American Journal of Law & Medicine

Confronting conflict: addressing institutional conflicts of interest in academic medical centers.

ABSTRACT

Individual conflicts of interest are rife in healthcare, and substantial attention has been given to address them. Yet a more substantive concern-institutional conflicts of interest ("ICOIs") in academic medical centers ("AMCs") engaged in research and clinical care-have yet to garner sufficient attention, despite their higher stakes for patient safety and welfare. ICOIs are standard in AMCs, are virtually unregulated, and have led to patient deaths. Upon review of ICOIs, we find a clear absence of substantive efforts to confront these conflicts. We also assess the Jesse Gelsinger case, which resulted in the death of a study participant exemplifying a deep-seated culture of institutional indifference and complicity in unmanaged conflicts. Federal policy, particularly the Bayh-Dole Act, also creates and promotes ICOIs. Efforts to address ICOIs are narrow or abstract, and do not provide for a systemic infrastructure with effective enforcement mechanisms. Hence, in this paper, we provide a comprehensive proposal to address ICOIs utilizing a "Centralized System" model that would proactively review, manage, approve, and conduct assessments of conflicts, and would have independent power to evaluate and enforce any violations via sanctions. It would also manage any industry funds and pharmaceutical samples and be a condition of participation in public healthcare reimbursement and federal grant funding. The ICOI policy itself would provide for disclosure requirements, separate management of commercial enterprise units from academic units, voluntary remediation of conflicts, and education on ICOIs. Finally, we propose a new model of medical education--academic detailing--in place of current marketing-focused "education." Using such a system, AMCs can wean themselves from industry reliance and promote a culture of accountability and independence from industry influence. By doing so, clinical research and treatment can return to a focus on patient care, not profits.

I. INTRODUCTION

Academic Medical Centers ("AMCs") have become the front line for the conflict between scientific integrity in medicine and corporate interests. Conflicts of interest occur on a daily basis in the practice decisions made by individual physicians, which have been well recognized in a variety of settings. (1) However, importantly, they also occur at the institutional, AMC level. These conflicts have created significant concerns regarding what approaches should be adopted to ensure that clinical and research decisions are made with social concerns foremost, rather than institutional self-interest. (2)

Conflicts frequently arise when pharmaceutical companies and AMCs wish to share in lucrative business arrangements originating from research underwritten by corporate funds performed at the AMC and the products arising therefrom. (3) The issues implicated by this conflict encompass patients and their safety, trust in physicians and medical institutions, the overall economic cost through increased health care expenditures, and academic and scientific integrity. (4)

Industry involvement and support of AMCs may nevertheless be acceptable if conducted in an appropriate manner. However, industry relationships with AMCs that give rise to conflicts of interest pose a significant concern and challenge to AMCs. Those relationships have the potential to compromise the integrity of an institution and undermine the public's trust in the medical and research community. Further, these conflicts can endanger patient lives with little or no benefit to the individual patient or society. These problems are analogous to similar concerns regarding individual and institutional conflicts of interest by lenders and universities which participate in federal government student loan programs. (5)

Unfortunately, AMCs have not substantively addressed institutional conflicts of interests ("ICOIs"), nor do they see it as a major concern. The limitations of the current framework have been illustrated by an analysis that found substantial variation in policies adopted by AMCs governing conflicts of interest, one-fourth of investigators had industry affiliations, two-thirds of academic institutions had equity holdings representing the presence of an ICOI, and management of conflicts of interest and enforcement or sanctions for failure to disclose were almost universally discretionary. (6) More recent studies show that though AMC conflict of interest policies are improving, 34% of AMCs continue to receive failing grades. (7) In addition, the methodology of these assessments continues to focus on individual conflicts of interest, and not on policies related to ICOIs. (8)

As centers for advancement in biomedical research and standards of excellence in clinical care, AMCs should set the example in dealing with these issues and mitigating ICOIs. Hence, this paper discusses approaches to ensure AMCs are effectively managing these conflicts.

In Part II, this paper examines the Jesse Gelsinger case, which resulted in his death after participating in a clinical study at the University of Pennsylvania. Upon assessment, this case illustrates the negative results of unmanaged ICOIs at AMCs and how they impact the lives of patients and the conduct of scientific research in a very real and tragic way.

