts-an Ethical Minefield,” Quintessence Znternational 27, no. 7 (1996): at 443; See Rennie, supra note 60.

66. R A. Phillips, J. Hoey, “Constraints of Interest: Lessons at the Hospital for Sick Children,” Canadian Medical Association 159, no. 8 (1998): 955-957.

67. J. Thompson, P. Baird, J. Downie, Report of the Committee of Znqui y on the Case Involving DT. Nancy Olivieri, the Hospital for Sick Children, the University of Toronto, and Apotex Znc. (Toronto: Canadian Association of University Teachers, 2001).

68. See De Angelis, supra note 7. 69. See Task Force on Financial Conflicts, supra note 14. 70. M. J. Finkel, “Should Informed Consent Include Information on

How Research is Funded?” Institutional Reviere, Board 13, no. 5

71. K. Chaurette, C. Jedrey, “Managing Conflicts of Interest in Human Subjects Research,” Medical Research Law @‘ Policy Report 1, no.

72. S. V. McCrary, C. B. Anderson, J. Jakovljevic, et al, “ANational Sur- vey of Policies on Disclosure of Conflicts of Interest in Biomedical Research,”New EnglandJoumlofMedicine343, no. 22 (2000):

73. B. Lo, L. E. Wolf, A. Berkeley, “Conflict-of-Interest Policies for In- vestigators in Clinical Mals,” New England Journal of Medicine 343, no. 22 (2000): 1616-1620.

(1991): 1-3.

14 (2002): 441-445.

1621-1626.

74. See OHRP, supra note 21. 75. See Task Force on Financial Conflicts, supra note 14 76. See OHRP, supra note 21. 77. See Task Force on Research, supra note 15. 78. See Task Force on Financial Conflicts, supra note 14. 79. See Task Force on Financial Conflicts, supra note 14. 80. See Emanuel, Steiner, supra note 32. 81. See OHRP, supra note 21. 82. See, Chaurette, Jedrey, supra note 71. 83. See Task Force on Financial Conflicts, supra note 14; See Task

Force on Research, supra note 15. 84. J. van Gin, “The Scribe of Stroke Mals,”European Neurology 49,

no. 2 (2003): 125-127; K. R. Lees, J. M. Orgogozo, “Acute Stroke: Trial by Jury. The Toothless Tiger (role of the principal investigator)” European Neurology 49, no. 2 (2003): 120-124.

85. M. A. Morse, R M. Califf, J. Sugarman, “Monitoring and Ensur- ing Safety during Clinical Research,” Journal of the American MedicalAssociation 285, no. 9 (2001): 1201-1205; A. S. Slutsky, J. V. Lavery, “Data Safety and Monitoring Boards,” New England JournalMedicine 350, no. 11 (2004): 1143-1147.

86. See Task Force on Financial Conflicts, supra note 14. 87. See OHRP, supra note 21. 88. American Association of Medical Colleges, Clinical ma1 Con-

tracts: A Discussion ofFour Selected Provisions, Washington, DC (2004); G. DuVal, “Institutional Ethics Review of Clinical Study Agreements,”JournalofMedicalEthics 30, no. l(2004): 30-34.

89. See OHRP, supra note 21.


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