Managing the Triple Helix in the Life Sciences

Over the past four decades, the increased financial, intellectual, personal, and legal interaction of academe, industry, and government has dramatically changed the structure of the life science enterprise, but the management systems to protect against conflicts of interest (COIs) and other abuses in these relationships have not kept pace. An analysis funded by the Kauffman Foundation found that there is little reliable and timely information about how these relationships are being handled at universities, and that government agencies employ a confusing mix of inconsistent policies and practices. A more transparent and coherent system for preventing abuse is necessary to preserve the integrity of the scientific endeavor, particularly in the biomedical and health-related sciences, and to prevent http self-interest from undermining the broad public interest that can be served if these innovative and productive relationships are effectively managed.

Developments such as the growth of the biotechnology industry, the passage of the Bayh- Dole Act to encourage commercialization of government-funded research, and the increased commercial activities of academic scientists have resulted in an expansion of the number and type of working relationships among academia, government, and industry (see sidebar). The most recent nationally representative data on the prevalence and magnitude of academic/industry relationships (AIRs) in the life and health-related sciences stem from surveys of company executives and faculty members that we at Harvard Medical School conducted in the mid-1990s. Our 1994 survey of senior executives of science companies revealed that over 90 percent of the firms responding to the survey participated in some form of relationship with academia, and 59 percent supported university-based research in the form of either a grant or a contract. Our 1995 survey of 2,052 faculty members in the life and health-related sciences at the 50 most research-intensive U.S. universities revealed that 28 percent of respondents reported receiving some research support from industrial sources. The prevalence of support was greater for researchers in clinical departments (36 percent) than those in nonclinical departments (21 percent).

But these industry connections reach further than simply direct research support. The most prevalent relationship was the retention of university faculty as consultants, a strategy used by 88 percent of life science firms. In the 1995 study, nearly 60 percent of scientists had consulted with industry in the three preceding years, and 26 percent of that group reported these activities as a major source of supplementary income. Seven percent of companies in our survey reported that faculty members were significant equity holders in their companies.

In addition to providing grants and contracts to university researchers, industry commonly makes contributions that can help with research. Among life science faculty in the 50 most research-intensive universities, we found that in the three years preceding the study, 43 percent received research gifts from industry. The most widely reported gifts were biomaterials (24 percent), discretionary funds (15 percent), research equipment (11 percent), and trips to professional meetings (11 percent). Separately, 38 percent of companies reported that they financially support the training of students and postdoctoral fellows.

As little as we know about AIRs, we know even less about government/industry relationships (GIRs). However, the recent series of newspaper articles regarding lucrative financial relationships between senior scientists at the National Institutes of Health (NIH) and industry resulted in questions from Congress about the nature and extent of these arrangements. In response, NIH Director Elias Zerhouni convened a special advisory group to explore the background and propriety of such relationships and to issue a report containing appropriate policy recommendations for dealing with them.

Benefits spur relationships

We should not be surprised by the large and growing number of AIRs, because they provide considerable benefits to the companies, universities, and individual researchers who participate. The institutional benefits have received the most attention, but more information is beginning to emerge about the personal financial benefits for academic researchers.

For the company and academic lab, AIRs can facilitate the bidirectional flow of the most recent research results, often months or even years before they are published. Industry sponsors of university research commonly demand 30 to 90 days to review the results of the research they fund before it is submitted for publication, and informal communications with researchers can provide useful insights even before the research is completed. University researchers benefit from access to industry biomaterials (such as cell lines, reagents, and tissues), equipment, and other research-related resources that might not be available outside of a relationship.

Universities obviously value the income to support research. In our 1994 survey, senior research executives at 306 life science companies reported that their companies supported more than 1,500 university-based research projects at a cost of over $340 million in the previous year. Based on these reports, it was estimated that the life science industry as a whole supported more than 6,000 life science projects and expended $1.5 billion for academic-based research in the life sciences.