In Part III, this paper examines ICOIs in more detail. Through this examination, it becomes apparent that these types of conflicts of interest are much more difficult to define and detect, and have not been adequately addressed by any of the relevant stakeholders, including AMCs themselves. The root cause of these forms of conflict arises from the commercialization of research through federal legislation, and the need for subsidization of scientific progress by the pharmaceutical industry. The interdependence between academia and commercial interests in these practices leads to a dangerous partnership that gives rise to questionable financial relationships, and has not spurred appropriate self-regulation to mitigate ICOI effects.

In Part IV, attempts by the federal government to respond to the challenges posed by ICOIs at AMCs are also discussed. This assessment reveals high-level principles and concepts for addressing ICOIs, but finds they fall short in providing an effective organizational framework that identifies, addresses, and proactively manages these conflicts.

In Part V, this paper analyzes and discusses the limitations of current responses and proposed solutions to ICOIs. This includes a discussion of the limitations of disclosure laws and legislation, academic policies on conflicts of interest, current regulations governing ICOIs, and the inherent challenges of relying on self-policing by AMCs and industry.

In Part VI, to address this issue, a set of policy proposals is presented. These proposals include the development of independent oversight mechanisms to ensure compliance of ICOI policies, mandatory adoption and standardization of policies and procedures to address ICOIs, and the development of alternative forms of scientifically-sound methods to limit the need of institutional-industry interactions, focusing particularly on medical education so as to promote a culture of institutional independence. The proposed solutions include the establishment of a centralized system to manage and administer conflicts of interests from an organizational standpoint, mandatory adoption by AMCs of a comprehensive policy on institutionally-based conflicts of interest, and adoption of academic-detailing programs. The integration of these policies addresses deficiencies in current self-regulation of ICOIs by AMCs.

II. THE JESSE GELSINGER CASE

It is important to realize that the negative implications of ICOIs are not merely theoretical constructs. These conflicts have resulted in serious negative outcomes for patients and research. (9)

A. THE DEATH OF JESSE GELSINGER

A prime example of the consequences of failing to manage ICOIs at AMCs is the death of Jessse Gelsinger, an 18-year-old study participant, in a gene therapy clinical trial conducted at the University of Pennsylvania. (10) Gelsinger suffered from a rare genetic disorder known as ornithine transearbamylase deficiency, which affects the body's ability to eliminate ammonia. (11) Though potentially life threatening, Geslinger had effectively managed his condition with a low-protein diet and medication, and otherwise enjoyed a productive and normal life. (12) Though Gelsinger allegedly understood that he would not benefit from his participation in the Phase I study of the gene therapy, his decision to participate was motivated by his hope that results from the study would free him from his restrictive diet routine in the future. (13)

Gelsinger began the study, but soon problems emerged. The night of his injection with the gene therapy, he experienced a high fever and abdominal pain, and by the next morning, he experienced severe hepatic failure and blood clotting, then lapsed into a coma. (14) From this point his condition rapidly deteriorated, and over the next few days, Geslinger suffered multi-organ failure and, subsequently, brain death. (15) Only four days after receiving the gene therapy treatment, he was removed from life support and died. (16) Jesse Gelsinger's death was then reported to government officials. (17)

B. INVESTIGATIONS

Initial investigations into Gelsinger's death suggested the gene therapy vector administered to him caused systemic inflammatory response syndrome, which led to acute respiratory distress syndrome. (18) This clinical status eventually led to his death from multiple organ failure due to anoxia. (19)

These initial investigations focused on the safety of the vector used in the gene therapy treatment, known as an adenovirus, (20) and possible human error. (21) However, during these assessments, highly troubling revelations of both individual conflicts of interests and ICOIs existing with the investigators and the university began to emerge, leading to more detailed scrutiny of the motivations and judgment exercised by those involved in the trial. (22)

A few months later, officials from the FDA announced that Gelsinger, due to the condition of his liver, should never have been a participant in the study. (23) Further, the University of Pennsylvania clinical investigators had violated FDA requirements by failing to immediately report information about participants who had experienced serious side effects prior to the Gelsinger study. (24) In addition, informed consent forms provided to participants were altered from that approved by the FDA through omission of important information regarding the death of animal subjects that had undergone similar treatment. (25)

Yet these FDA announcements were just the beginning. Gelsinger's death eventually led to worldwide negative publicity on gene therapy, an independent investigation, FDA suspension of clinical trials at University of Pennsylvania's Institute for Gene Therapy, FDA and Senate subcommittee investigations and hearings, (26) enforcement action by the U.S. Department of Justice, and a wrongful death lawsuit that was settled for an undisclosed sum. (27)

