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<?xml version="1.0" encoding="iso-8859-1"?> <!DOCTYPE html PUBLIC "-//W3C//DTD XHTML 1.1//EN" "http://www.w3.org/TR/xhtml11/DTD/xhtml11.dtd"> <html> <head> <title>Responsible Conduct Research : Conflicts of Interest</title> <link type="text/css" rel="stylesheet" title="master styles" href="../c/master.css"> <script language="JavaScript" src="../j/newConsole.js"></script> <link rel="stylesheet" href="https://search.sites.columbia.edu/cu-privacy-notice/cu-privacy-notice.css" /> <script src="https://search.sites.columbia.edu/cu-privacy-notice/cu-privacy-notice.js"></script> <link rel="stylesheet" href="https://search.sites.columbia.edu/cu-privacy-notice/cu-privacy-notice.css" /> <script src="https://search.sites.columbia.edu/cu-privacy-notice/cu-privacy-notice.js"></script>  <script async src="https://www.googletagmanager.com/gtag/js?id=G-B3WXBGZ16S"></script> <script> window.dataLayer = window.dataLayer || []; function gtag(){dataLayer.push(arguments);} gtag('js', new Date()); gtag('config', 'G-B3WXBGZ16S'); </script> </head> <body id="body"> <div id="siteholder"> <a id="top"></a> <div id="header"> <a href="../../index.html">Home</a> | <a href="../winHelp.html">Help</a> | <a href="../winCredits.html">Credits</a> | <a href="../winFeedback.html">Feedback</a> </div> <div id="content"> This section includes relevant background text, definitions and examples, policy statements, a video debate, and expert commentary. It should be read by those looking for a thorough understanding of conflicts of interest. <div id="nav"> <a href="../introduction/index.html">Introduction</a> <a href="../case/index.html">Case Study</a> <a href="../q_a/index.html">Q & A</a> <a href="../annotatedcase/index.html">Annotated Case</a> <a href="../foundation/index.html">»Foundation Text«</a> <a href="../winResources.html">Resources</a> <a href="../conclusion/index.html">Conclusion</a> </div> <img class="teaser" src="../img/mainimageFoundation.jpg" alt="" width="574" height="121" /> <h1>»Foundation Text«</h1> Table of Contents <a href="#1">1: Why Should You Care About Conflicts of Interest</a>      <a href="#1_1">1.1 Definition of a Conflict of Interest</a> <a href="#2">2: Conflicts of Interest at the Individual Level</a>      <a href="#2_1">2.1 Academic Conflicts of Interest or Intellectual Bias</a>      <a href="#2_2">2.2 Other Types of Conflicts of Interest</a>      <a href="#2_3">2.3 Clinical Research</a>      <a href="#2_4">2.4 The Bayh-Dole Act (1980)</a>      <a href="#2_5">2.5 Professional Societies and Associations</a>      <a href="#2_6">2.6 Managing Conflicts of Interest at the Individual Level</a> <a href="#3">3: Conflicts of Interest at the Institutional Review Board (IRB) Level</a>      <a href="#3_1">3.1 Managing Conflicts of Interest at the IRB level</a> <a href="#4">4: Conflicts of Interest at the Institutional Level </a>      <a href="#4_1">4.1 The Death of Jesse Gelsinger</a>      <a href="#4_2">4.2 Activities in Response to Institutional Conflict of Interest</a>      <a href="#4_3">4.3 Managing Conflicts of Interest at the Institutional Level</a> <a href="#5">5: There Will Always be Conflicts of Interest </a> <img src="../img/blank.gif" width="1" height="50"> <h2><a name="1"></a>1: Why Should You Care About Conflicts of Interest</h2> Researchers have a tradition of free inquiry and free exchange of ideas, "united in the shared purpose to create knowledge, to critique existing knowledge, and to disseminate knowledge."<a name="sup1">1</a><a href="#sup1ref">1</a> Trust, the core ethical value in this issue, is essential in the scientific pursuit of the truth. A relationship based on trust is necessary with colleagues, the government, the study sponsors, and, of course, the public. Objectivity is fundamental to this trust. Conflicts of interest are intrinsic to the researcher's enterprise. And that is why conflicts of interest are so serious. Not only can a conflict lead to injury or harm to particular study participants but, on a larger scale, a conflict of interest can damage an entire research enterprise by reducing the trust and confidence that people generally have in research. <a href="#top"> <img class="toparrow" src="../img/arrowtop.gif" alt="" width="12" height="11" /></a> <a name="1_1"></a>1.1 Definition of a Conflict of Interest A conflict of interest involves the abuse -- actual, apparent, or potential -- of the trust that people have in professionals. The simplest working definition states: A conflict of interest is a situation in which financial or other personal considerations have the potential to compromise or bias professional judgment and objectivity. An apparent conflict of interest is one in which a reasonable person would think that the professionals judgment is likely to be compromised. A potential conflict of interest involves a situation that may develop into an actual conflict of interest. It is important to note that a conflict of interest exists whether or not decisions are affected by a personal interest; a conflict of interest implies only the potential for bias, not a likelihood. It is also important to note that a conflict of interest is not considered misconduct in research, since the definition for misconduct is currently limited to fabrication, falsification, and plagiarism. At the current time, the definition for misconduct (fabrication, falsification, and plagiarism) is pending acceptance by all US Public Health Service (USPHS) agencies. There are many varieties of conflicts of interest, and they appear in different settings and across all disciplines. While conflicts of interest apply to a "wide range of behaviors and circumstances," they all involve the use of a person's authority for personal and/or financial gain.