Transparency, Sunshine Shape Research

Public access to information about ongoing clinical trials and the results of biomedical studies has increased in recent years, thanks to new laws and regulations that expand trial registration requirements and the disclosure of research findings. However, evidence that much information from clinical trials still remains hidden from view raises questions about the impact of such transparency policies and how well both commercial and academic sponsors comply with multiple disclosure policies.

Jill Wechsler

Related concerns about industry influence on drug prescribing and medical practice also require sponsors to disclose payments to doctors for clinical research services, in addition to educational and consulting activities. This "Sunshine" policy has raised qualms at research organizations that public reporting of pharma fees will taint investigators and discourage them from participating in clinical research.

Seeking results

The good news is that sponsors of clinical studies regulated by the Food and Drug Administration (FDA) are doing a better job in registering trials on clinicaltrials.gov, as required by the FDA Amendments Act of 2007 (FDAAA). This has created a fairly massive clinical research database at the National Institutes of Health (NIH), now containing more than 100,000 clinical studies. Most of the listings include extensive data on study sites, enrollment criteria, and nature of investigational product that sponsors often omitted in the past.

What seems to be missing, though, are required reports summarizing the results of registered studies. FDAAA gives sponsors 12 months following study completion to post results. And disclosure of results for preapproval studies can be delayed for up to three years to protect proprietary information. However, a study published last year in the journal Health Affairs by researchers at the University of British Columbia (UBC) found that results appear within a year for only 12% of completed studies. Interestingly enough, pharma and biotech companies are much more likely to post study results than investigators funded by NIH, but no one is doing very well in this area.

Delays in reporting results from Phase IV research is a particular concern for author Michael Law of the UBC Centre for Health Services and Policy Research and colleagues. The researchers noted that only 14% of postmarketing studies issue results within a year, despite the importance of timely information on safety issues for drugs already in use by patients.

Similar analysis appeared in studies published in the British Medical Journal (BMJ) in January 2012 by researchers from the University of Nottingham. A report by Andrew Prayle et al. in BMJ finds that only 22% of registered trials subject to mandatory reporting in 2009 made results available within a year of study completion.

To improve clinical trial transparency, the analysts propose stricter enforcement of reporting requirements. NIH could withhold future grants to slow responders, and FDA could levy $10,000-a-day fines for noncompliance. Members of Congress agree. Three leading Democrats on the House Energy and Commerce Committee sent letters in February to FDA Commissioner Margaret Hamburg and to NIH Director Francis Collins seeking explanations for delays in obtaining research summaries within the required timeframe, particularly for studies involving drugs already on the market. Reps. Henry Waxman (D-Ca.), Edward Markey (D-Mass.), and Diana DeGette (D-Colo.) want to know whether the FDA has issued any warning letters or imposed fines on violative firms and if the agencies have sufficient resources and authority to enforce disclosure policies.

Despite problems in obtaining results under the current reporting program, transparency advocates want to extend disclosure to include data on clinical trials involving experimental products that fail to gain FDA approval. While all investigational studies have to register on clinicaltrials.gov, disclosure of summary results applies only to studies for medical products that eventually gain FDA market authorization. Many clinical research experts believe that much useful information can be obtained from failed studies, and that it could help sponsors and investigators avoid repeating unsuccessful research.

One new policy that might improve registration and disclosure is the FDAAA requirement that sponsors advise trial participants that information on the study they are enrolling in will be entered into a public database. This rule, which went into effect March 2012, aims to bolster protections for biomedical research subjects. The process of advising study participants on the public disclosure process also could reinforce the need for sponsors to register clinical trials and report results. FDA recently issued guidance to help small biomedical companies, investigators, and institutional review boards (IRBs) understand and comply with the new rule, which involves revising informed consent documents to make patients aware of the scope and nature of public disclosure. Small feasibility studies and Phase I trials are excluded, but the regulation applies to all other studies of drugs, biologics, and medical devices regulated by FDA.

Too much sunshine?

Another policy that will increase public information on clinical research requires pharmaceutical, biotech, and medical device companies to report all payments and transfers of value to doctors for inclusion in a new government database that will be available to the public.

The main thrust of this new "Sunshine" policy, which was included in the Affordable Care Act of 2010, is to disclose industry payments related to continuing medical education and consulting activities that theoretically could influence physician practice and prescribing. Fees to teaching hospitals and physicians for research activities also are included, raising objections from medical societies that this kind of disclosure makes payments for bona fide research activities look like big handouts from pharma.

The American Thoracic Society, in comments filed with the Centers for Medicare and Medicaid Services (CMS) on its December 2011 proposed rule for implementing Sunshine, said that public reporting of research payments implies that "research is somehow an inappropriate activity for physicians." Congress included reporting on research, the surgeons note, to prevent industry and physicians from "hiding" other payments under the guise of research, but not to taint investigators.

A specific problem cited by sponsors and research organizations is that the proposed reporting system will lead to double counting of payments for R&D services. This will occur, as Pfizer explains in its comments, because under the current proposal, a $10,000 payment to a teaching hospital serving as a clinical study site also would be reported as a $10,000 "indirect research payment" to the associated principal investigator. To prevent such errors, the Association of American Medical Colleges (AAMC) proposes that research-related payments to institutions be reported only as payments to those entities, and not to individual physicians.

AAMC further asks that CMS list payments for research in a separate section of the database and provide clarity about the nature of funding for research-related grants to institutions. At a minimum, the CMS database should distinguish between payments to physicians for research activities and fees for other services. The American Association of Family Physicians and other medical groups go further and propose that research that has been reviewed and approved by IRBs be exempt from reporting. Similarly, the Association of Clinical Research Organizations (ACRO) wants to cancel reports on payments from manufacturers to fund legitimate research activities "as there is no evidence that such payments bias prescribing or other practice behavior." ACRO predicts that public reporting of legitimate research activities could cut the number of physicians participating in clinical research by one-fourth.

Comments from many medical groups reflect confusion about how payment data will be posted and complain that the program fails to provide sufficient time for them to review and correct inaccurate information. Because CMS issued the Sunshine regs months past the original due date, the agency is postponing when it will start collecting this data from pharma companies until after it finalizes its proposed regulations. No one knows, though, exactly when that will occur or how the data filing process will be carried out. As with the rules for disclosing results on studies registered on clinicaltrials.gov, the Sunshine regulations permit a delay up to four years in posting information on company payments to clinical investigators involved in preapproval studies to prevent early disclosure of confidential information.

Sponsors asked CMS to clarify which physicians and organizations are covered by the reporting requirements and to provide more contextual information on the website that describes the nature of relationships and interactions between manufacturers, physicians, and teaching hospitals. Without many of these changes, says ACRO, data related to research will be "incomplete at best, terribly inaccurate at worst."

Jill Wechsler is the Washington editor of Applied Clinical Trials, (301) 656-4634 jwechsler@advanstar.com