JAMA papers raise questions about FDA drug and device approval

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An important series of papers was published in the Journal of the American Medical Association this week.

Clinical Trial Evidence Supporting FDA Approval of Novel Therapeutic Agents, 2005-2012,” by Dr. Joseph Ross and colleagues, concluded that the quality of clinical trial evidence used by the FDA as the basis of approving new drugs varies widely.  A couple of interesting data points:

  • in the seven-year period of analysis, 37% of drugs were approved on the basis of a single pivotal trial.
  • trials using surrogate end points as their primary outcome formed the exclusive basis of approval for 45% of drugs approved. (See our primer, “Surrogate markers may not tell the whole story.”)

In an opinion piece,  “Opening the FDA Black Box,” Drs. Steven Goodman and Rita Redberg said the study:

“…raises a host of questions needing further exploration. Despite the FDA requirement for evidence from a minimum of 2 randomized clinical trials supporting an effect on health outcomes, 37% of product approvals were based on only 1 trial, 53% of cancer trials were nonrandomized, and an active comparator was used in only 27% of non–infectious disease trials. Surrogate end points were used in almost all approvals via the accelerated approval process and in 44% of nonaccelerated approvals. Trials were comparatively short, with most lasting less than 6 months, even those assessing chronic treatments for chronic diseases. Cancer drugs, perhaps predictably, were more often approved via the accelerated process and with weaker designs.”

Another paper looked at the reasons that FDA marketing approval for new drugs was delayed or denied.

And a fourth paper looked at FDA regulation of medical devices, “a process that has received relatively little attention,” according to Goodman and Redberg, who continued:

“There are 2 different pathways of devices to market. The most rigorous is the premarket approval (PMA) route, which requires some evidence of clinical effectiveness and safety data, although only 14% of high-risk devices have been assessed in even 1 randomized controlled trial, usually unblinded. As a result of the 2004 Medical Devices User Fee Act, which requires the FDA to require the “least burdensome route” to approval, less than 1% of medical devices are approved through this most rigorous pathway.For moderate- and low-risk devices, the other route is the 510(k) pathway, which allows devices to be marketed if they show “substantial equivalence” to existing devices.A 2010 Institute of Medicine committee strongly recommended elimination of this path.

(That paper also describes) an underexamined third way for a device to reach the market via the “supplement” process, used for modifications of devices originally approved through a PMA. Focusing on cardiac implantable electronic devices in the period from 1979-2012, Rome et al found that there were 5825 supplemental PMA applications for 77 original devices—a median of 50 supplements per device, of which about half were for design changes. It is not surprising that many of the devices are, according to the authors, “much different from the original.”

Rome et al report that supplemental PMA applications are commonly approved without clinical testing, based on reviewer judgments, suggesting that “in some cases, preclinical testing may be superior to clinical testing in assessing changes.” The main role of preclinical testing is to identify devices that demonstrate problems in the laboratory setting and thus avoid clinical testing of that device change. However, the absence of problems in the laboratory setting might not reliably predict the long-term fate of the device in the human body, where environmental and physiologic forces impossible to replicate in the laboratory setting work in combination. The malfunction of implantable cardioverter-defibrillator leads, which resulted in a widespread recall,and the hazards posed by particles shed from metal-on-metal hip replacements were not predictable based on engineering insights or in vitro studies. More empirical work is needed to assess the validity of reviewer judgments about whether clinical data are needed prior to certain types of device approval. Moreover, if the approval process depends on subsequent clinical trials, a less obvious consequence of constant design modification is that it could be difficult to know what device versions were used in the trials and whether results are generalizable to other versions of the device.”

In USA Today, Liz Szabo wrote a good summary of the JAMA papers under the headline, “Not all FDA-approved drugs get same level of testing: Evidence behind FDA-approved drugs and devices often has major limitations.”


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