Resolving Conflicting Interests
As a result of such questions, senators including Grassley are seeking to enact the Physician Payment Sunshine Act, which would require pharmaceutical and medical device companies to disclose payments of more than $500 to doctors. Industry has grudgingly supported the measure as preferable to a proliferation of different state disclosure laws and ongoing investigations into conflicts of interest (COI) involving marketing and research practices.
Elsewhere, the Institute of Medicine (IOM) has convened a blue-ribbon panel headed by University of California San Francisco professor Bernard Lo and former National Institutes of Health (NIH) official Wendy Baldwin to evaluate the role of pharmaceutical and medical product manufacturers in funding clinical research, managing publication of research results, and supporting continuing medical education (CME) of health professionals. The panel is examining disclosure policies and codes of conduct at academic medical centers, pharma companies, professional societies, and government agencies. The panel's report, due next year, will propose principles for managing COIs and for ensuring the objectivity and validity of biomedical research.
Repeated disclosure failures and lax institutional oversight have raised doubts, however, about the enforcement of appropriate safeguards. And expanding government support for more medical evidence reviews and practice guidelines has raised alarms about even more opportunities for industry to influence medical practice. Meanwhile, universities and pharmaceutical manufacturers are revising policies and establishing new disclosure and funding practices. The University of Minnesota Medical School is weighing full disclosure of all relationships between faculty and the drug industry, as well as a ban on gifts from medical companies. Eli Lilly and Merck recently made headlines by announcing that they will voluntarily disclose all payments of more than $500 made to physicians for advice, speeches, and other services. Lilly began posting educational grants and charitable contributions last year, and will add payment information next year, followed by fees for clinicians conducting research.
While neither manufacturers nor academic institutions are eager to cut off the more than $1 billion industry provides each year for CME, the desire to avoid any appearance of undue influence is taking a toll on industry support for medical education of doctors and health professionals. Both sides maintain that such programs are vital to keeping physicians alert to the latest disease treatments.
But the cutoffs have already begun. Last summer, Stanford University Medical Center said it would halt direct funding of CME courses by drug and device makers. Instead of making individual grants to specific programs, medical schools now want pharma companies to fund CME through central educational funds. Pfizer adopted such an approach, and says it will end direct support of CME through commercial educational providers.
FDA faces similar challenges in establishing partnerships with industry to support its Critical Path Initiative (CPI) for translating biomedical research and genetic discovery into new therapies. Such collaborative efforts raise concerns about industry influence over regulatory decisions, along with a host of legal issues. Congressional objections to any industry financial support for FDA programs (even user fees) have blocked federal funding of the Reagan-Udall Foundation for fear it would provide a back door for industry to influence FDA decisions on market approval for new drugs. Reagan-Udall chair Mark McClellan, a former FDA commissioner now at the Brookings Institution, is working to establish bylaws and safeguards to separate outside funders and foundation operations in order to gain budget authorization for Reagan-Udall next year.
In addition, CPI is updating clinical research methods. The Clinical Trials Transformation Initiative (CTTI), a collaboration involving FDA, Duke University, and other partners, seeks to establish national standards for research functions, new review models for multi-site trials, accreditation programs for investigators and sites, and improved data management systems.
Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), says it's time to shift CPI from concept to implementation. The goal is to replicate the massive investment in research and flexible regulatory approaches that stemmed the tide of the AIDS epidemic 20 years ago. That effort produced new surrogate markers and accelerated approval processes to spur development of new treatments, recalls Mark Harrington of the Treatment Action Group. Yet that achievement was an exception, and has not been extended to research and regulation for treatment of other infectious diseases.
Establishing those initial PPPs took months of negotiations involving data standards, information sharing, access to results, and protection of proprietary information. Lawyers had to work out approaches for dealing with conflicts of interest and intellectual property protections, as well as ensuring that collaborative groups complied with federal statutes. Neutral third parties—such as the Critical Path Institute in Arizona and the National Institutes of Health [see sidebar]—provided venues for creating partnerships that meet legal and technical requirements.
The good news is that better biomarkers and clinical trial methods may yield new treatments. An FDA initiative, the Analgesic Clinical Trials Project (ACTP), aims to spur R&D on novel painkillers by developing new efficacy endpoints, and by evaluating innovative study designs likely to improve the success rate of clinical studies for these products. Bob Rappaport, director of CDER's Division of Anesthesia, Analgesia and Rheumatology Products, has received internal funding to re-analyze data from failed analgesic trials to assess ways to maintain study sensitivity and to explore high placebo response rates. A broader PPP will expand the scope of the project to address analgesic use in preventing chronic post-surgical pain.
Novartis scientists are hopeful that new biomarkers for detecting liver damage from drugs could lead to market approval for its Cox-2 inhibitor Prexige. The drug is highly effective but has an "Achilles heel" of severe hepatoxicity in certain patients, explained Timothy Wright, head of translational science at Novartis, at a September DIA workshop on CPI. Last year, FDA rejected the drug, calling for additional safety data. A genetic marker that identifies patients most likely to develop liver damage from the drug might warrant additional clinical trials to support approval, Wright suggested.
FDA has advanced these efforts to link postmarket adverse events back to clinical trials, establish biomarker data warehouses, build a knowledge base of product quality, and establish a bioinformatics platform for data standards—all with just a $20 million investment in CPI, Woodcock points out. The agency's goal over the next five years is to obtain sufficient resources to build on this expanded understanding of disease and pharmacology to ensure product quality and safety.
"Drug development tomorrow will not look like drug development today," Woodcock predicts.
Jill Wechsler is Pharmaceutical Executive's Washington correspondent. She can be reached at
Supply Chain Strategy: Managing risk and opportunity in a changing global landscape