FDA Regulatory Process Variable
January 22, 2014

Study Finds FDA Approval Standards Vary Widely

Rebekah Eliason for redOrbit.com – Your Universe Online

According to a recent study, the approval of drugs by the Food and Drug Administration (FDA) is based on widely varying clinical trials between 2005 and 2012.

The background from the article states that “FDA review of new drug applications is guided by the Federal Food, Drug, and Cosmetic Act, which requires 'adequate and well controlled investigations' to determine efficacy. Many patients and physicians assume that the safety and effectiveness of newly approved therapeutic agents is well understood; however, the strength of the clinical trial evidence supporting approval decisions by the US FDA has not been evaluated.”

Nicholas S. Downing, A.B., of the Yale University School of Medicine, New Haven, Connecticut, along with his colleagues characterized key features from clinical trials which provide the FDA with a basis for drug approval. These trials, known as pivotal efficacy trials, were evaluated based on the strength of evidence that supported FDA approval decisions regarding new therapeutic agents.

Using publicly available FDA documents, researchers found 188 novel therapeutic agents approved between 2005 and 2012 for 206 indications based on 448 pivotal efficacy trials. Of the pivotal trials, 89 percent were randomized and 79.5 percent were double blinded. Over half of the trials, 55 percent, used a placebo for comparison. An active comparator, such as another drug, was used for 32 percent and 13 percent did not have a comparator.

The authors write, “The variation in the [amount and type] of clinical trial evidence used by the FDA to assess the efficacy of novel therapeutic agents highlights the agency's flexible standards for approval. Such regulatory flexibility allows for a customized approach to approval, including the ability to rapidly approve potentially effective therapies for life-threatening diseases, such as certain cancers, or those diseases for which there is no existing effective treatment, such as orphan diseases. These approvals can be made without requiring costly and time-consuming randomized, double-blinded, controlled trials, although these trials are regarded as the gold standard for evaluation.”

Researchers noted that understanding the clinical trial evidence that underlies newly approved therapeutic agents has important implications for patients and physicians. “When medications become available on the market, decisions must be made about their use, likely informed by how well safety and effectiveness are understood. Comparative effectiveness information, which is not required as part of FDA approval and involves comparison of an intervention with an active control, was available for less than half of indications, consistent with prior research, but leaving uncertainty about the benefits and safety of these medications when compared with other available therapeutic agents.”

The authors write that the wide variation in clinical trial evidence “has the potential to inform current FDA regulatory approval standards and postmarket surveillance initiatives.”

The study also discovered that many currently used cardiac implantable electronic devices such as pacemakers were approved by the FDA based on a review process that assumed they were safe because of previously approved versions of the devices.

According to the authors of the study, “In the United States, the Food and Drug Administration (FDA) reviews high-risk medical devices—those that support human life, prevent illness, or present an unreasonable risk—via the premarket approval (PMA) pathway, through which manufacturers collect preclinical and clinical data as necessary to provide 'reasonable assurance' of the device's safety and effectiveness,”

Recently the PMA process has attracted attention after device components such as leads from Medtronic Sprint Fidelis and St. Jude Medical Riata implantable cardioverter-defibrillators (ICDs) were recalled. These devices did not undergo human clinical trials before approval since they were only design changes to devices already on the market. Newer models are considered ‘supplements’ to PMA applications which had been submitted almost ten years earlier.

The processes of approval by premarket approval supplement “allow[s] patients to benefit from incremental innovation in device technology by providing efficient and inexpensive FDA review pathways for smaller device changes. Supplements may include major or minor design changes as well as routine changes in labeling, materials, or packaging. By statute, the FDA must seek only the 'least burdensome' supporting data necessary for review.”

Benjamin N. Rome, B.A., of Harvard Medical School and Brigham and Women’s Hospital, Boston, along with colleagues, used the PMA database from the FDA to review CIEDs, including pacemakers, ICDs and cardiac resynchronization therapy (CRT) devices that were approved as PMA supplements from 1970 through 2012. The team identified the amount of supplements to each original PMA as well as characterized the type of change for each supplement.

Researchers discovered that 77 approved PMA applications for CIEDs (46 pacemaker devices, 19 ICDs and 12 CRT devices) were the basis for 5,829 PMA supplement applications. There was a median of 50 supplements for each original PMA. Over the last decade, the amount of approved supplements increased annually to 704. On average, excluding manufacturing changes which did not alter device design, the number of supplements that were approved each year was 2.6 per PMA per year.

Of the supplements represented, 37 percent at least had minor alterations to the design or materials of the device.

According to the authors, “Our results should not be interpreted to indicate that the FDA is failing to review PMA supplement applications to determine safety and effectiveness. However, clinicians and patients should … be aware … that clinical data are rarely collected as part of PMA supplement applications prior to marketing. The recalled Medtronic Sprint Fidelis and St. Jude Riata ICD leads were both PMA supplements — Fidelis a 180-day supplement and Riata a real-time supplement [a type of FDA review process]. Neither lead was studied in human trials prior to FDA approval. The FDA's approval of many supplements without new human trials, as in the case of these recent ICD changes, highlights the importance of collecting rigorous postapproval performance data.”

This study was published in the January 22/29 issue of JAMA.