<a name="sup2"></a><a href="#sup2ref">2</a> Conflicts of interest may involve individuals as well as institutions. Furthermore, individuals, in certain circumstances, may have conflicts occurring on both an individual and an institutional level, as may be seen among members of an Institutional Review Board (IRB). Conflicts of interest are broadly divided into two categories: intangible, i.e., those involving academic activities and scholarship; and tangible, i.e., those involving financial relationships. Raise your sensitivities to the intangible conflicts of interest that can easily be missed . This e-seminar will define and describe specific types of conflicts of interest that involve the individual, the IRB member, and the institution. <a href="#top"> <img class="toparrow" src="../img/arrowtop.gif" alt="" width="12" height="11" /></a> <h2><a name="2"></a>2: Conflicts of Interest at the Individual Level</h2> Objectivity is the sine qua non of scientific discovery. But bias in judgment is virtually impossible to eliminate. There are often subtle, and not so subtle, pressures that can influence how we perceive and how we act. All research professionals understand the pressures to publish, to get funding, appointments, promotions, and to earn respect from peers. Many strive for the ultimate validation and highest order of recognition -- the Nobel Prize. In an effort to succeed, there are myriad areas where bias can influence judgment and diminish objectivity. A desire to validate a pet theory, overconfidence about a particular concept, overreliance on a belief held by a special group, ruling out data that don't support a hypothesis, and internal or external pressures to get a specific result are all influences that may lead to distortions in objectivity. Any of these biases or pressures may lead to what sociologists call selective inattendance. Your mind-set may cause you to overlook important data or to misperceive critical observations. Bias can be too subtle to recognize and too difficult to control. It can creep into how research questions are selected and framed, the choice of research design, the selection of research participants, and how the data are collected, analyzed, interpreted, and ultimately published. Whether you describe the glass as half empty or half full is influenced by what you want your results to look like. Bias can even influence the sharing of the results of the study. <a href="#top"> <img class="toparrow" src="../img/arrowtop.gif" alt="" width="12" height="11" /></a> <a name="2_1"></a>2.1 Academic Conflicts of Interest or Intellectual Bias "Academic scientists have special responsibilities to disseminate knowledge, to maintain academic standards, to critique the current state of knowledge, to synthesize existing knowledge, and to apply knowledge to solve basic and applied problems."<a name="sup3"></a><a href="#sup3ref">3</a> The peer-review system is the benchmark of the scientific process. An academic conflict of interest could occur if an individual interferes with the peer-review process for some type of intangible personal gain. For example, bias can cause a reviewer to respond positively to a manuscript because it presents results favoring a method or production in which the reviewer has a personal interest, or a reviewer may act to delay the publication of a competitor's manuscript in order to strengthen his or her own chances for publication or funding. Dr. David Blumenthal, of Massachusetts General Hospital, has, along with others, studied the publication practices of researchers and has found not only that negative results are less likely to be published but that even positive findings are withheld if this is perceived as advantageous for the authors. In one study, 20% of researchers reported delaying publication of results for their own advantage.<a name="sup4"></a><a href="#sup4ref">4</a> These are intangible interests, and they are indigenous to every researcher. Indeed, the drive for recognition can be overwhelming, particularly when a future position or livelihood depends on these public achievements. These are the sources of "intellectual bias" that have long been recognized by the research community but that must also be recognized and addressed by the individual researcher. <a href="#top"> <img class="toparrow" src="../img/arrowtop.gif" alt="" width="12" height="11" /></a> <a name="2_2"></a>2.2 Other Types of Conflicts of Interest In addition to academic conflicts of interest, there are other intangible conflicts that can compromise objectivity. For example, conflicts of commitment, which may also be called conflicts of effort or conflicts of obligation, occur when the extent of time spent on a secondary activity competes with the time expected to be spent on teaching, research, or service by the primary employer. Most universities have policies allowing 20% of a faculty member's effort, or one day a week, for outside activity. (<a href = "http://www.columbia.edu/cu/vpaa/fhb/app/app_j.html" target="blank">Columbia Policy in Faculty Handbook</a>) A conflict of conscience occurs when personal beliefs influence objectivity in research. For example, a scientist may have a particular view on abortion that influences his or her view of the scientific merit of a study that uses human embryonic stem cells. <a href="#top"> <img class="toparrow" src="../img/arrowtop.gif" alt="" width="12" height="11" /></a> <a name="2_3"></a>2.3 Clinical Research Clinical researchers subscribe to three basic elements: scientific integrity, patient safety, and investigator objectivity. Yet these researchers are likely to experience conflicts of interest by virtue of their altruistic dedication to the pursuit of knowledge while striving to maintain the welfare of the human volunteers participating in their investigations. Bias and decreased objectivity are of particular concern in the clinical-research setting, where the rewards and risks are both potentially great. Here, bias in judgment might creep in not only to influence the questions pursued and the choice of research design but also to affect the selection and retention of research participants, the reporting and attribution of adverse events, and the collection, statistical analysis, interpretation, and reporting of the data. It is in the clinical setting that bias and loss of objectivity not only can damage the entire