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Curbs on consulting and financial interests aim to restore researchers' credibility.
It may be difficult for the biopharmaceutical industry to quell demands for more information on clinical trial activity and study results as concerns about unethical researcher behavior continue to emerge. The latest controversy involves clinical investigators sharing information about ongoing research with Wall Street analysts. At the same time, industry consulting by scientists at the National Institutes of Health (NIH) has prompted new ethics rules and limits on stock holdings. Meanwhile, analysis from the Food and Drug Administration indicates that pharmaceutical companies still do not list all eligible trials on its clinicaltrials.gov Web site, a situation likely to further fuel mandates for full disclosure of clinical research.
The hot issue of the summer involved prominent researchers receiving hefty fees from investment companies to talk about emerging medical treatments, particularly involving clinical trials on important new drugs. Although participating physicians and scientists insist that they discuss only publicly available information—and never talk about current research projects—the high fees (reportedly over $1000 for a half-hour chat) raised skepticism about such limitations.
An article in a June 1, 2005 issue of the Journal of the American Medical Association (JAMA) criticized physicians who consult for investment firms, particularly hedge funds. Senate Finance Committee chairman Charles Grassley (R-Iowa) called on the Justice Department and the Securities and Exchange Commission (SEC) to investigate the possibility of doctors leaking confidential information on drug research to investment firms.
Since the ImClone case four years ago, the SEC has had its eye out for situations where advance knowledge of drug trial results may lead to insider trading on biotech and pharmaceutical companies. Even unintentionally, physician investigators may reveal information about how an experimental compound is performing in clinical trials or whether FDA has raised questions about a study. Such disclosures could violate confidentiality agreements that investigators routinely sign with sponsors. The main issue for the SEC is whether disclosures by physicians or scientists involves "material" information that could have a serious impact on the financial health of a small biotech company.
Even if clinical researchers are not violating any laws, advisory arrangements with financial firms appear unethical and are likely to generate new curbs by sponsors as well as research organizations. For similar reasons, the National Institutes of Health (NIH) has issued new ethics rules that prohibit all NIH employees from engaging in paid outside consulting with pharmaceutical and health care companies. The rules also limit the amount of stock that high-level NIH officials may own in drug, biotechnology, medical device or other health care companies, but softens proposed curbs on activities involving professional organizations.
The final stock ownership rule applies to only the 200 most senior NIH employees, a considerable reduction in scope from a February draft proposal that would have required some 6000 NIH scientists to sell off all their pharmaceutical stock holdings. Under the new policy, junior NIH officials could face limitations on stock holdings if warranted by specific circumstances, which would be reviewed on a case-by-case basis.
NIH Director Elias Zerhouni announced the final revised rules in August, drawing a collective sigh of relief from NIH employees. The more stringent financial holdings policy threatened to hinder NIH recruitment and retention of top scientists and appeared unfair to the rank-and-file. But despite considerable opposition, Zerhouni decided to retain a total ban on outside consulting as necessary to restore public trust in NIH—and because NIH has no way to prevent abuses, Zerhouni noted. NIH launched this ethics reform exercise following revelations in 2003 about high-level officials accepting huge consulting fees and stock options from biomedical companies. The situation led to Congressional hearings and demands for reform. NIH's February draft was considered too draconian on many sides, more appropriate for a regulatory agency such as FDA than for a broader research organization.
The final policy also was loosened to permit staffers to participate in activities of professional and scientific organizations, serve on data safety monitoring boards, present lectures, and review scientific grants. NIH scientists may seek prior approval to be paid for teaching university courses, writing textbooks, reviewing scientific journal articles, and lecturing to physicians and scientists as part of continuing professional education programs. Physicians working at NIH may continue to practice medicine in accordance with existing rules. And no prior approval will be needed to coach soccer or engage in other activities unrelated to NIH duties.
