The earlier presentations in this series describe mechanisms for technology development and transfer as you work to transform your research findings into beneficial products for improved health care and health. As this interest in commercialization and in programs and activities that connect universities with industry increases, so, too, do discussions of the benefits and the risks of these relationships for research, researchers, universities, industry, professions, patients, and the public. In this presentation, we will briefly discuss some of the ethical issues that are being raised by the growing academic focus on technology transfer and research commercialization. The ethical issues relate largely to real and potential conflicts of interest (COIs) that might impact individual and institutional integrity and objectivity in research (and especially human subjects' protection), as well as in training and clinical care. These concerns are not new, although the policies to address them continue to evolve.
Case presentations often can facilitate ethics discussions, so 2 related scenarios are presented below (Table 1). As you read these cases, see whether you identify any matters of concern, and if so, also consider what assumptions you are making in reaching your assessments. I will return to these cases later on.
THE CLINICAL RESEARCH CONTINUUM-WHO IS DOING WHAT?
The model for drug development, described earlier by Freeman and Dervan, outlines processes by which basic science discoveries may be developed into potential new beneficial therapies. Historically, academic researchers have been leaders in the basic science (discovery) aspects, and clinical investigators at academic health centers (AHCs) have been involved in clinical trials and in the diffusion of new products (including via their training programs). Pharmaceutical companies have been key players in later product development, clinical testing (together with AHC researchers), and in the production and marketing of new interventions. However, the applied (a.k.a., development or translational) research and related activities that are needed to bring a research-based product idea to the point at which a company wants to take on its further development and commercialization continue to pose difficult scientific and funding challenges. A hope that research knowledge and innovation will lead to tangible societal benefits underlies the strong public support for research and for academic institutions. Toward this goal, universities and AHCs have been increasing their focus on technology transfer and research commercialization. As you consider the effects of these activities, it helps to review some of the events that have contributed to them.
In contrast to some other countries' governments, the US government, historically, has strongly supported basic biomedical research (largely via National Institutes of Health [NIH] and National Science Forum) but not research commercialization. Partly in response to the world wars and to calls to address national defense needs, academic involvement in more applied research started to increase initially in the physical and engineering sciences with targeted defense-related research-contract supports.1 Universities accepted these funds and developed programs, some of which later were spun off into separate entities to promote technology transfer (eg, Draper Laboratories and MIT; http://draper.com/history/history.html). The parallel development in biomedicine was more controversial2 and lagged, but was later catalyzed by several key events including the following:
1. The Rise of Biotechnology: Genetic engineering and other biotechnologies can quicken the discovery-to-product time lines for some types of innovations (eg, developing DNA-based diagnostic tests). With these tools, biotechnology companies were established to fill some of the research-to-product translational gaps, and industry became more involved in earlier stages of product discovery and development. Academic researchers, some of whom were founding participants in biotechnology companies, also increased their focus on product development. This shift toward commercialization involved academic institutions as well, supported by new government policies and programs.
2. Increased Government Support for Development Research: In 1980, Congress was interested in promoting the international competitiveness of US businesses, and biotechnology was seen as a strong new sector for development. Although patenting of research discoveries by academics was controversial,2,3 Congress passed the Bayh-Dole Act (Public Law 96-517, the Patent and Trademark Law Amendments Act) granting patent rights for government-funded research to universities, if the universities would work to commercialize them. Congress also enacted the Stevenson-Wydler Technology Innovation Act of 1980 (Public Law 96-480; later revised in the Federal Technology Transfer Act of 1986; P.L. 99-502) to encourage technology transfer and cooperative research agreements between government laboratories and private companies. Soon thereafter, Congress authorized the Human Genome Project,4 directly supporting genetics research (a cornerstone of biotechnology). Programs, such as the SBIR and STTR, (described by Smith earlier in this series) and the NSF Engineering Centers were established to connect academics and industry and to foster development-related research. This trend of promoting academic-industry collaborations and research applications has continued in some of the NIH roadmap initiatives for reengineering the clinical research enterprise and in the proposed new National Center for Advancing Translational Sciences. Academic institutions have continued to respond.