research enterprise, which we know reduces the public's trust in research, but can also, more grievously, lead to injury and harm to study participants. We know of two egregious examples in the history of research ethics where conflicts of interest in research existed: the<a href="javascript:openSideBar('sideBar_tuskegee.html','300','400')"> Tuskegee Study of Syphilis in the Negro Male (1932-1972)</a> and the <a href="javascript:openSideBar('sideBar_willowbrook.html','250','400')">Willowbrook Hepatitis Studies (1963-1966)</a>. The clinical investigators in both studies were so caught up in the scientific aspects of their projects that they ignored the welfare of, and ultimately harmed, the participants in these studies. In assessing conflicts of interest, we need to consider the likelihood of bias as well as the consequences of the conflict of interest, because at times the consequences can be lethal. Recent headlines have called attention to conflicts of interest in clinical research, even at notable institutions such as the University of Pennsylvania<a name="sup5"></a><a href="#sup5ref">5</a>, the Fred Hutchinson Cancer Center<a name="sup6">6</a><a href="#sup6ref">6</a>, and St. Elizabeth's Medical Center<a name="sup7">7</a><a href="#sup7ref">7</a>, in Boston. In these situations where there was the appearance of a conflict of interest, there were research deaths. <a href="#top"> <img class="toparrow" src="../img/arrowtop.gif" alt="" width="12" height="11" /></a> Safeguards The scientific method includes a series of steps to ensure that the results of any study are unprejudiced and repeatable. These steps include: identifying a problem through observation, formulating a hypothesis, testing the hypothesis through data collection and analysis, and deriving a conclusion that either confirms or fails to confirm the hypothesis. Fortunately, there are safeguards that can be put into place to help reduce bias and improve objectivity. Conscientious application of the scientific method is one such safeguard. For clinical trials, randomized controlled trial designs and/or a Data and Safety Monitoring Board (DSMB) may be required. Vigilance is always necessary. The Commercialism of Clinical Research The research community has long recognized academic conflicts of interest. Lately, however, there has been a sea change within the research enterprise, whereby the accelerating commercialization of biomedical research is of mounting concern. A few statistics are telling: research-and-development investments by pharmaceutical companies increased from $1.3 billion in 1977 to $32 billion in 2002, a 24-fold increase in just 25 years, and PhRMA companies alone spent more on pharmaceutical R. & D. than the total 2002 NIH operating budget of $24 billion. "The number of private practice physicians involved in drug studies increased by 60% over a five-year span. Conversely, the proportion of trials conducted in academic medical centers dropped from 80% to 40% over the same time period during which the industry as a whole was enjoying steady growth."<a name="sup8"></a><a href="#sup8ref">8</a> Clearly, commercialism is driving the scientific establishment, and this, indeed, can be beneficial. Yet the intertwining of academic research and commercial interests can lead to financial conflicts of interest. A financial conflict of interest involves some type of financial payment, such as a consulting fee, equity in a company, or other monetary reward, which influences an individual to prefer one outcome to another. Any of these can be problematic if they are related to the product under study or the sponsor of the research. Financial conflicts of interest are considered tangible conflicts, because they can be seen and measured. While they appear easier to deal with than intangible conflicts of interest, they may not be. Financial arrangements with sponsors are affecting many areas of scientific life. A growing literature is documenting, with disturbing accounts, how the new entrepreneurial environment is altering the publication practices and prescribing patterns of investigators and clinicians.<a name="sup9"></a><a href="#sup9ref">9</a> "Subtle and not-so-subtle perversions of science are very difficult to detect..." <a href="javascript:openSideBar('sideBar_perversions.html','400','400')">read more</a> Intangible conflicts of interest, as previously described, are problematic, but they are widely recognized and shared. What has captured the attention of the federal government, the scientific community, and the public are those conflicts caused by money and financial relationships, the tangible conflicts of interest. Many fear that the cost of these relationships could be the integrity of science itself. <a href="#top"> <img class="toparrow" src="../img/arrowtop.gif" alt="" width="12" height="11" /></a> <a name="2_4"></a>2.4 The Bayh-Dole Act (1980) The history of the rise of commercialism in science is revealing. Before 1980, the federal government retained the rights to the research and discoveries of the investigators it funded. Concurrently, biotech companies were having difficulty obtaining licenses to manufacture and market their discoveries. The research enterprise was not thriving during this period. Congress responded in 1980 by passing the Bayh-Dole Act, which: <ul> <li>permits recipients of federal funds to obtain the title to the inventions they develop under their federally funded projects, and to transfer the technology to the private sector. <li>requires federally funded researchers to obtain a patent for products developed, to seek commercial opportunities, and to report to the National Institutes of Health (NIH) on the use of their discoveries.