Presidential Address, 55th Annual American Society for Artificial Internal Organs Conference

I am both humbled and honored to have been given the opportunity to serve the American Society for Artificial Internal Organs (ASAIO) as president for this past year. As some of you know, I am a cardiac surgeon and as such, I am keenly aware that governance of a society, like open heart surgery, is best accomplished by a dedicated, experienced group of individuals. Favorable outcomes in cardiac surgery and management of a society are dependent on a successful team effort. This past year I was quite fortunate to have been surrounded by a very dedicated and actively engaged group of individuals. As many of ASAIO's presidents have done in the past, I would like to thank Karen Burke, Executive Director for her commitment to ASAIO. Karen is truly the heart and soul of our society. I would also like to thank the ASAIO Board and, in particular, the members of the executive committee: Bill Holman, David Humes, Bill Wagner, and Kurt Dasse. Their collective wisdom and vision for the society made the management task far simpler than I would have imagined and assures me that our society is in very good hands for the future. In choosing a topic for the presidential address, I felt that conflict of interest considerations are not only timely but also of particular interest to the diverse membership of our society. Given that our membership roster has representatives from clinical medicine, engineering, basic science, the federal government, and industry, I believe we are in a unique position to acknowledge the potential for conflict of interest and influence the process by which such conflicts are managed. A conflict of interest has been defined 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).”1 Although financial gain is the most easily recognized and readily quantified, it is only one of a number of possible secondary interests. Physician-scientists are driven to participate in clinical research out of a desire to advance knowledge thereby providing better therapeutic modalities for their patients. Academic medical centers exist to foster an environment in which such advances are made possible. A successful investigative effort oftentimes results in ongoing grant support and academic recognition.2 Academic medical centers derive nonfinancial gains from research conducted by their faculty. There is great prestige associated with recognition as a leading research institute. Personal career advancement and institutional recognition are powerful secondary interests. The common perception is that any relationship between an investigator or academic institution and industry creates doubt about the validity of an investigative effort and may jeopardize the quality of care provided to a research subject. However, the presence of a conflict of interest should not be considered evidence of misconduct on behalf of the investigator, academic institution, or industrial partner. Rather, conflicts of interest are inherent in the investigative process. The goal is to manage the conflicts of interest in an ethical manner thereby ensuring that a study is conducted with unquestionable scientific validity and that the patient's care is uncompromised. It is important to understand how human subjects research evolved to the point where conflicts of interest can occur. Public Law 96-517 known as the Bayh-Dole Act, was cosponsored by Birch Bayh of Indiana and Robert Dole of Kansas.3 This legislation was enacted on December 12, 1980, became effective in July 1981, and created a patent policy that permitted universities, for the first time, to elect title to inventions made under federal sponsorship. Universities were expected to file patents and subsequently commercialize these inventions. This piece of legislation is generally credited as the originator of academic technology transfer whereby university research, inventions, and intellectual property are transferred to private industry for purposes of commercialization. By doing so, public welfare is enhanced and industrial growth made possible, as university generated technology is developed into real world products. Currently, around 5,000 licenses and options are executed annually by universities with private industry, growth of more than 500% since 1991.4 Such tech transfer translates into $1.39 billion in annual licensing income to universities, a nearly $1 billion increase since 1995. The enhanced relationship between academic institutions and industry has led to a multitude of medical advances and the creation of biotechnology markets. However, an unintended consequence of the relationship is an academic institution's increased reliance on industrial funding to support further research. Between 1980 and 2000, industry's share of the total investment in biomedical research and development increased from 32% to 62%.5,6 Support from the federal government fell during the same period. The complex financial relationship among investigators, academic institutions, and industrial partners is well documented. Of 2,052 life science faculty at 50 US universities receiving research funding from the National Institutes of Health, surveyed in a report published in 1996, 28% received research support from industry.7 In 1984, 46% of life science companies supported academic research, whereas in 1994, 57% of firms provided such support, a number that achieves statistical significance (p = 0.05).8 In 1999, the Association of University Technology Managers reported that 124 of 183 members (68%) in the United States and Canada held equity ownership in businesses that sponsored research at the same institutions.6 Patent royalties and, to a greater extent, equity holdings by investigators and academic institutions create an entirely new dynamic in their relationship with the industrial partner.6 The creation of a new revenue model for research scientists and universities has blurred the lines between academic and commercial values. The rise in institutional entrepreneurialism carries with it a responsibility for business stewardship. Such a shift in mind set can easily portend a shift in academic mission. The potential for research bias ensues. The promise of financial rewards raises justifiable concern about the conduct, interpretation, and reporting of funded research.2 There is a well documented disparity in outcomes between industry-sponsored and nonindustry sponsored research. In one review of 332 randomized controlled trials, industry funded studies were 1.9 times more likely to report positive results, a statistically significant proindustry finding.9 Bekelman et al.6 summarized eight articles that compared the outcomes of industry-sponsored versus nonindustry sponsored research studies. These eight articles collectively evaluated 1,140 original studies. The summary odds ratio from these studies was 3.60, with the conclusion favoring industry regardless of whether the study was a randomized controlled trial or other study design. Although perhaps an overstatement, industry-sponsored research is, in general, designed to affirm a hypothesis that is anticipated to be affirmed.10 Industry studies are intended, in