3. Changes in Clinical Research: Industry has long been a key funder of clinical trials at AHCs, although, previously, the funded trials were mostly initiated, designed, and overseen by academic researchers. This changed as independent clinical research organizations were established to design and run clinical trials in nonacademic clinical settings for the growing biotech/pharmaceutical industry.5 Drug companies became more directly involved in trial design, implementation, and analysis and could then approach AHC investigators with already developed studies to invite their participation (often as one of a multisite study). Academic sites afford access to AHC patients and add academic cache to the research. They also can involve clinical medicine thought-leaders, who might then write and inform other clinicians and trainees about the innovations, thereby potentially giving endorsement for the product's diffusion into practice. However, this newer clinical trial model limits academic investigators' input into a trial's design (including what is tested). If a protocol is not accepted by an AHC investigator, a company might take it, along with its funds, to another researcher and center. In an environment of constrained research funding, this can put pressure on AHC faculty and institutions to accept trial protocols.
4. The Rise of Managed Care: Academic relationships with insurance and pharmaceutical industries that relate to clinical practice often are not viewed in the same way as the research-related academic-industry connections for drug development, clinical trials, and commercialization. Because inappropriate industry influences on clinical practice raise ethical concerns for practitioners in nonacademic settings as well, the addressing of practice-related industry relationships often focuses on the individual practitioners and the clinical profession rather than the academic affiliation. That said, a hospital's academic connections might increase its visibility and the public's expectations of its clinicians. Additionally, academic researchers, in part responding to managed care, have increased their study of health services research and health care financing. As this research is used in guiding clinical management and training, understanding connections to related industries and stakeholders becomes important.
So with these (and other) changes, academic technology transfer activities and industry ties have become common. In a 2006 survey of department chairs at 125 medical schools and 15 large, independent teaching hospitals, 60% of responders reported personal relationships with the industry, and 67% of responding department chairs affirmed industry connections in their departments' funding.6 This funding was generally more prevalent in clinical departments, although the nonclinical departments reported greater technology transfer and intellectual property-related revenues. Among surveyed AHC biomedical researchers, translational, clinical, and multimode researchers reported more significant industry relationships compared with basic science researchers (61%, 67%, and 71%, versus 42%, respectively).7
This prevalence of industry ties attests to the benefits they provide to academe. In addition to help in seeing one's research transformed into a beneficial intervention and to the obvious financial advantages of funding for research and training programs, other benefits might include, access to industry expertise and materials (eg, potential new compounds to be tested, placebos for use in trials, expertise on product production, and expertise on the dissemination of information to practitioners) and career opportunities. It also has been suggested that faculty with industry support may be more productive than their colleagues.3,8 Yet as academic involvement in technology transfer and commercialization continues to be promoted, concerns about the impacts of these activities on academic research, training, and culture; on academic medicine; and on the public's trust in academe continue to grow.
WHAT ARE SOME CONCERNS?
Media reports on biotechnology, managed care, and biomedical research have increased public awareness of the connections between research (basic and clinical) and medical innovations, between academic institutions and commercial enterprises, and between biomedicine and money. In addition to highlighting research and biotechnology successes, there also have been disclosures of scientific misconduct and harms to human research participants. It has become common for newspapers to report on the (potential) undue influences of industry monies on key university and AHC activities (eg, in research,9 education/training,10 and clinical care11).
PUBLIC TRUST AND COIs
Universities and, by extension, their faculty hold special positions in society because of their missions to extend knowledge, scholarship, and teaching for public benefit and not for profit. In alignment with public expectations of societal benefits from biomedical research, university missions have been expanded to include applications of knowledge and scholarship, such as economic development, technology transfer, and community education and service.1 However, although technology transfer and beneficial drug development are the common goals of both academe and industry, companies also have their clear profit motives. As academics focus more on applying their research, as university-industry connections expand to commercialize (produce and use) new discoveries, and as the universities themselves become further invested in these commercialization processes, there are concerns about the blurring of missions and of untoward impacts of commercial influences on academic centers, their work, and the public's trust.