</ul> The Bayh-Dole Act, in essence, removed the ban on campus entrepreneurship and allowed academic researchers to take an active role in the private applications of their research. This act has been a tremendous boon, especially to universities that now encourage, and even exhort, their faculty members to apply for patents for their discoveries. Of course, this enables the universities to benefit significantly from the shared royalties. Ultimately, many universities have thrived on their relationships with industry. "...among companies that sponsor academic research, 58% require their investigators to withhold results for more than six months to give them time to apply for a patent or to provide a lead over competitors..." <a href="javascript:openSideBar('sideBar_blumenthal.html','400','400')">read more</a> But there is a downside to entrepreneurial relationships. Financial arrangements with sponsors are having effects on publication practices, on the prescribing patterns of investigators and clinicians, and even on the assignment of students or trainees to work on projects from which the researcher is likely to benefit financially. This literature is growing, and it is disturbing. Potential or actual financial conflicts of interest are the unintended consequences of the Bayh-Dole Act. Federal Conflict-of-Interest Regulations Responding to the sea change in the research enterprise, in 1995 the US Public Health Service, which includes the NIH, and the National Science Foundation (NSF) enacted regulations entitled "<a href="http://grants.nih.gov/grants/guide/notice-files/not95-179.html" target="blank">Responsibility of Applicants for Promoting Objectivity in Research </a>". These regulations require institutions to establish standards and procedures that ensure that the design, conduct, or reporting of research is not biased by any conflicting financial interests of the investigator. Designed to promote objectivity in the conduct of research, the goals of the federal regulations are to manage, reduce, or eliminate financial conflicts of interest. The key components of these regulations are: <ul> <li>The institution, not the federal government or the sponsor, has the primary responsibility to develop its own internal policies and procedures. The institution is to designate an official to review disclosure of significant financial interest and manage conflicts of interest. <li>Investigators must disclose any "significant financial interest" to the institution. <li>The institution must report to the federal funders if it believes an investigators significant financial interest could affect the research.</ul> For these regulations, "investigators" are defined as those persons responsible for the design, conduct, or reporting of research, and the investigator's spouse and dependent children are included in the definition. "Significant financial interest" is broadly defined as anything of monetary value that could include salary or payment for services from an outside institution, any equity (stock) interests, and any intellectual-property rights. It does not include salary, royalties, or other remuneration from the investigator's home institution; income from seminars, lectures, or teaching sponsored by public or nonprofit entities; or income from service on advisory committees or review panels for public or nonprofit entities. <div class="supplement"> LIMITS FOR EQUITY INTEREST TOTAL for investigator and his/her spouse and dependent children. Does not exceed $10,000 in value       And Does not represent more than 5% ownership in any single entity.       Or Total salary, royalties, or other payments from the outside source are not expected to exceed $10,000. </div> The rules define a threshold for reporting a significant financial interest as anything of monetary value including equity interests (e.g., stocks, stock options, or other ownership interests) that exceed $10,000 in value and represent no more than a 5% ownership interest in any single company, regardless of value, if that equity or ownership interest is held in a company whose financial interests would reasonably appear to be affected by the researcher's activities. According to these rules, the equity interests of the investigator's spouse and dependent children are aggregated to determine the threshold for disclosure. The word "significant" has become contentious and, given our entrepreneurial climate, many feel that the currently defined threshold is inappropriate and unrealistic. There are problems with Federal Regulations..." <a href="javascript:openSideBar('sideBar_federalproblems.html','400','400')">read more</a> In 1998, <a href="http://www.access.gpo.gov/nara/cfr/waisidx_99/21cfr54_99.html" target="blank">the FDA issued its final rule </a> requiring disclosure by sponsors, reporting that their investigators' financial interests were below $25,000, which is considered a more realistic and reasonable total. Many institutions and the federal government are currently examining the existing definitions and policies, and new guidance or regulations may be forthcoming. <a href="#top"> <img class="toparrow" src="../img/arrowtop.gif" alt="" width="12" height="11" /></a> <a name="2_5"></a>2.5 Professional Societies and Associations Many professional societies and associations, such as the Association of American Medical Colleges (AAMC), the American Association of Universities (AAU), and the Council of Government Relations (COGR), <a href="javascript:openSideBar('sideBar_policies.html','400','400')">have developed policies on conflicts of interest</a>. While disclosure is seen by many as the best means to manage conflicts of interest, there are others who, like Dr. Marcia Angell, believe that financial conflicts can never be managed. Clinical researchers must be able to design and conduct their studies in an unbiased and objective manner that is free from conflicts caused by significant financial involvement with the commercial sponsors of the research. In this case, the only sure safeguard is for the investigator to have absolutely no financial relationships with entities that support his or her research. This approach has often been referred to as "zero tolerance."