Universities also benefit when industry commercializes faculty inventions, because universities often receive revenues from commercial ventures. For example, academic institutions may support the costs of filing a patent in exchange for a portion of the licensing revenues, or they may provide venture capital funding for a startup in exchange for a share of the future profits of that firm. However, it is important to note that universities can receive royalties whether or not they support the costs of patenting. On rare occasions, universities have also reaped sizable rewards from royalties on licensed patents and from the sale of equity in startup companies based on faculty research.

For the researcher, the benefits are professional and personal. Contrary to what many believe, the receipt of industry research funding is not associated with detectable adverse effects on academic productivity. Indeed, if anything, research funding from industry is associated with significantly greater academic productivity on the part of university investigators. In our 1994–1995 survey of more than 2,000 life science faculty, those with funding from industry published significantly more articles in peer-reviewed journals in the previous three years than faculty without industry funding (14.6 versus 10.1, respectively). Of course, our research could not establish causality.

A number of additional benefits may accrue to faculty as a result of the commercial opportunities of AIRs, including financial returns, the opportunity to see the results of their university-based research developed into useful products and services, and enhanced career opportunities in the industrial sector. Compared to faculty without research relationships, those with industry funding are significantly more likely to report that they had applied for a patent (42 percent versus 24 percent), had a patent granted (25 percent versus 12.6 percent), had a patent licensed (18.5 percent versus 8.7 percent), had a product under review (26.7 percent versus 5.5 percent), a product on the market (26.1 percent versus 10.8 percent), or a start-up company (14.3 percent versus 6.0 percent).

Risks are real

On the other hand, these relationships also exacerbate fears about the scientific objectivity of research results, the health risks to study subjects, and the social structure of scientific exploration. Derek Bok, the former president of Harvard University, articulated the risks of industry relationships when he wrote that “[university-industry] relationships may divert the faculty. Graduate students may be drawn into projects in ways that sacrifice their education for commercial gain. Research performed with an eye towards profit may lure investigators into conflicts of interest or cause them to practice forms of secrecy that hamper scientific progress. Ultimately, corporate ties may undermine the university’s reputation for objectivity.” Although much of this concern is the result of a few highly publicized cases of questionable relationships, several empirical studies have supported the existence of risks associated with secrecy in science, bias in the reporting of research, negative effects on education, and conflicts of interest.

There is strong evidence supporting the belief that relationships with industry may compromise the norms of openness and objectivity in academic science. Data from a national survey of genetics researchers and other life scientists found that those with research funding from industry were significantly more likely to delay publication of their research results by more than 6 months to allow for the commercialization of their research. Delays of this kind might lead to a waste of time and tax dollars when individual scientists continue to work on problems that have already been solved.

In recent years, a significant body of research has emerged suggesting that relationships between academic scientists and industry have an impact on the content of scientific reports emerging from industry-supported research. A 2004 meta-analysis of 23 studies of the impact of AIRs on the outcomes of research found “a statistically significant relationship between industry sponsorship and pro-industry conclusions.” Examples of scientific areas in which industry funded studies that led to pro-industry conclusions include randomized clinical trials for treatment of multiple myeloma, economic analyses of oncology drugs, the cognitive effects of nicotine, and the clinical effectiveness of nonsteroidal anti-inflammatory drugs or calcium channel blockers. This is not to say that industry-funded research is intentionally biased toward pro-industry findings. It may be that industry selectively funds research that is likely to yield favorable conclusions or that industry-funded studies address different questions than non-industry funded studies. Regardless of the reason, the association between industry relationships and pro-industry results exceeds what would be expected on the basis of chance alone.

Another risk mentioned by Derek Bok is whether research relationships with industry might have a negative effect on scientists in training, but there is little evidence to support or refute this claim. A 1985 survey of 693 advanced trainees in the life sciences at six universities found that 34 percent of respondents whose faculty advisor(s) were supported by industry felt constrained in discussing their research results with other scientists and had fewer publications than their peers who did not have industry support. Lack of visibility could hurt their careers.