CONFLICTS OF COMMITMENT
For an academic institution, as an individual researcher focuses more on commercializing his/her research, there is the possibility that conflicts with the faculty member's commitments to the institution might develop. Universities typically expect their faculty to have a professional allegiance to the institution with their primary commitments of time and intellectual energies being directed toward their academic obligations (education, research, and scholarship).12 Faculty members build and also benefit from the reputation and status of their academic institutions. Many universities allow (even encourage) their faculty to engage in activities outside the institution to enhance their academic endeavors and, in part, also to fulfill the universities' missions for community involvement. Conflicts of commitment may arise if a faculty member spends more than the permitted time on outside activities or if those external activities (or, for that matter, their internal institutional works) are not aligned with the university's missions and policies. Some have questioned the balancing of institutional commitments and academic freedoms,13 but to maintain the university's special societal status, its faculty's works need to reflect the societal expectations of academic research integrity and objectivity and of nonprofit works for public benefit.12 Whether an industry-related product-development activity by a faculty member poses a conflict of commitment for a university may differ by institution, and one wonders whether this might change were the institution itself to have an interest in the research commercialization.
Individual COIs arise when personal interests conflict with one's professional role(s) and obligations or when a person has multiple roles with conflicting responsibilities. For a physician-researcher, role responsibilities arise both from professional obligations (eg, physicians' codes of ethics and conduct) and from academic institutional commitments and roles. Conflicts in research and teaching roles depend on academic obligations, whereas conflicts in clinical practice also stem from one's clinical professional responsibilities. There are potential conflicts between these roles-for example, when a physician also is a researcher and her/his patient is a research participant.14 For an academic-clinician-researcher-mentor who also is trying to bring her or his research into the clinic via a spinout company, things get even more complicated. There is a need to ask, which "hat is being worn" at any given time? Are others aware of these multiple roles? Does one role adversely affect the other(s)?
For research, a key concern is that COIs may introduce bias or otherwise negatively affect research integrity and objectivity. Because research integrity is based on trust, this concern is not just about actual COIs, it also is about potential or perceived conflicts that might lessen that trust. Bias can impact outcomes at many points in a research study. The topic you choose to study, the specific question you ask, and your study design all shape the data you can obtain. Your choice of outcome(s) and analyses can influence the conclusions you might draw. Although research and publication biases may be unrelated to technology transfer or commercial interests, some studies have suggested that commercial funding may bias research conclusions.15,16 In one study of research meeting abstracts and their respective conclusions, 24% of the industry-sponsored works reported positive results, whereas 90% of their conclusions gave a positive (industry-favorable) spin to the outcomes.16 Importantly, these studies report associations, not proofs of cause and effect.17 Yet they raise critical questions that need further investigation.
Professional entities (eg, peer-reviewed journals) and, in particular, academic institutions are relied on for oversight. Recall the case of the research publication. Did you have a different level of comfort (or trust) in the results when the researcher was at an academic institution, and the study was funded by NIH, without industry connections? When a researcher also is an industry consultant, the potential for a COI is recognized, although the disclosure does not tell us whether this actually affected the work. It is not always clear how one should respond to this disclosure in evaluating the research.18 If the research is discounted, then its potential benefits may be eliminated, and this is particularly problematic for human subject research if participants agreed to undertake risks based on these potential benefits. To prevent this, any real, potential, and perceived conflicts need to be assessed by institutional review boards (IRBs) in determining whether a research protocol as proposed is permissible. For this, full disclosure is a first step. However, determining exactly what constitutes a significant conflict to then limit involvement in the research remains a key challenge for IRBs and for institutions (via their COI policies).19
Conflicts of interest with regard to academic technology transfer and university-industry relations heavily focus on financial COIs. This may, in part, be due to the recognized power of money and to the greater ease of quantifying monetary amounts and limits. Also, the profit motive is presumably a key difference between industry's and academe's otherwise common interest in product development. However, there also are significant nonfinancial interests that might adversely affect integrity or objectivity in research,20 for example, interests relating to career advancement, recognition for achievement, or even to a zeal for advancing a particular theory or research approach. These interests perhaps relate more to structures within the academe rather than specifically to technology transfer or commercialization activities. As academic institutions incorporate the latter goals into their cultures (and their reward and promotion criteria), any overlaps in conflicts of academic interests and financial COIs (from companies or within academic institutions) warrant consideration.