<a name="sup10"></a><a href="#sup10ref">10</a>  <div class="rcrvideocontainer contentvideo"> <div class="rcrvideo"> <iframe width="240" height="204" src="https://www.youtube.com/embed/CGEiQ6WtbGo?feature=oembed&controls=0" frameborder="0" allow="autoplay; encrypted-media" allowfullscreen></iframe> </div> <div class="rcrvideocaption"> <div id="name">Video Debate: Zero Tolerance</div> <div id="link">Nancy Dubler [<a href="javascript:openSideBar('bio_dubler.html','400','400')">Bio</a>]</div> </div> </div> <div class="rcrvideocontainer contentvideo"> <div class="rcrvideo"> <iframe width="240" height="204" src="https://www.youtube.com/embed/QwebQYnmMjg?feature=oembed&controls=0" frameborder="0" allow="autoplay; encrypted-media" allowfullscreen></iframe> </div> <div class="rcrvideocaption"> <div id="name">Video Debate: Zero Tolerance</div> <div id="link">Thomas Murray, Ph.D. [<a href="javascript:openSideBar('bio_murray.html','400','400')">Bio</a>]</div> </div> </div> <div class="rcrvideocontainer contentvideo"> <div class="rcrvideo"> <iframe width="240" height="204" src="https://www.youtube.com/embed/YwG1IAzMBCE?feature=oembed&controls=0" frameborder="0" allow="autoplay; encrypted-media" allowfullscreen></iframe> </div> <div class="rcrvideocaption"> <div id="name">Video Debate: Zero Tolerance</div> <div id="link">David Rothman, Ph.D. [<a href="javascript:openSideBar('bio_rothman.html','400','400')">Bio</a>]</div> </div> </div> <div class="rcrvideocontainer contentvideo"> <div class="rcrvideo"> <iframe width="240" height="204" src="https://www.youtube.com/embed/z1tDOvzBvxM?feature=oembed&controls=0" frameborder="0" allow="autoplay; encrypted-media" allowfullscreen></iframe> </div> <div class="rcrvideocaption"> <div id="name">Video Debate: Zero Tolerance</div> <div id="link">David Strauss, M.D. [<a href="javascript:openSideBar('bio_strauss.html','400','400')">Bio</a>]</div> </div> </div> Several professional societies have issued conflict-of-interest policies. Following the death of Jesse Gelsinger in a gene transfer/therapy experiment at the University of Pennsylvania in 1999, the American Society of Gene Therapy (ASGT) (see the American Society of Gene Therapy on Financial Conflict of Interest in Clinical Research policy, issued on April 5, 2000, found <a href="http://ccnmtl.columbia.edu/projects/rcr/rcr_conflicts/misc/Ref/AGST_CoI.pdf" target="blank">here</a>) has been especially proactive in following this approach and was one of the first to adopt a "zero-tolerance" policy. The ASGT resolved that "all investigators and team members directly responsible for patient selection, the informed consent process and/or clinical management in a trial must not have equity, stock options or comparable arrangements in companies sponsoring the trial."<a name="sup11">11</a><a href="#sup11ref">11</a> The American Society of Clinical Oncology published a <a href="http://ccnmtl.columbia.edu/projects/rcr/rcr_conflicts/misc/Ref/JCO_CoI.pdf" target="blank">Revised Conflict of Interest Policy</a> in 2003<a name="sup12"></a><a href="#sup12ref">12</a> which also advocates zero tolerance, stating that members should not hold any stock or equity interest in the trial sponsor or receive from the sponsor honoraria, gifts, or payments that exceed the true cost of the research activity (e.g., a recruitment bonus or incentive for early completion of the study are not permissible). <a href="#top"> <img class="toparrow" src="../img/arrowtop.gif" alt="" width="12" height="11" /></a> Concerns with Disclosure Journals increasingly are requiring that authors list the companies that fund their research. Often, those lists are very long, indicating that researchers have many ties to industry. Concomitantly, investigators increasingly have concerns with privacy and breach of confidentiality when having to disclose their financial status and financial relationships, and these concerns can act as a deterrent to disclosure. In addition, there is a growing concern that investigators reputation and work are tarnished if they hold equity in a company that is supporting their research. Some are worried that the preoccupation with financial conflicts of interest has a chilling effect on disclosure and promotes Web sites that act as conflict-of-interest "police." (See the <a href="http://www.cspinet.org/integrity" target="blank">Integrity in Science Web site</a>.) <a href="#top"> <img class="toparrow" src="../img/arrowtop.gif" alt="" width="12" height="11" /></a> <a name="2_6"></a>2.6 Managing Conflicts of Interest at the Individual Level Conflicts of interest must be recognized and identified, then managed, reduced, or eliminated. In handling individual investigator conflicts of interest, disclosure and oversight of the research by an independent board seem to be the most common management strategies. Specific steps might include: Increasing numbers of journals require authors to disclose their financial relationships with sponsors of their studies when publishing reports of clinical trials. Many now also require disclosure for editorials or commentaries. <ul> <li>The investigator's financial interests with the sponsor of the trial could be fully disclosed to any human research volunteers. <li>The investigator's financial relations to the sponsor should be included in all written and oral presentations, publications, and abstracts.</ul> Depending on the seriousness of the conflict, other management strategies could include: <ul> <li>Modifying the research plan, including changing the site(s) of the trial. <li>Monitoring of research by independent reviewers. This could include special oversight and approval of any consulting agreement language when faculty consult with companies in which they also hold equity interests. In a clinical study, oversight could include participant recruitment and enrollment, the informed-consent process, analysis of the study data, and the subsequent reporting to the sponsor. <li>Divestiture of significant financial interests. <li>Severance of relationships that create actual or potential conflicts. <li>Disqualification of the researcher from part or all of the research project </ul> <a href="#top"> <img class="toparrow" src="../img/arrowtop.gif" alt="" width="12" height="11" /></a> <h2><a name="3"></a>3: Conflicts of Interest at the Institutional Review Board (IRB) Level</h2> The complexity of the issues raised by the Bayh-Dole Act (1980) and the 1995 federal regulations generate intriguing ethical dilemmas. Until recently, conflicts of interest at the IRB level, which includes IRB involvement in handling conflicts of interest of investigators and IRB members themselves, were rarely addressed. Yet conflicts of interest that occur on the IRB level are recognized now as critically important. Several federal agencies and private organizations have been actively working to issue guidance that is both current and appropriate. There are many potential sources of conflicts of interest that are intrinsic to the individual IRB member and those which emanate from the institution. The chart below lists many of these sources.