part, to mature a concept or product along a linear fashion, whereas government-funded studies may be designed to ask broader, more conceptual questions.10 More worrisome are potential impediments to the investigator's access to data and freedom to publish the results of industry-sponsored research studies. There are reported instances where publication of the results of research that were unfavorable to an industrial product were delayed or blocked altogether by the companies that had provided financial support for the study.11–13 In one survey of academic investigators, 19.8% of 410 respondents reported publication of their research results had been delayed for more than 6 months to slow the dissemination of undesired results and to resolve disputes over ownership of intellectual property, among other reasons.13 So, why the seeming sudden interest in recognition and management of conflicts of interest? The Joint Commission defines a sentinel event as “an unexpected occurrence involving death or serious physical or psychological injury … Such events are called ‘sentinel’ because they signal the need for immediate investigation and response.”14 The event that accelerated efforts to address the influence of conflicts of interest on the safety of research subjects occurred in 1999.15,16 Jesse Gelsinger was an 18-year-old man who suffered from a mild disorder of nitrogen metabolism known as ornithine transcarbamylase deficiency.16 On September 13, 1999, as part of a gene therapy clinical trial, he received an intrahepatic injection of adenovirus vector particles containing a gene to correct the genetic defect. He died 4 days later of what was presumed to be an immune reaction to the virus vector. This death was the first in a gene therapy trial. In the firestorm that ensued, it was alleged that investigators at the University of Pennsylvania where the death occurred held patents covering several aspects of the technology employed. In a wrongful death lawsuit, it was further alleged that James Wilson, the Director of the Institute for Human Gene Therapy at the University of Pennsylvania, and the University itself were reported to have equity holdings in Genovo, the private sector biotechnology company collaborating on the project.15,16 These conflicts of interest were allegedly never disclosed to the trial participant. The fallout from the tragedy in Philadelphia and elsewhere called into question physician–industry relationships and the impact of those relationships on the clinical investigative process. Kim et al.17 from the Psychiatry Department at the University of Rochester looked specifically at potential research participants' views of researcher and institutional financial conflicts of interest. In their article published in 2004, the authors presented seven different scenarios of financial conflicts of interest to 5,478 individuals. The majority of individuals surveyed responded that knowing conflict of interest information was “extremely” or “very” important. Sixty-four to 87% of respondents (depending on conflict of interest scenario) felt that financial conflicts of interest should be disclosed as part of the informed consent process. Although the majority of those individuals surveyed would chose to participate in a study in the face of a known financial conflict of interest, the effect of such a conflict of interest resulted in a sizeable minority to be less inclined (range, 3%–44%) to participate or would chose not to participate (range, 2%–32%). The erosion of trust was further reflected in the fact that pharmaceutical and medical technology companies paid more than $2.5 billion in healthcare fraud settlements in 2001 and 2002.10 Public trust had to be regained, and potential research participants needed assurance that clinical investigation could be conducted free of bias. The question to be answered was where to begin. On May 23, 2000, in direct response to the death of the patient in the gene therapy clinical trial, former Secretary of the Department of Health and Human Services, Donna Shalala, announced five new initiatives that were specifically designed to ensure patient safety and increase public confidence in clinical trials.18,19 Two of the five new initiatives specifically addressed conflicts of interest. The purpose of these initiatives was to “clarify and enhance the informed consent process” and specific mention was made “that any researchers' financial interest in a clinical trial be disclosed to potential participants.” A conference that specifically addressed financial conflicts of interest was held in Bethesda, MD, on August 15–16, 2000. Subsequent to that conference, a draft interim guidance document was prepared and made available for public comment on January 10, 2001. A second draft guidance document appeared in 2003, whereas the Final Guidance document entitled “Financial Relationships and Interests in Research Involving Human Subjects: Guidance for Human Subjects Protection” was made available in 2004.20 In part, these guidelines suggested that institutions establish a Conflict of Interest Committee to identify and address potential individual or institutional conflicts of interest. The Conflict of Interest Committee was to function in concert with the Institutional Review Board (IRB). The mandate of the latter committee is to protect the rights and welfare of human research subjects. As the Department of Health and Human Services was in the process of developing guidelines to address financial conflicts of interest in human subjects research, the Association of American Medical Colleges (AAMC) announced their own intent to examine the same process. In October 2000, the president of the AAMC, Jordan Cohen, announced the formation of a task force whose assignment was to revise and extend the AAMCs existing conflict of interest guidelines based on contemporary events and increased concern about the impact of financial conflicts of interest on public trust in the objectivity of human subjects research.21 Jordan charged this task force to address three issues: 1) To recommend upper limits of allowable financial interests that would motivate investigators to pursue the clinical research with due diligence but not raise concern that remuneration for research serve as a financial windfall for those providing oversight for the scientific process. 2) To consider inaugurating a voluntary, institution-based certification process for research faculty. The certification process would function much like board certification and would ensure that those involved with funded research were cognizant of the rules and regulations governing such research. 