Although initial COI policies have largely focused on individuals, there is increasing recognition of the need to also address institutional concerns. Institutions can have multiple roles, such as educational institution, research center, hospital, and commercial partner, and here, also, interests might conflict.
So what about the university holding the drug patent in our publication case? Potential institutional COIs have been explored21,22 but, as yet, not as thoroughly addressed. In one survey of IRB members, who have critical roles in reviewing clinical studies and protecting human research subjects, some IRB members acknowledged not disclosing a conflict with a protocol and voting on it.23 In another survey of academic institutions, a majority reported policies in place for institutional officials (senior officials, 71%; mid-level officials, 69%; IRB members, 81%; and governing board members, 66%), but only 38% reported policies for their institutions.24 As academic institutions benefit directly from research patents and other industry connections (eg, funding for faculty, spinout companies), are these institutional interests influencing their culture and missions or adversely affecting their oversight of research and researchers? Because of potential conflicts, the question has been raised as to whether an institution (not just a researcher) should be undertaking the testing of a compound for which it holds the patent?25
WHAT IS BEING DONE AND WHAT NEEDS TO BE DONE?
While promoting technology transfer and research commercialization, including ties with industry, academics also need to preserve integrity and trust in biomedicine. Academic institutions and many professional and government groups have been examining university-industry relationships and developing policies to mitigate and manage COIs. Table 2 provides a partial listing of Web site links for some related reports, policies, and guidelines. Among these, the recent report by the Institute of Medicine (IOM)19 provides an extensive review of the issues and related ongoing activities as well as recommendations for addressing COI concerns in medical research, training, practice, and clinical guideline development. The report also gives guidance on the processes for developing and implementing COI policies, advocating for transparency (be open and accessible to all), accountability (clearly identifying parties responsible for oversight and compliance), fairness (be equitably implemented across institutions and personnel), and calling for proportionality (adequately addressing concerns without unduly limiting or encumbering legitimate, responsible activities). How best to attain proportionality remains a very difficult challenge with the many and varied types of academic-industry connections and with many differing perspectives on what the risks are and what remedies and preventive measures are needed. As mentioned earlier, industry relationships that are research related often are viewed separately from those for clinical care, and relationships with pharmaceutical, medical device, and biotechnology companies often are viewed differently than arrangements with the insurance industry. However, in bridging research and practice, there are overlaps as well as unique new considerations, and there are researchers who are also clinicians. In developing these policies, the additive impacts of policies are critical to assess.
To reach consensus and increase the success of COI policy implementation, the IOM report advocates for voluntary, inclusive collaborations among stakeholders (public and private) in formulating COI policies. It also identifies a need for further research to help in developing policies and for assessing their effectiveness. Academe and industry are urged to self-regulate, but if these efforts fail to adequately address public and congressional concerns, the IOM report acknowledges that further external regulations likely will follow.
As most of you know, the NIH has policies to address objectivity in research, the protection of human research subjects, and financial COIs in research (http://grants.nih.gov/grants/policy/). Grantee institutions are charged with implementing and overseeing these policies for their funded projects and researchers. The current NIH financial COIs policy requires that all "significant financial interests that reasonably appear to affect the research for which you're seeking funding and in entities whose financial interests might be affected by the research need to be disclosed to the grantee institution." It defines a "financial interest" as essentially anything of monetary value, although it makes exception of monies connected with the grantee institution itself (salaries as well as royalties). The current limit for disclosure exclusion is an aggregated monetary value of less than $10,000 or a less than a 5% ownership in a company. An institution may impose more stringent disclosure requirements, so you have to know your own institution's specific policies. The NIH is currently revising its policy with, among other changes, lowering monetary limits for disclosure exclusions (http://grants.nih.gov/grants/policy/coi/major_proposed_changes.pdf).