<a name="sup13"></a><a href="#sup13ref">13</a> <div class="supplement"> <table width="440" border="0" cellspacing="0" cellpadding="0"> <tr> <td width="210" valign="top"> <h3> Individual Level </h3> <h3> Member is an investigator on research under review Members or staff hold significant financial interest in sponsor of research Loyalty to colleagues submitting for review Members closely tied to area of research under review       If familiar = too lenient       If competitor = too critical Possible impact of decisions on member's own work (e.g., policy changes) Personal agendas, deeply held beliefs Non-IRB roles of members       Contracts and grants office       Legal counsel </h3> </td> <td width="20"> </td> <td width="210" valign="top"> <h3> Institutional Level </h3> <h3> Pressure or desire to protect institution Concern for institutions reputation or prestige Promoting research vs. protecting subjects Undervaluation of IRB service Potential liability Institutional or community values Pressure for speedy reviews Institutional equity or ownership Review fees </h3> </td> </tr> </table> </div> Little is known about the exact nature and the extent of conflicts of interest that affect IRBs. Mandated by the federal government to <a href="http://ohsr.od.nih.gov/mpa/45cfr46.php3" target="blank">protect the rights and promote the welfare of human participants in research </a>, IRBs examine submitted research protocols to weigh the risks and benefits of the research to the participants and to ensure that a thorough informed-consent process is provided. IRBs were created with the knowledge that there is an inherent conflict of interest between the dual roles of the clinical investigator as physician, whose primary responsibility and duty are to ensure the welfare of his or her individual patients, and as researcher, whose duty is to advance science for the sake of society. Many IRB members have equity interests, and these equity interests may be in companies sponsoring studies that the members are reviewing. <a href="http://ohsr.od.nih.gov/mpa/45cfr46.php3#46.107" target="blank">Federal regulations</a> require that members recuse themselves from voting on protocols if they or their families have any financial interests that could influence the members' deliberations on a protocol. Many IRBs now charge fees to sponsors and investigators to cover the costs of reviewing their protocols. This raises concerns that IRBs might approve borderline protocols to maintain their clients, or that investigators will shop around for IRBs that are more "user-friendly", that is, likely to approve their protocols. Sometimes the institution may pressure the IRB to approve a protocol. IRBs must approve protocols for serious, high-risk studies. These studies may generate a great deal of public attention and provide a strong incentive for the investigator to conduct the study. Groundbreaking research is essential, but it puts considerable pressure on IRBs to approve the protocols. Protocols may be submitted by close colleagues or department members raising loyalty issues that may bias decision-making. Investigators involved in the conduct of the research generally complete a disclosure statement for the institution and the IRB that describes their financial relationships with the sponsor of their research. Many IRBs are including a statement in the informed-consent form which notifies the prospective research participant of this relationship (e.g., "The investigator of your study is supported by the sponsor"). However, it is not known what effect this will have on the research participant's decision to join the study. Some potential research participants might think this statement means that if the study is successful the investigator will make money and the participant will get better -- a "win-win" situation. Others might think the investigator is more interested in the money than in the participant. Most potential research participants probably do not even understand the complexity of the issue. This is a question that needs further study. <a href="#top"> <img class="toparrow" src="../img/arrowtop.gif" alt="" width="12" height="11" /></a> <a name="3_1"></a>3.1 Managing Conflicts of Interest at the IRB level Many IRBs are currently developing strategies to deal with conflicts of interest that may interfere with their objectivity and deliberations. A recent Inspector General's report estimated that about 25% of IRBs in the NIH study were taking action to recognize and manage conflicts of interest among members.<a name="sup14"></a><a href="#sup14ref">14</a> In the future, as the seriousness and complexity of conflicts of interest are recognized more fully, IRBs will take more proactive steps to manage, reduce, or eliminate conflicts of interest. <a href="#top"> <img class="toparrow" src="../img/arrowtop.gif" alt="" width="12" height="11" /></a> <h2><a name="4"></a>4: Conflicts of Interest at the Institutional Level </h2> The Bayh-Dole Act of 1980 was designed to encourage institutions to commercialize their discoveries and, indeed, in recent years academic institutions have thrived on their relationships with industry as they have emphasized bringing their discoveries directly to the marketplace. We are increasingly aware of the strong ties that bind academia to industry, and these ties grow stronger every day. Given the cutbacks in federal spending, this is not necessarily a perilous relationship and in fact is usually beneficial, as funding is necessary in order for technology to advance. The extent of these burgeoning university-industry ties is as impressive as the consequences. Bekelman and his colleagues found that approximately two-thirds of academic institutions hold equity interests in start-up companies that sponsor research at those institutions, and that industry sponsorship is significantly associated with both pro-industry research conclusions and restrictions on publications and data sharing.