The illustrates a typology of public concerns about the system of evaluating drugs and devices. We have categorized selected recent controversial issues by alleged problem: Design, conduct, or analysis of the study; lack of public information about the study existence or results; and regulatory agency decision making.
Sample medical product safety concerns by category of perceived problems.
FDAAA 801 directly addresses issues stemming from a lack of transparency in clinical trials, represented by the examples in the highlighted section of the . For instance, GlaxoSmithKline (GSK)-sponsored trial data for the heavily promoted antidepressant Paxil showing efficacy and safety concerns in children and adolescents were not available to the public.(9
) The resulting 2004 legal settlement between GSK and the New York State Attorney General’s office required GSK to develop a publicly accessible online results database(27
) for the timely, comprehensive, posting of results of company-marketed drugs to prevent similar incidents in the future.(28
) In the case of Vioxx, a COX-2 non-steroidal anti-inflammatory drug (NSAID) “several early, large clinical trials … were not published in the academic literature for years after Merck made them available to the FDA, preventing independent investigators from accurately determining its cardiovascular risk …(p.122)”(30
) With evidence that Vioxx is associated with increased cardiovascular risk from subsequent clinical trials, the drug was voluntarily withdrawn from the market in September 2004.
More recently, questions have focused on the ENHANCE trial, an industry-sponsored study of Zetia, a marketed non-statin
cholesterol-lowering drug that is also a component of the cholesterol-lowering drug Vytorin. Issues include delayed trial registration and results reporting, and attempting to modify pre-specified primary outcome measure.(31
) Results, generally regarded as negative, were revealed in a company press release(32
) following intense media attention and a Congressional investigation of these irregularities.(2
Issues related to the design or conduct of clinical trials, including research ethics, are not covered by FDAAA 801. For example, allegations of human research protections violations in a 1996 Trovan (antibiotic) study on children in Zaire(33
) and data integrity questions about Ketek (antibiotic) study 3014, in which FDA inspectors detected data fraud and other serious violations(34
), would not be affected by FDAAA 801. Further, Merck studies of Arcoxia, a COX-2 NSAID, involving over 34,000 patients, were judged by the FDA to be of limited scientific interest because of the use of an “inappropriate” comparator with many known side effects of its own.(35
) Nevertheless, it is possible that complete trial registration and results reporting might have helped institutional review boards (IRBs) assess the need for each additional Arcoxia trial.
While current policies have focused on interventional studies, observational studies play an increasingly critical role in biomedical research, especially in the assessment of safety after an intervention comes into widespread use. Postmarket observational studies provide data about rare, unanticipated adverse effects from the exposure of large numbers of heterogeneous individuals over periods of time longer than typically studied in controlled trials.(36
) Despite methodological limitations such as susceptibility to confounding factors and other sources of bias which potentially lead to inconclusive or misleading results (e.g., data on risks of postmenopausal hormone replacement therapy from the Women’s Health Initiative(37
)), observational research nevertheless can play a useful, complementary role to interventional studies.(38
) Yet observational studies have received less attention in the quest for transparency.
In the case of a cholesterol-lowering drug Baycol, a company-conducted observational study showed a higher relative rate of muscle breakdown for Baycol compared with another marketed statin. This finding was never reported publicly, but became available as a result of litigation.(39
) In another case, results of a Bayer-commissioned post-market observational study of 67,000 patients which raised concerns about associations between Trasylol, a clotting drug, and cardiovascular or renal risk, were not released by the company until after an FDA advisory committee meeting to evaluate the safety of Trasylol.(36
) In November 2007, Bayer announced the voluntary suspension of Trasylol sales worldwide pending further analysis of safety data. Some cases reflect a deficiency in monitoring serious adverse events once a drug or device is marketed. In other cases, such as Guidant’s Ventak Prizm 2 DR implantable cardioverter-defibrillator, information about a problematic adverse event profile (i.e., device malfunctions) was not publicly disseminated in a timely fashion(41
Other concerns relate to thresholds for determining what and how much data are sufficient to prompt regulatory decisions regarding the availability or labeling of a medical product. For example, questions have been raised about the timeliness and adequacy of FDA’s response to data on Avandia(42
), trials of Ketek(34
), and on the use of some antidepressants in children(43
). Transparency policies alone do not address these issues, though they could help to empower members of the public who believe that regulatory action is warranted. For example, FDA mandated changes to the Avandia label in November 2007 to reflect the risk of myocardial infarction; this risk was first publicized in a meta-analysis published in June 2007(3
) that used, in part, data from the GSK database mandated by the Paxil settlement.