For the biomedical community, the NIH policy establishes a new model for conflict-of-interest policy. High-level executives will have to limit stock holdings in any single drug company to $15,000, and in health care sector funds to $50,000. No payments of any kind will be allowed from industry, a limitation that outside scientists fear will severely reduce interaction among public and private researchers. Zerhouni's objective is to ensure that NIH research is based on "scientific evidence that is not influenced by any other factors, but the NIH director has promised to review the ethics policy annually and to make needed changes.
One way to prevent insider information disclosure and conflicts of interest is to make available more information on clinical trial activities and results. Proposals are surfacing in Congress to require clinical trial sponsors to post on Web sites more detailed information about early stage research and study results. Sponsors claim that such broad disclosures, including information on exploratory clinical trails and results from unsuccessful studies, could have negative impacts and discourage certain clinical development programs.
Unfortunately, policy makers may pay little attention to industry concerns because pharmaceutical companies have done a poor job in complying with current FDA requirements for posting basic clinical trial information on its clinicaltrials.gov Web site. FDA issued a long-awaited report on this program in August, which found that many trial sponsors still fail to provide important information on current studies on drugs that treat serious or life-threatening diseases. More information on eligible trials are being posted now compared to an FDA review in 2002, but certainly not all, even though FDA now has issued a final guidance document and simplified its Web-listing procedures.
The purpose of this current clinical trial posting program is to inform patients and doctors of opportunities to participate in studies of new critical therapies and to learn about new treatments for critical diseases that may become available. FDA's earlier evaluation of 2002 protocols found a sorry 30% posting rate for those clinical trial protocols covered by the program. The new review of trials for cancer drugs indicates that biopharma companies listed trial protocols for 76% of eligible drugs in 2004, a slight improvement over the 61% rate in 2002. And overall, listings continue to rise: the clinicaltrials.gov Web site posted information on almost 1300 recruiting studies in August 2005, compared to 754 open studies listed in June 2004. However, many listings fail to include drug name or company name and other important information, making it difficult for individuals to determine whether they might be able to participate in a study.
Industry's improved compliance rate most likely is a response to the public clamor for more information on clinical trials and research results. In the past, companies objected to posting details about study sites or test drug indications for fear that competitors would gain some advantage. But members of Congress and patient advocates find it hard to detect any harm in providing information on clinical research that might help cancer patients and others suffering from life-threatening diseases.
The expansion in information on clinicaltrials.gov also aims to stem the proliferation of proposals to require even more disclosure of clinical research activity. A panel formed by the Institute of Medicine is publishing a proposal this fall for a national clinical trial registry, along with comments from participants in a workshop on the topic last June. The IOM report will avoid making specific recommendations but aims to offer consensus on various registry options that have surfaced in the last year, including those from the World Health Organization, the International Committee of Medical Journal Editors, and members of Congress. The IOM model registry is expected to seek listings of all FDA-approved clinical trails beyond the exploratory stage—many more studies than under the current FDA program. It also would require disclosure of much more information than the pharmaceutical industry's voluntary Web site. Patient advocates pressed the panel to mandate registration of all exploratory and Phase I studies, but that could involve thousands of listings of limited use to the public. Drug companies want to delay full disclosure of study results until a drug is approved for market, while some researchers and advocates oppose waiting that long.
Another contentious issue is whether any central or national clinical trial registry should pre-empt individual state disclosure policies. Maine adopted a law in June requiring companies doing business in the state to report information on all drug clinical trials, which affects most pharmaceutical companies. Similar legislation has been introduced in more than 15 other states.
Meanwhile, FDA is revising its guidance for clinicaltrials.gov listings to clarify further the specific information that is required and which compounds fall under the policy. In the current atmosphere when industry opposition to full disclosure raises suspicions of covering up information, sponsors get little hearing for arguments that listing protocols, trial sites, and patient enrollment criteria exposes them to unfair competition. Instead of trying to halt the push for bigger and broader clinical research registries, they should be expanding their operations to ensure that needed information becomes available to patients and the public.
Jill Wechsler is the Washington editor of Applied Clinical Trials, (301) 656-4634 firstname.lastname@example.org