On January 22, 2014, the Journal of the American Medical Association (“JAMA”) took a closer look at the FDA approval process for drugs and medical devices. On the surface these studies were designed to characterize the type of pivotal data relied on by FDA for approval (or denial) of new drugs and devices. The conclusions from these studies and some of the associated “Opinion” articles suggest, however, that the editors of JAMA, and perhaps its members, believe that FDA should make physicians and patients more acutely aware of the information relied on for new approvals, as well as side effects observed following approval.
The main article, entitled “Clinical Trial Evidence Supporting FDA Approval of Novel Therapeutic Agents, 2005-2012“, took as a starting point that physicians and patients do not understand or have the tools to evaluate the different strengths of clinical evidence used by FDA to approve new drug and device therapies. Based on an Internet-based study, for example, the study reported that a national sample of 4316 adults (68% response rate) found that 39% believe FDA approves only “extremely effective” drugs and 25% only drugs without adverse events, which the authors said may reflect the opinions of some physicians.
Taking a closer look at these approvals, the authors concluded:
Our characterization of pivotal efficacy trials . . . demonstrates that the quality of clinical data evidence used by FDA to make approval decisions varied widely across indications. Although the vast majority of indications were supported by at least 1 randomized, double-blinded trial, there was wide variation in trials’ choice of comparators and end points, duration, size, and completion rate. In addition just more than one-third of indications were approved on the basis of a single pivotal efficacy trial.
As a result, the authors suggest that FDA adopt a “life-cycle” approach for drug safety and effectiveness, communicating a therapies risk and benefit information in an updated summary that distinguishes between the types of evidence relied on for initial and continuing approval. Recognizing that certain therapies, such as cancer, or may not lend themselves to larger, placebo or comparative trials, the authors acknowledge that “FDA has publicly declared its intention to use innovative trial designs that are as effective as standard designs but less burdensome and time-consuming and to identify qualifying biomarkers that accurately predict outcomes to make clinical trials more efficient . . . ” But the authors appear concerned that physicians and patients require this additional “life cycle” information to properly compare therapies, especially because comparative clinical trials are not required for approval of new therapies (and available for less than half of the indications studied). In addition, the authors believe that there should be “adequate and robust postmarket surveillance systems that allow reassessments of drug efficacy and safety after market introduction.”
Reporting on this a day before the official publication date, The Washington Post writer Brady Dennis reported that FDA spokesperson, Stephanie Yao said, “The agency applies the same statutory approval standards of safety and efficacy to all drugs, but uses regulatory flexibility in applying those standards. Some drugs may be tested in clinical trials that enroll hundreds of participants while others, particularly those seeking to treat rare diseases, may be tested in trials that enroll only a handful of patients. . . . [FDA maintains] a robust program for postmarketing surveillance to help ensure the benefits of marketed drugs continue to outweigh their risks.”
A second study in the same JAMA issue, “Scientific and Regulatory Reasons for Delay and Denial of FDA Approval of Initial Applications for New Drugs, 2000-2012”, sought to determine the reasons for new drug applications for fail obtaining approval during the first review cycle to help, so these delays may be prevented or reduced. Of the 302 new molecular entities examined, 50% received approval when first submitted and 73.5 % were ultimately approved. Approximately 70% of the applications required one or more resubmissions before approval. From the unsuccessful first-time applications, the main failures included: dose selection uncertainties (15.9%), choice of study end points that failed to adequately reflect a clinically meaningful effect (13.2%), inconsistent results when different end points were tested (13.2%), inconsistent results when different trials or study sites were compared (11.3%), and poor efficacy when compared with the standard of care (13.2%).
The third main study, “FDA Approval of Cardiac Implantable Electronic Devices via Original and Supplement Premarket Approval Pathways, 1979-2012”, took a look a this category of high-risk medical device to determine how much clinical testing was required for initial versus supplement approvals. The authors founds that FDA approved 77 original and 5,829 supplements premarket approval applications (“PMAs”) for this type of devices with a median 50 supplements per original PMA (37% approved PMA supplements involved a change to the device’s design). Excluding manufacturing changes that did not alter the device design, there were about 2.6 supplements per PMA per year during this time period. From the 64 PMA supplements involving significant design changes (180-day review clock) during 2010-2012, 23% included new clinical data to support safety and effectiveness. The authors concluded that because FDA determined many new cardiac implantable electronic devices are safe and effective based on PMA supplements without requiring new clinical data, “rigorous postapproval surveillance” is important for these types of devices.
In addition to these published studies, the same JAMA article included editorials suggesting that FDA should require more randomized clinical studies during the early phases, not just the pivotal study, and more clinical studies to support PMA supplements involving device design changes. In addition, while the authors of the editorial acknowledged that FDA has been making increased use of alternate approval mechanisms, particularly for rare or difficult to study products, the authors believed FDA should provide additional information to physicians and patients to evaluate the evidence used for these newer-type approvals versus other approved therapies to treat the same diseases or conditions.