3) To consider additional safeguards that might be necessary to “address the potential downside of financial conflicts at the institutional level,” recognizing that institutions, as opposed to individual scientists, might also have a financial stake in the outcomes of clinical trials conducted onsite. The task force ultimately published two documents: one dealing with individual22 and the second with institutional23 financial conflicts of interest in research involving human subjects. Recommendations in these two reports also include the creation of a Conflict of Interest Committee or, in lieu of a committee, a conflict of interest official. The Conflict of Interest Committee is responsible for identifying, quantifying, and potentially reducing the financial conflict of interest of any individual conducting human subjects research. Findings from the Conflict of Interest Committee are to be made known to the IRB. Institutions were tasked with developing written policies detailing substantive prohibitions and restrictions, reporting, implementation, disclosure, monitoring, and review of financial conflicts of interest. The AAMC task force recommendations specific to managing institutional conflicts of interest make particular reference to the makeup of the Conflict of Interest Committee. The membership roster is to include only individuals who are independent of the direct line of authority for clinical research oversight within the institution. The task force further recommended the inclusion of at least one or more individuals with to the institution The institutional of Technology is to report to the Conflict of Interest Committee any licensing into by the institution that equity interest, and the reporting guidelines are recommended for institutional In potential financial conflicts of interest should be disclosed by the individual conducting the research. The should be into the patient consent and the financial interest in question should be and not to additional to the welfare of the research participants or to the of the industrial representatives also to their own of dealing with investigators and academic The Research and of developed a on with This effect on July and was in January Of greater interest to the membership of this society is the of on with Health by the Medical Technology Association is a of medical technology and the of was on January The of the into effect on July This and document such important as company conducted product and with healthcare and research and to the of the include guidelines that address with healthcare and the of companies that their of the for public review on The of have also done their part to for and the scientific of human subjects research. The two leading in the of surgery, the of and and the of that authors report any financial conflicts of interest a is for The of those have the of such conflicts on the title of the article at the of However, the of only one of a conflict of interest. To ensure that authors of research data and the freedom to publish the results of clinical research, the Committee of Medical the for to and for to of potential conflicts of interest, this document that authors potential conflicts to study participants and that they have done within the of the The document further that in reference to conflicts of interest to support should not into an that with their access to the data and their to and to and publish To ensure that investigators are for their own research, authors of a study funded by a with a or financial interest in the may also be to a to the effect that had access to the data in this study and I responsibility for the of the data and the of the data The of the of and and the of have new to their for that a policy in which a a study in which “an other than the investigator had of the data or had over might be on that Such policies serve two to research scientists in their with industrial in developing and to ensure of the have information to make an informed judgment about potential bias in the research In the since the death in the gene therapy clinical trial, significant has been made in the and management of of conflicts of interest. However, this is a process in The majority of management policies are in the of recommendations or There has been a response from institution to institution with to developing and on policies and that are a number of in which potential conflicts of interest can be and In clinical trials, investigators be involved in aspects of trial the of and In funded research, investigators of data and data The research scientists be the freedom of publication of a conflict of interest on behalf of the investigator or the institution at which funded research is should be should be in the consent document that a potential research to the presence and of a possible conflict of interest. By doing so, the potential research is made aware of the conflict and is the opportunity to an as to the impact of such a conflict on the investigative process. such written should include financial the of It has also been suggested by one that informed consent should include a of the quality of medical evidence on which recommendations are should an opportunity for between the investigator and the potential research the latter is that safety is and the study is conducted bias. of conflicts of interest is the responsibility of not only the investigator but also the institution. In to the informed consent of conflicts of interest and Institutional Conflict of Interest should be developed with a mandate to review potential conflicts of interest and ensure that such conflicts are disclosed and Conflict of Interest Committee membership should include research scientists who have conflicts with the institution, the investigators, or the clinical trial in which the faculty of the academic institution is To one or more members of the Conflict of Interest Committee should be from the institution. The Conflict of Interest Committee should be charged with developing policies for management of potential conflicts and should with the to ensure that such policies are It has been suggested that a for to AAMC guidelines might be better accomplished by the guidelines into the companies should to of should be in and an need for the and that such was for should be with and not based on the or of the business academic medical the Conflict of Interest Committee should oversight for faculty members who into The and potential research participants should be made aware of and be that such in influence the or of clinical research. A financial be it an investigator or institution should not serve as investigator or data in a clinical trial. The of a financial on industrial support or on an investigator's or institution's equity interest in an industrial have to be In for patient care should be first and in the of involved in human subjects research. To the of the scientific such investigation be conducted free of or advances in medical in general, and in particular, a relationship among academic medical and industrial In the would that may be an increased reliance on industry for financial support in the future. The of our society since has been to advance medical technology for the of our patients. To this ASAIO is with a membership that an and of to the task at The of our society is our to a clinical a to address that the new and, in and clinical trials our the complex process and more understand the process by which new technology is to the To ensure that we to be to new to the board and technology to the clinical we be open and in our management of conflicts of interest, the of our clinical research are and our to participate in the process

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