For the general public, the primary concern is that there will be a financial conflict of interest (COI) when a researcher’s primary professional interest is inconsistent with a secondary personal financial interest. We argue that the primary interest of life scientists is the search for understanding of biological processes and communication of that understanding to the research community, and in many instances, the education of the next generation of scientists. Physician researchers in academic health centers have the additional responsibility of providing patient care. The primary interest of administrators of government and academic scientific organizations is leadership of the organization to facilitate the work of scientists. All other interests, including institutional or personal financial gain or enhancing one’s professional status, power, or recognition are secondary,.

These secondary interests are not improper in and of themselves. As noted by the editors of the Journal of the American Medical Association, “Conflicts of interest are considered ubiquitous and inevitable in academic life, indeed, in all professional life.” In fact, secondary interests, such as consulting and the faculty ownership of equity in a company stemming from one’s research, are often approved, and in some cases encouraged, by institutions. They often exist as a by-product of a researcher’s primary interest and can provide resources to enhance the pursuit of the researcher’s primary mission.

Attempting to eliminate all financial COIs from university research would be misguided. Some financial COIs are the inevitable result of the structure of science rather than a form of misconduct. When addressing these risks, one needs to determine the level at which these conflicts pose a serious threat to the scientific enterprise.

The balance in government

The benefits of GIRs are probably similar to those associated with AIRs. Relationships that foster more interaction among scientists with shared goals are likely to enhance creativity and productivity. Financial incentives are likely to be effective motivators of individual and organizational behaviors—for good and ill—in government as well as elsewhere. To the extent that these relationships can speed the development of new discoveries and technological advances, society can benefit. Government will also probably find it easier to recruit and retain the very best scientists if these scientists are able to supplement their relatively low government salaries with additional income from arrangements with industry.

However, to believe that these goals are likely to be achieved without the potential for abuse by some in the system is naïve. Because the government does not receive compensation for intellectual property or commercialization of products, it is likely that the financial benefits of such relationships flow primarily to the companies and the government scientists involved in these relationships. Indeed, the primary financial benefit of GIRs is likely to be personal compensation. According to a January 2004 New York Times article, between 1995 (when NIH relaxed its financial disclosure rules) and 2004, consulting relationships between NIH scientists and industry increased, in some cases amounting to many tens of thousands of dollars to over a hundred thousand dollars cumulatively for some very senior individuals. In some cases, these relationships existed with companies that stood to benefit financially from the actions of the NIH officials. Such relationships have the potential to color objectivity in the grant-making process and to undermine the credibility of NIH.

Current practice

Efforts to disclose and manage AIRs in the university sector take a number of forms, ranging from reliance on unwritten academic norms to explicit university policies to federal agency regulation. Academic norms tend to support principles such as academic freedom, freedom of publication, and university control of research direction and outcomes. A compelling case, however, can be made that norms alone have not proven effective in managing the risks of AIRs and GIRs, because both academic and government scientists have actively resisted strengthening prohibitions against establishing financial relationships with industry, even when they pose clear conflicts of interest.

A content analysis of the COI policies at the 100 universities that received the most funding from NIH in 1998 found that the disclosure policies varied widely across institutions. For example, 55 percent of the policies required disclosures from all faculty members, whereas 45 percent required only faculty who were principal investigators to disclose. Also, fewer than 20 percent of institutional policies specified limits on faculty financial relationships with industry, and 12 percent provided specific limits on the amount of time that publications could be delayed.

The public sector has long complemented institutional culture and norms with explicit regulation of AIRs. Since 1995, government agencies such as the Public Health Service (PHS) and the National Science Foundation (NSF) have had established regulations regarding individual financial COIs, including COIs on the part of university officials in research sponsored by one of those two federal agencies. These regulations require institutions to have in place policies and procedures that require disclosure of some, but not all, relationships and appropriate action to manage or eliminate the conflict before the expenditure of federal research funds.