<a name="sup15"></a><a href="#sup15ref">15</a> Institutional conflicts of interest can be introduced simply by the institution having a license agreement..." <a href="javascript:openSideBar('sideBar_agreement.html','400','400')">read more</a> The definition of an institutional conflict of interest is when financial interests of the institution or of an institutional official might affect or reasonably appear to affect institutional processes including the conduct, review, or oversight of human research. According to the Council on Government Relations, "institutional conflicts of interest may occur when one or more aspects of either internal relationships between different units within the university or external relationships between the university and other entities are incongruent with institutional core values, and result, or have the potential to result in choices or actions that are harmful to the missions, the obligations, or the values of the university."<a name="sup16"></a><a href="#sup16ref">16</a> <a href="#top"> <img class="toparrow" src="../img/arrowtop.gif" alt="" width="12" height="11" /></a> <a name="4_1"></a>4.1 The Death of Jesse Gelsinger The death of 18-year-old Jesse Gelsinger, at the University of Pennsylvania in a gene-transfer trial, has become a metaphor for egregious science. The universitys Institute of Human Gene Therapy, the trial sponsor, has come under scrutiny because the researchers involved with the trial and the university had apparent financial conflicts of interest. The tragic results of this widely publicized trial alarmed the public and the research community. The University of Pennsylvania has subsequently changed many of its policies, and has discontinued all human gene-transfer experimentation at the Institute of Human Gene Therapy. The principal investigator, James Wilson, stepped down as president of the institute.<a name="sup17"></a><a href="#sup17ref">17</a> <a href="#top"> <img class="toparrow" src="../img/arrowtop.gif" alt="" width="12" height="11" /></a> <a name="4_2"></a>4.2 Activities in Response to Institutional Conflict of Interest While financial relations between academia and industry continue to develop, there are no federal regulations to guide institutions in how to identify, manage, or eliminate conflicts of interest. Should we be concerned, for example, if an institution that holds a patent for a discovery then conducts research whose outcome could provide financial benefit to the institution? Should disclosure to the funding agency be required? Should the funding agency receive statements from the institution regarding how it manages such potential conflicts? The <a href="http://ccnmtl.columbia.edu/projects/rcr/rcr_conflicts/misc/Ref/AAU_CoI.pdf" target="_new">AAU Report</a> on Individual and Institutional Conflict of Interest defines these conflicts of interest and tries to promote some understanding of the issues. The <a href="http://ccnmtl.columbia.edu/projects/rcr/rcr_conflicts/misc/Ref/AAMC_2002CoIReport.pdf" target="_new">AAMC has submitted Principles and Recommendations</a> for Oversight of an Institution's Financial Interests in Human Subjects Research. The concerns about institutional conflicts of interest have generated a number of activities. In 2001, the Office for Human Research Protections (OHRP) drafted guidelines for institutions entitled "<a href="http://ccnmtl.columbia.edu/projects/rcr/rcr_conflicts/misc/Ref/OHRP_CoI.pdf" target="blank">Financial Relationships in Clinical Research: Issues for Institutions, Clinical Investigators, and IRBs to Consider When Dealing with Issues of Financial Interests and Human Subject Protection</a>". In 2000, the NIH published "<a href="http://grants2.nih.gov/grants/guide/notice-files/NOT-OD-03-026.html" target="blank">Financial Conflicts of Interest and Research Objectivity: Issues for Investigators and Institutional Review Boards</a>". The NIH has created an extremely useful resource, "<a href="http://grants2.nih.gov/grants/policy/coi/resources.htm" target="blank">Conflict of Interest Information Resources Available on the Web</a>", with many links to varied resources and guidance documents. Harvard University, <a href="javascript:openSideBar('sideBar_aamc_aau.html','400','400')">the Association of American Medical Colleges (AAMC), and the Association of American Universities (AAU)</a> have also addressed institutional conflicts of interest and have published thoughtful commentaries and guidances. <a href="#top"> <img class="toparrow" src="../img/arrowtop.gif" alt="" width="12" height="11" /></a> <a name="4_3"></a>4.3 Managing Conflicts of Interest at the Institutional Level Strategies are emerging to manage institutional conflicts of interest, several of which are similar to conflicts of interest that occur on the individual level.