C. INSTITUTIONAL CONFLICTS OF INTEREST

Importantly, this case was rife with substantive institutional wrongdoing spurred by unmanaged financial conflicts. First, reports submitted to the FDA, NIH, and IRBs misrepresented the actual clinical findings, and proper disclosures to participants did not occur in the informed consent process. (28) Further, upon additional investigation, it was found that both the director of the institute leading the research, and the institution itself had significant financial interests in the biotechnology company that would bring the therapy to market. (29) Indeed, both the former dean of the University of Pennsylvania Medical School and James Wilson, the lead investigator of the study, stood to benefit financially from the commercialization of the therapy through their ownership of patents. (30) In addition, the AMC itself also had an equity stake in Genovo, the biotechnology company collaborator, which would have profited from commercialization of the gene therapy treatment. (31)

Further revelations showed even deeper problems. The university culture was passive, and resulted in nothing being done to address these conflicts. Although a university committee expressly recognized and noted that there were one or more conflicts of interest between Genovo and university employees, it nevertheless approved their presence and continued to allow these individuals to plan and conduct the clinical experiments. (32)

The presence of these ICOIs in the Gelsinger case brought into question the clinical decisions that were made during the course of the study. (33) Specifically, concerns were raised regarding whether investigators proceeded forward with the study despite their knowledge of negative data, such as the risks the adenovirus vector posed to study participants, whether investigators were incorrectly motivated by financial incentives to develop a marketable product that may have influenced their clinical decisions, whether investigators were misleading in setting expectations of therapeutic benefit and the risks of participation in the study, and the decision of whether Gelsinger was eligible for the study given his impaired liver function. (34)

These types of issues are pervasive when conflicts of interest exist in clinical research, and pose the danger of real harm to participants, and serve to undermine the legitimacy of scientific research. This incident also catapulted the issue of ICOIs into the national media, while at the same time dealing a major setback to the progress of gene therapy. (35) In February, 2005, the Department of Justice issued a release detailing the enforcement actions taken against both the University of Pennsylvania and the three investigators involved in the research. (36) These included over one million dollars in punitive fines for false claims allegations, and placement of restrictive controls on the clinical research activities of the named investigators. (37) Gelsinger's death also led to the adoption of more stringent policies related to conflicts of interest in clinical research by the Association of American Medical Colleges, Association of American Universities, and the U.S. Department of Health and Human Services, and led to the formation of the Association for Accreditation of Human Research Protection Programs, which provides voluntary accreditation for organizations which conduct human subject research. (38)

The Gelsinger case epitomizes the inherent risks associated with ICOIs as they exist in scientific research and serves as an important case study for identifying deficiencies in monitoring and managing ICOIs at AMCs. It also acted as a catalyst for current calls for additional oversight of ICOIs in clinical research, but has yet to lead to comprehensive reform. This case is not isolated, with other examples of patient death resulting from financial interests of investigators in clinical research also reported.(39)

III. INSTITUTIONAL CONFLICTS OF INTEREST

A. OVERVIEW

Individual conflicts of interests between physicians and the industry are well documented and have undergone detailed scrutiny from the public, media, and the government. (40) However, ICOIs have yet to be given the same level of attention, even though they pose an equal or even greater risk to the integrity of academic research and to patient safety as made evident in the Gelsinger case. (41) Currently, no laws or regulations (42) directly regulate ICOIs or the representatives of institutions that make decisions on behalf of the institutions as a whole. (43)

In a broad sense, ICOIs are defined as "when the institution, any of its senior management or trustees," a department or other sub-unit, or any "affiliated foundation or organization, has an external relationship or financial interest" with the industry that also has a financial interest in research being conducted at or by the institution. (44) These types of conflicts encompass decisions made by institutional units and departments. The most common forms of ICOIs that currently exist in AMCs are: (a) equity holdings or royalty arrangements; (b) intellectual property transfer arrangements in research programs; (e) decisions by university officials unduly influenced by conflicts of interests ("COIs") that have institution-wide implications; and (d) university officials participating as members of the board of a corporation with a potential COI. (45)

ICOIs also arise from institutional representatives that have individual COIs that are then transferred to decisions made by the institution as a whole due to the authority and influence over research that these individuals exercise. (46) ICOIs in this context include situations where an institution has equity in a company funding the institution's research; investigators who are employed by the institution and "conduct research that could affect the value of the equity interest;" or when an institution has intellectual property which it then licenses to companies and investigators employed by the institution to conduct research. (47)

