Regulations weren’t meant for protection
More concerned with data integrity
As both public and private funding of clinical research continues to increase rapidly, federal health officials need to do more to monitor possible financial conflicts of interest in clinical research to ensure that human subjects are adequately protected, say two new reports released in December 2001.
A Government Accounting Office (GAO) study1 of financial disclosure policies at five major research universities found that while the institutions had disclosure policies in place well before federal law required them to do so, these policies varied greatly from institution to institution with varying degrees of implementation. And since there is no federal requirement that investigators report possible conflicts directly to the IRB, information about possible conflicts of interest may go undetected by those charged with protecting subjects, according to a report prepared by the Washington, DC-based Association of American Medical Colleges (AAMC).2
A key problem, notes Jennifer Kulynych, JD, PhD, director of biomedical and health sciences research for the AAMC, is that financial disclosure regulations were not originally designed as measures to protect human research subjects. "They reflect a concern for ensuring the integrity of the data," she says. "That is the problem that is reflected in those regulations. They didn’t really reference the human subjects protection regulations." Historically, financial disclosure regulations and human subject protections mandates are totally separate areas, she explains.
Rules for financial disclosure vary based on whether the research is federally funded, or whether the research is privately funded but regulated by the U.S. Food and Drug Administration (FDA). "For federally funded research, the institution is required to appoint an official to oversee financial conflicts of interest," Kulynych explains. "And, that person collects the financial disclosure statements from investigators and then decides if there is a conflict of interest and how the institution will deal with that," she says. "But, that person is not required to give any information to the IRB. Some institutions do, as a matter of practice. But, there is no requirement. That is one of the things we are addressing."
For privately funded research regulated by the FDA, no prior review of possible conflicts is required, she adds. "The financial disclosure regulation that the FDA has only requires the sponsor to keep track of the financial interests of the investigators and the sponsor. The sponsor does not have to give the information to the FDA for review until it submits its marketing application, which is well after all the research is complete."
Funding skyrockets
Funds for biomedical research have skyrocketed over the past two decades, both in the private and public sector. The budget of the National Institutes of Health (NIH), the main federal agency funding biomedical research, jumped from $3 billion in 1980 to more than $20 billion this year. Funding from pharmaceutical companies for drug development research grew even more rapidly, from $1.5 billion in 1980 to $22.4 billion in 2000.
The growing amount of research that is funded with both public and private dollars, and the increasing number of clinical research initiatives sponsored by private companies, has spurred calls for greater examination of financial incentives that might encourage researchers to overlook risks to subjects. It is becoming more common for researchers to hold ownership interests in private companies dedicated to developing new medical products and procedures. When these companies fund projects at the institutions where their minority owners conduct research, in some cases funding the research itself, then objectivity is obviously called into question.
However, the potential conflict of interest has to be made known to those in charge of monitoring subject safety in order for objectivity to be evaluated, she explains. "I think it is partly that these kinds of [public-private] relationships are increasing in number and also that there have been litigation over harm that has occurred to participants in some human trials — the Gelsinger case, the Hutchinson case, for example — in which one of the issues raised by the litigants was the financial interest of the investigators," she says.
Recommendations
In order for potential financial incentives to be out in the open, the AAMC is recommending that research institutions set up a formal committee to review conflict-of-interest issues, rather than relying on a single official. "We are also recommending that when the committee reviews these interests, if it is human subjects research, there should be a rebuttable presumption against the financial interest," Kulynych says. "In other words, we recognize that in some cases, circumstances might warrant allowing that particular investigator who has financial interest to still conduct the research, but that basically that person should have to make the case to the committee, and the committee should impose conditions that are necessary to oversee the potential conflict."
Possible conditions would include having someone else obtain the informed consent of the subjects, and having a monitoring panel review the research, she says. Plus, any significant financial interests should be disclosed both to the public and research participants.
"We recommend that whenever the committee would agree to let someone with a financial interest do their research, that this should be communicated to the IRB. And if they still approve the research — if they felt there was any risk that they felt was inappropriate to human subjects, the IRB could still not approve it — the consent forms should mention that there is a financial interest and offer the subject more information if they would like it," she says. "And, we make recommendations that the committee should require disclosure in every publication or presentation of research."
Institutions should also standardize the thresholds at which a financial interest becomes report-able, she adds. The standards used by the U.S. Public Health Service (PHS) are more stringent than those required by the FDA, and the AAMC is recommending use of the PHS thresholds. "For example, we recommend that for companies that aren’t yet publicly traded, any equity interest or any options should be reported to the conflict-of-interest committee and reviewed," she says, not just those interests deemed to be worth more than a specific dollar amount. "Stock options don’t hold much current value but they could dramatically increase based on the outcome of the research."
One of the areas in need of much closer examination and regulation is the area of institutional financial conflicts of interest, rather than just the possible conflicts of individual researchers, stated both the AAMC’s and GAO’s reports. "It is actually a very complicated situation because there are a number of ways an institution could have a financial interest," says Kulynych. "It could have an equity interest in a private company that was managed by the Office of Technology and Licensing. Or it could have an equity interest in its general endowment that is managed by a management company at arm’s length from the university. So, that is the same interest, but the two situations pose different challenges."
Federal guidance needed
Currently, there is no federal guidance available about evaluating possible institutional conflicts of interest, let alone regulations requiring disclosure, she says. "That’s the thing we have our task force is working on right now — the question of defining what kinds of interests should be the subject of concern," she notes.
In addition to the current regulations, the U.S. Department of Health and Human Services (HHS) needs to develop more comprehensive guidelines for institutions on how the regulations should be implemented and how institutional issues should be addressed, the GAO report recommends. "The universities we visited indicated some confusion about what the PHS regulation specifically required them to report to NIH," the authors state. "NIH and FDA have recently taken steps to improve oversight and monitoring, such as conducting site visits, taking an inventory of institutions’ financial conflict-of-interest policies, and providing guidance to reviewers of financial conflict-of interest information. In addition, HHS has developed draft guidance on financial relationships in clinical research, which is promising. However, this guidance does not provide detailed advice on managing institutional financial conflicts of interest."
Offer guidance
The office recommends that HHS:
• develop and communicate information on best practices for institutions to consider for identifying and managing investigator and institutional financial conflicts of interest in biomedical research;
• develop specific guidance or regulations concerning institutional financial conflicts of interest.
Officials at HHS agree with both recommendations and were moving to develop such resources prior to the report’s publication, noted HHS Inspector General Janet Rehnquist in a letter drafted in response to the report. "Best practices evolve from public and private efforts," she noted, referring to the initial recommendation. "The NIH has efforts already under way to collect and develop such information for posting on their web pages, based on their proactive site visits, and their analysis of financial conflict-of-interest policies from the top NIH grantee institutions."
The NIH’s draft interim guidance on financial conflicts in clinical research (available on-line at: http://ohrp.osophs.dhhs.gov/humansubjects/finreltn/finguid.htm) touches on both of these issues, and the agency is working to address them further, as are the AAMC and the Association of American Universities, she noted.
References
1. United States General Accounting Office. Biomedical Research: HHS Direction Needed to Address Financial Conflicts of Interest. Report: GAO-02-89. Available on-line at: www.gao.gov.
2. American Association of Medical Colleges. Protecting Subjects, Preserving Trust, Promoting Progress. Policy and Guidelines for the Oversight of Individual Financial Interests in Human Subjects Research. Available on-line at: www.aamc.org.
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