<a name="sup18"></a><a href="#sup18ref">18</a> <ul> <li>Encourage transparency via disclosure of conflicts of interest among trustees and former trustees as well as university officials who often have close connections with boards of companies doing business with the institution. <li>Place limits on involvement of faculty members and other institutional officials in companies. <li>Exercise caution when technology-transfer official's remuneration is tied to stock values, as personal biases can influence judgments regarding stock sales or the acceptance of sponsored research agreements. <li>Manage and review conflicts of interest using independent sources and external reviewers. <li>Build organizational firewalls so that potentially conflicted parties do not interact. The institutional technology-transfer office should not be in the decision chain of identifying or managing conflicts of interest. <li>Anticipate situations that could be perceived as compromising research and fiduciary integrity. </ul> The sources of institutional conflicts of interest are myriad. But they must be addressed if we are to both avoid undermining the credibility of our scientific enterprise and ensure that the highest standards of ethical conduct of research are sustained. The search for truth must not be contaminated by even a perception of bias. <a href="#top"> <img class="toparrow" src="../img/arrowtop.gif" alt="" width="12" height="11" /></a> <h2><a name="5"></a>5: There Will Always be Conflicts of Interest </h2> It is clear that conflicts of interest will not go away. Intangible and tangible conflicts of interest will always exist. Financial conflicts of interest will inevitably become more complex and involved. Devising new strategies to manage, reduce, or eliminate conflicts of interest will be an ongoing challenge. "Most conflicts of interest created by academic-industry relationships are real, consequential, but tolerable, so long as they are managed to contain their risks while preserving their benefits."<a name="sup19"></a><a href="#sup19ref">19</a> We must be vigilant against conflicts of interest that lead to bias and loss of objectivity. The enterprise of research depends on it. <a href="#top"> <img class="toparrow" src="../img/arrowtop.gif" alt="" width="12" height="11" /></a> Continue to the next section: <a href="../winResources.html">→ Resources</a> <h2>Reference Notes</h2> 1 <a name="sup1ref"></a>Bradley SG. Managing Conflicting Interests, p. 136. In: Magrina FL, editor. Scientific Integrity: An Introductory Text with Cases. Washington, DC: American Society for Microbiology; 2000, pp. 131-157.     <a href="#sup1">back</a> 2 <a name="sup2ref"></a>Bradley, p. 136.     <a href="#sup2">back</a> 3 <a name="sup3ref"></a>Bradley, p. 144.     <a href="#sup3">back</a> 4 <a name="sup4ref"></a>Blumenthal D, Campbell E, Anderson M, Causino N, Louis K. Withholding Research Results in Academic Life Science. Evidence from a National Survey of Faculty [Comment]. JAMA 1997; 277(15): 1224-1228.     <a href="#sup4">back</a> 5 <a name="sup5ref"></a>Smith L, Byers JF. Gene Therapy in the Post-Gelsinger Era. Jona's Healthcare, Law, Ethics and Regulation 2002; 4(4): 104-110.     <a href="#sup5">back</a> 6 <a name="sup6ref"></a>Uninformed Consent: What Patients at "The Hutch" Weren't Told About the Experiments in Which They Died. Seattle Times, Local News, Sunday, March 11, 2001.     <a href="#sup6">back</a> 7 <a name="sup7ref"></a>Hilts PJ. A Second Death Linked to Gene Therapy. The New York Times on the Web. May 4, 2000; Science.     <a href="#sup7">back</a> 8 <a name="sup8ref"></a>Nelson DK. Conflict of Interest: Researchers in Amdur and Bankert ed. Institutional Review Board: Management and Function: Sudbury, MA, 2002, pp.197-203.     <a href="#sup8">back</a> 9 <a name="sup9ref"></a>Bodenheimer T. Uneasy Alliance -- Clinical Investigators and the Pharmaceutical Industry. N Engl J Med 2000; 342(20): 1539-1544.     <a href="#sup9">back</a> 10 <a name="sup10ref"></a>Angell M. Is Academic Medicine for Sale? N Engl J Med 2000; 342(20): 1516 - 1518.     <a href="#sup10">back</a> 11 <a name="sup11ref"></a>American Society of Gene Therapy. <a href="http://ccnmtl.columbia.edu/projects/rcr/rcr_conflicts/misc/Ref/AGST_CoI.pdf" target="_blank">Policy of The American Society of Gene Therapy on Financial Conflict of Interest in Clinical Research.</a> 2000. Retrieved 2003 May 28 from <a href="http://www.asgt.org" target="_blank">http://www.asgt.org</a>.     <a href="#sup11">back</a> 12 <a name="sup12ref"></a>American Society of Clinical Oncology: Revised Conflict of Interest Policy [ASCO Special Article]. Journal of Clinical Oncology 2003; 21(12): 2394-2396.     <a href="#sup12">back</a> 13 <a name="sup13ref"></a>Nelson D. Conflict of Interest: IRBs. In: Amdur R and Bankert E. Institutional Review Board: Management and Function. Sudbury, MA: Jones and Barlett, 2002. p. 213.     <a href="#sup13">back</a> 14 <a name="sup14ref"></a>Department of Health and Human Services. Office of Inspector General. Protecting Human Research Subjects: <a href="http://ccnmtl.columbia.edu/projects/rcr/rcr_conflicts/misc/Ref/OIG_CoI.pdf" target="_blank">Status of Recommendations</a>. April 2002. Accessed July 23, 2003, at <a href="http://www.unmc.edu" target="_blank">http://www.unmc.edu</a>.     <a href="#sup14">back</a> 15 <a name="sup15ref"></a>Bekelman JE, Li Y. Scope and Impact of Financial Conflicts of Interest in Biomedical Research. JAMA 2003; 289(4): 454-465.     <a href="#sup15">back</a> 16 <a name="sup16ref"></a>Adapted from: Council on Government Relations. Institutional Conflicts of Interest Points for Consideration. November 21, 2000.     <a href="#sup16">back</a> 17 <a name="sup17ref"></a>Sanders E. <a href="http://ccnmtl.columbia.edu/projects/rcr/rcr_conflicts/misc/Ref/UPENN_IHGT.pdf" target="_blank">Researcher Wilson to Step Down as IHGT Head.</a> The Daily Pennsylvanian, April 23, 2003. Accessed July 23, 2003, at <a href="http://www.dailypennsylvanian.com" target="_blank">http://www.dailypennsylvanian.com</a>.     <a href="#sup17">back</a> 18 <a name="sup18ref"></a><a href="http://ccnmtl.columbia.edu/projects/rcr/rcr_conflicts/misc/Ref/COGR_CoI.pdf" target="blank">Recognizing and Managing Personal Conflicts of Interest.</a> Council on Government Relations (COGR), Winter 2002. From <a href="http://www.cogr.edu/" target="blank">http://www.cogr.edu</a>     <a href="#sup18">back</a> 19 <a name="sup19ref"></a>Blumenthal D. Ethics issues in academic-industry relationships in the life sciences: the continuing debate. Acad Med. 1996 Dec; 71(12):1287-90.     <a href="#sup19">back</a> </div> <div id="footer"> </div> </div> </body> </html>