Specifically, PHS policy requires that all relationships that might affect PHS-funded research and that result in the receipt of more than $10,000 annually or 5 percent of the total equity in a company must be disclosed to university officials. The nature of such relationships need not be reported to the federal agencies. The agencies need only be informed that a COI was identified and managed or eliminated. The details of how conflicts are identified and managed and whether such management is appropriate or effective are not currently reported to the federal government. Operationally, this puts the burden of management solely on the institution rather than the government, and the institutions therefore bear any costs and risks associated with this oversight.

In 1998, the Food and Drug Administration (FDA) adopted its own set of rules for disclosing and managing financial COIs on the part of external parties. These rules require that investigators who receive compensation in excess of $25,000 from a corporate sponsor of a clinical trial in which the investigator is engaged disclose that relationship to the FDA, but not until the time of filing for the new drug application, after the study has already been completed. If the FDA determines that the relationship may have undermined the objectivity of the data, the agency can decline to accept those data in support of the market approval or labeling indication. Although this is probably sufficient to dissuade most investigators and companies from manipulating studies, disclosure of conflicting relationships before launching a trial would achieve the same results while also eliminating the potential risks to patients within the trial.

Some states have laws regulating COIs on the part of state officials and state employees, including some employees of state universities. For example, California state law requires that principal investigators within the California State or University of California System who receive more than $500 from a nongovernmental source must publicly disclose their financial interests in the sponsor of the research to the state’s Fair Political Practices Commission.

In addition, professional organizations have developed explicit policy positions on AIRs in clinical research, marking a significant advance in debate on this issue. The American Medical Association and the Pharmaceutical Research and Manufacturers Association have issued guidelines for the conduct of physicians and sponsors within a clinical trial. Similarly, a task force of the Association of American Medical Colleges (AAMC) made specific recommendations to prevent possible risks to human subjects of research, resulting from COI. It is too soon to truly measure the impact of these voluntary policies and practices on the disclosure and management of AIRs.

Measure and manage

The research findings above provide for only a limited ability to intelligently sort the risks associated with AIRs and GIRs. Under the tenet that “you manage what you measure,” we argue for more information and disclosure regarding the prevalence and magnitude of industry affiliations. Below, we suggest several policies that define which types of scientists and relationships require disclosure, as well as how these disclosures should be handled by both the institution and the researcher.

At present, there is wide variation in the disclosure policies and practices at universities. A content review of the disclosure policies at all U.S. medical schools and the 170 institutions that received more than $5 million in funding from NSF found that in almost every instance, penalties for nondisclosure were totally discretionary. In order to remove the possibility that lax rules could be used to attract industry funding, we suggest that uniform policies related to the disclosure of AIRs should be developed and adopted by the entire academic community. Specifically, we propose that all faculty who teach or conduct research and all institutional administrators at the level of department chair and above disclose their own and their immediate family members’ relationships with industry to a committee designated to receive and review such disclosures. We suggest that universities require annual disclosure by all faculty of licensing, consulting, honoraria, and gift relationships that have an annual value of $10,000 or more and are related to an individual’s area of professional expertise. Further, researchers should annually disclose all equity relationships (excluding equity held as part of a mutual fund, 401K, etc.) valued at $10,000 or more, or when an individual’s or immediate family member’s holdings represent more than 5 percent of all of a firm’s stock of any company with a connection to the individual’s area of professional expertise. We also recommend that institutions adopt a uniform policy governing how long researchers can delay publication of results, to ensure that scientific findings are published in a timely manner.

Academic institutions have the responsibility to carefully review the disclosures of scientists and administrators. PHS requires that institutions designate a single individual to review disclosures related to PHS-funded research. However, since most major universities probably have a large number of people who would be required to disclose under the suggestions above, and because of the complex nature of certain relationships, we believe that disclosures should be reviewed by a formal committee made up of members from the institution and the local communities that is adequately staffed in order to provide a measure of transparency similar to the review of clinical research protocols by institutional review boards.

Since there is wide variation between universities in the frequency of certain types of AIRs, the organizational structure of universities, and each institution’s decisionmaking processes, it is important to give institutions significant discretion regarding the review and oversight of AIRs at the local level. In providing oversight, we suggest that institutions have flexibility to decide which relationships require oversight and how to design, implement, and evaluate institutional oversight plans and activities.