Once disclosed, there has to be a determination of whether the financial interest is significant as regards a specific research, training, or other academic activity. An earlier Association of American Medical Colleges (AAMC) report on COI policy recommendations (https://www.aamc.org/initiatives/coi/) advocated that individuals with significant financial interests do not conduct research involving human subjects. That said, it also acknowledged a need for gray areas in criteria. For example, if a person with significant financial interests is the only person deemed capable of doing certain research or training, then institutions need some flexibility to see if oversight and monitoring can be put in place to still permit this investigator's involvement. Related to this, one of the proposed changes to the NIH financial COI policy would call for institutions to disclose to the NIH their plans for determining and for managing significant financial inerests in relation to specific research projects.
Some of the other research-related recommendations, by AAMC and others, include prohibitions of funding for results, policies about intellectual property and publications (including for example, ghostwriting), restrictions of industry funding for continuing medical education, and specific protections for trainees and students, recalling the case of the graduate student (Table 1). The AAMC guidelines recommend avoidance of any restrictions or nondisclosure agreements for a student's work, as well as for any agreements that might conflict with the students' degree requirements. There has to be full disclosure to students by faculty of potential COIs, and if there are any potential concerns, there should be oversight and scrutiny by a COI committee that is outside of the laboratory or the department. Here again, some trainee-mentor conflicts (eg, what you may take with you when you leave the laboratory) can arise irrespective of industry connections or support. For students, postdoctoral fellows and their advisors/mentors, the AAMC has developed some compact templates that may be helpful.26,27 Additional resources, such as the FASEB toolkit (Table 2), also provide practical guidance (http://www.faseb.org/coi/Home.aspx). Again, be sure to learn your institution's policies.
Many other activities involving academic-industry connections are addressed in COI policies. The policies largely focus on individual COIs with the academic institutions being given the responsibility for policy implementation and monitoring. Going forward, the feasibility (including cost) and effectiveness of these policy arrangements for individuals and institutions need to be assessed. With institutions being responsible for this oversight, the further evaluation of institutional COIs and of nonfinancial COIs is needed, and their effects should be assessed. As noted in the IOM report, it is critical that individuals as well as institutions that are actively involved in translational research and in industry relationships all be active in shaping appropriate COI policies.
A RAPIDLY CHANGING LANDSCAPE
Changes have been taking place in rapid order to address real and perceived COIs. Legislatively, these have focused more on conflicts in clinical practice and, specifically, the disclosure of payments to physicians. For example, in Massachusetts, a law passed in 2009 (M.G.L. c.111N: 105 CMR 970.000) bans gifts to physicians and requires industry to disclose fees paid if more than $50 to those covered by this law. Similarly, on the national level, the Physician's Sunshine provisions of the Patient Protection and Affordable Care Act (passed March 2010) requires companies to disclose funds paid (if more than $10 or when aggregated equaling $100/yr) to physicians or covered entities. Universities also are further responding to concerns about COIs in practice and research. The AAMC updated its recommendations and called for their implementation within 2 years (https://www.aamc.org/initiatives/49750/coi/) and, in 2010, issued a new report focused specifically on Physician Financial Relationships and Clinical Decision Making (https://services.aamc.org/publications/index.cfm?fuseaction=Product.displayForm&prd_id=303&prv_id=375). Stanford Medical School was one of the first schools to put its faculty disclosures online, starting with its medical school with plans to broaden this.28 Other institutions are following suit, for example, Harvard University announced changes to its policies for faculty-industry relationships.29 As previously noted, NIH is finalizing policy changes with regard to financial COIs in research, and it also will be important to see how COI matters are addressed for the proposed new NIH institute's activities.
In conclusion, this paper has raised many questions about the impact of increased academic focus on technology transfer and commercialization. There are differing views both on the extent of the problems and on what to do in response. Some people believe that more regulation will stifle progress and that we are having enough hard time bringing research-based products into practice as it is.30 Others believe that policies currently in place are not accomplishing what is needed and propose further modifications.31 As policies evolve, maintaining the public's trust in the integrity and objectivity of academic institutions' missions and work is critical. Conflicts will always exist, and there is a need to carefully figure out how they can be minimized and managed to reach our goals and those of patients and society in this rapidly changing landscape.
The author thanks Carie Lambert, for editorial and technical writing assistance in preparing this manuscript for publication.
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