ICOIs can also arise from more complex arrangements such as when AMCs engage in incorporation of start-up companies where the institution and its faculty act as major shareholders, secure cash payments for right of first refusal options on discoveries, market or exploit branding of commercialized products, (48) and maintain and profit from corporate equity positions in university endowments or gift funds. (49) However, a chief characteristic underlying all ICOIs is that arrangements are made at an institutional level, often at a department or unit of an AMC, or when AMC representatives make decisions with broad, institutional impact. These are often the product of AMC dependence on the industry for research funding or AMC-industry commercialization of advances in life sciences through licensing and technology transfer.

B. LIMITED ATTENTION TO ICOI

Based on concerns arising from highly publicized ICOI incidents, the Association of American Universities ("AAU"), Association of American Medical Colleges ("AAMC"), and the Department of Health and Human Services ("DHHS"), through their recommendations and guidance, have urged institutions to recognize and address ICOIs as a separate area of concern, (50) and mitigate these issues through disclosure, managing conflicts, and prohibiting these kinds of activities. (51) However, recent studies show that among AMC respondents, less than 38% have adopted ICOI policies, 37% have begun to work on them, and one quarter of respondents were not working on a policy or "did not know." (52)

This low compliance rate is in stark contrast to much higher affirmative responses in addressing individual financial COIs in these same institutions. (53) Hence, it appears that in the four years since the issuance of guidance from the AAMC, (54) only approximately one-third of AMCs have actually adopted such policies even though these relationships continue to be commonplace and pose a potential threat. (55) These results also imply that monitoring of ICOIs is simply not a priority for AMCs.

C. DRIVING ICOIs: BAYH-DOLE ACT

Possibly the most highly debated issue regarding managing ICOIs in AMCs is the situation where an institution holds an equity position or has royalty agreements with a company that will utilize the AMC's developed technology. These forms of AMC-industry collaboration were encouraged through the passage of the Bayh-Dole Act in 1980. (56) Under this law, the U.S. government sought to facilitate cooperation between private industry and research institutions by allowing them to enter into technology transfer arrangements to better utilize developed innovations and accelerate their use for products brought to market. (57) Specifically, the Bayh-Dole Act allows for the grant of patent rights for innovator inventions conceived and funded in government-sponsored research and development programs, and allows grantees to profit from its commercialization. (58) The law provides for the ownership of patents by universities, nonprofit corporations, and small businesses, as well as permitting licensing arrangements. (59)

As a result of the passage of this Act, relationships between AMCs and the industry have rapidly accelerated, with industry investment in biomedical research increasing from 32% in 1980, to 62% in 2000. (60) Concomitant financial benefits from licensing arrangements with industry are estimated to generate close to $2 billion dollars annually for AMCs. (61)

While the Act may have resulted in the development of cooperation between AMCs and industry, (62) these relationships have promoted a framework of ICOIs that have the potential to compromise research integrity and patient safety in favor of institutional financial interests. (63) Fundamental to this problem is the fact that the Act allows AMCs to make patenting and licensing decisions on behalf of taxpayer-funded public agencies based on the AMC's own motivations, which usually includes a profit motive, at the expense of facilitating future research and maximizing social benefit. (64) In addition, it is difficult to effectively monitor these decisions by AMCs given their complexity and the subject matter expertise necessary to evaluate the technology and its potential commercial use. (65) Indeed, questions have been raised regarding whether there have been any actual social benefits for technology licensing under the Bayh-Dole Act. (66)

Importantly, the cultures of these institutions are focused upon financial benefits, and its representatives act accordingly. A survey in 2001 revealed that administrators and faculty researchers at AMCs believed that the most important outcome of technology transfer activity was the generation of revenue, not scientific progress. (67) Another survey reported that 68% of AMCs held equity positions in companies who sponsored their research. (68) These skewed motivations and the close financial ties between industry and academia that are encouraged and even mandated by the Act result in a plethora of ICOI situations, and have also resulted in negative consequences for human participants in research. (69)