Currently, the federal government has done little to assist individual institutions in this regard. Government controls on financial COIs form an overlapping, incomplete, and occasionally conflicting message to investigators and institutions involved in partnerships with industry, making compliance difficult and creating the potential for considerable variation in actual policy at the local level. In order to assist universities, we suggest that the federal government provide universities with unambiguous guidance concerning their responsibilities and accountabilities with regard to assuring the integrity of research in the context of AIRs.

To eliminate the dearth of data without violating privacy, we suggest that aggregate de-identified data on annual disclosures by faculty members and senior administrators (including a summary of the decisions of the institutional oversight committees regarding these relationships) be made public on a regular basis. De-identified data protect the privacy of both the researcher and corporate representatives. Allowing other scientists and policy advocates to review these relationships and their institutional management will create a public record that details the institution’s stance on AIRs with more nuance than any broad policy document could communicate. Further, the natural variation in policies across different institutions will make it possible to determine whether relaxed policies on AIRs pose substantial threats to life science research, scientific education, or patient safety.

Similarly, corporate sponsors of clinical trials and the FDA should adopt and adhere to a policy that the results of clinical trials, regardless of outcome, be made available to the public in an appropriate format. In June 2004, the American Medical Association proposed that the Department of Health and Human Services maintain a national listing of all the clinical trials it sponsors and that listing a trial be a prerequisite for publishing the results of the trial or using it to support regulatory approval of a product. In response, the Pharmaceutical Research and Manufacturers Association recently initiated a Web site registry of late-stage clinical trials (www.clinicalstudyresults.org). However, critics point out that participation is voluntary and that there are no time limits on when results must be published.

Given the amount of research at most universities and the highly technical nature of the research, we believe that the responsibility for protecting the integrity of scientific publications and presentations rests primarily with the investigators leading the research efforts. As a result, we suggest that all authors and presenters should fully disclose all industry relationships, in addition to the source of the research funding, related to a publication in a journal or a presentation at a conference or professional meeting.

The substantial corpus of empirical data, collected primarily through large national surveys and case studies, shows that AIRs in the life sciences are a fundamental part of the modern life science enterprise. These data, which are now relatively old, have supported the development and implementation of policies and practices of individual universities, scientific journals, and professional associations to address the risks associated with these relationships.

However, although we know that government scientists and administrators comprise an important part of the life science enterprise, there are no comprehensive publicly available data to illuminate the risks and benefits of their relationships with industry. Such studies are desirable and possible. Two sources of such data are apparent. The first source could be case studies and anonymous surveys of government scientists and agency administrators at NIH, NSF, the FDA, and others. A second potential source of data about GIRs is the annual disclosure forms filed by federal employees. These forms, de-identified if necessary, should be made available for analysis.

Because NIH and other federal research funding agencies have the primary responsibility for managing the public investment in science, openness and disclosure of GIRs are essential. Thus, the risks of GIRs, while similar in nature to those of AIRs, may be perceived by the public and elected officials as even more problematic. One can make a case that these reporting requirements must be at least as stringent as those for academic institutions, although we argue that a broad consistent policy across all sectors would be the most reasonable and effective approach.

At present, we believe that relationships between academic or government scientists and industry are a fundamental part of the modern life science enterprise and should not be eliminated. However, the benefits of these relationships should not be overstated, nor the risks ignored. Although disclosure of relationships with industry is common, if not universal, some standardization of the disclosure and management processes is desirable. Failure to do so could compromise the integrity and fundamental norms underlying the social structure of the modern life science enterprise.

Eric G. Campbell ([email protected]) is an assistant professor at the Institute for Health Policy at Harvard Medical School and Massachusetts General Hospital. Greg Koski is a senior scientist at the Institute and an associate professor in the Department of Anesthesiology and Critical Care. Darren E. Zinner is a doctoral student at Harvard Business School. David Blumenthal is the director of the Institute and a professor of medicine and health policy.