Beyond the doubts raised regarding the effectiveness of the Act in promoting patent and licensing activities at AMCs, questions related to increased costs to the healthcare system have led to greater scrutiny of the Act. (70) For example, Emtriva, a drug developed by researchers at Emory University for the treatment of HIV, embodies the complexities surrounding AMC-industry collaboration in patenting and licensing, where scientific discovery is mired in patent litigation, delays in drug approval, and disputes regarding inventorship. (71) In this case, researchers were in parallel development of very similar compound which led to multiple lawsuits over rights and licensing of the compound. (72) This included four challenges at the U.S. Patent & Trademark Office and several more in other foreign regulatory bodies, millions of dollars in legal expenditures, and a decade and a half of continuing disputes in court. (73) However, this case represented only one of 494 patent suits filed by pharmaceutical companies from 1992 to September 2003 and represents a significant cost and burden to both taxpayers and consumers of pharmaceutical products. (74) Cases such as Emtriva lead to an increase in the ultimate cost of pharmaceuticals to consumers, barriers to access, questionable return on investment for taxpayer-funded research, and retardation of the dissemination and sharing of scientific discoveries. (75) These costs, coupled with stagnation in the development of more novel and innovative drugs, (76) the government's failure to exercise "march-in rights," (77) and questions regarding whether universities as a whole actually profit from patenting and licensing activities, (78) bring the merits of the Act into serious question.

Despite the debates on the extent of the law's influence on AMC commercialization incentives, the Bayh-Dole Act has certainly created an environment in which individual researchers and institutions can derive direct financial reward through industry collaboration. (79) This general fact presents serious challenges in self-policing of ICOI situations in AMCs, given that researchers and institutions share a collective interest in profiting from commercialization of scientific discoveries,s[degrees] In this respect, the Act continues to encourage and facilitate ICOI situations that flourish in an environment free from external oversight. (81)

D. DRIVING ICOIs: RESEARCH OVERSIGHT

The closely linked practices of biomedical and scientific research and commercialization of advances from that research have created economic partnerships between AMCs and industry with questionable benefits to society. The conflicts of interest that arise from these partnerships have become imbedded into the organizational operations of AMCs. (82)

AMCs clearly have a vested interest in the performance, success, and marketability of research that allows a transfer of technology, given that the more successful the results, the more potential revenue it provides to the AMC. (83) These ICOIs in the research arena may serve to negatively affect an institution's ability to make neutral, independent decisions, may incorrectly incentivize individuals to make decisions based on their own financial interest that then implicates institutional actions, and may make it difficult for institutions to produce unbiased and scientifically-sound data in research. (84) Further, the mere presence of these ICOIs brings into question the motives and decisions made by AMCs and their representatives, and compromises public trust in research regardless of whether a COI has been acted upon or not.

Distrust in institutions because of ICOIs in research appears well-founded. The prevalence of institutional academic-industry relationships is alarming. A recent study reported that an astounding 67% of departments and 60% of department chairs have relationships with the industry. (85) This data is alarming not simply due to extensive presence of ICOIs among institutional representatives who make decisions on behalf of AMCs, but also due to the fact that most AMCs do not have systematic processes to address these forms of ICOIs.

These partnerships have produced a lucrative revenue stream for AMCs, but at the same time have created an environment where institutional medical entrepreneurism has become the norm in academic operations, (86) Some have argued that the consequences of these incentives have led AMCs to shift away from their primary goal of unfettered scientific research, to focus on industry-oriented research and technology transfer incentives, which has transformed them into corporate research laboratories, dampening the progression of discovery. (87) Hence, the AMC can be seen as an actor interested in research that can result in patent exclusivity, which in the drug development context results in higher costs of pharmaceuticals, with a focus on prioritizing projects with immediate marketability. (88) AMCs are consequently similar to corporate actors that focus on commercialization for their (or individuals who act in their name) financial benefit. This undermines the basic tenet of the AMC, and the physicians and researchers who work within it, to benefit the public good first.

In addition, the primary system used for review of clinical research fosters a number of ICOI issues due to the nature and relationship between Institutional Review Boards ("IRBs"), research sponsors, and researchers. (89) While IRBs are meant to serve the important role of independent and formally designated review and monitoring of biomedical research to ensure the rights and welfare of human participants are protected. (90) oftentimes funding sources for an IRB may be identical to the institution conducting the research; further, preexisting relationships may exist between IRB members and research faculty who will perform the work. (91) This results in a lack of IRB functional autonomy, and the overshadowing presence of financial ties in monitoring places serious constraints on the IRB's ability to make decisions in the best interests of the study participant.

The heavy financial burden of financial costs for providing the infrastructure of research facilities and IRBs to monitor clinical research creates the need for corporate sponsorship, which again may give rise to ICOIs. …

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