A prominent legislator on the House of Representative's Energy and Commerce Committee, Rosa DeLauro (D-CT), has called on the US Food and Drug Administration (FDA) to answer questions about the integrity of its drug and device approval processes, saying some products may be receiving approval prematurely.
The 6 February 2014 letter, addressed to FDA Commissioner Margaret Hamburg, notes the congresswoman's "growing concern over recent trends related to the approval of drugs, as well as the classification of devices by FDA."
"While I recognize FDA has made improvements in meeting performance goals for new drug applications and biologic license applications … major improvements are still needed to ensure the safety and efficacy of all medical products," she wrote.
Expedited Approval in the Crosshairs
DeLauro noted her particular concern over expedited approval pathways, including an FDA proposal to allow for an alternative approval pathway for drugs intended to meet unmet needs, which would only rely upon one-rather than the usual two-clinical trials.
While the proposal has won cautious support from industry even as it has questioned the need for such an approval mechanism, DeLauro seemed to paint a gloomier picture of the proposal in her letter.
"[The pathway] may not necessarily measure a meaningful health outcome," she said. "In addition, if the FDA permits smaller sample sizes, it would not be feasible to conduct subgroup analyses for safety and efficacy in women and men, in different racial and ethnic groups, or across age." She noted similar difficulties in determining appropriate doses for each of these respective groups.
The congresswoman has also noted existing problems in similar approval mechanisms, such as FDA's accelerated approval pathway, which uses surrogate endpoints to support a tentative approval decision. In other cases, FDA will require manufacturers to conduct postmarketing studies to determine risks unknown at the time of approval.
Manufacturers have often been slow or simply failed to obtain the data required by FDA, DeLauro noted in her letter. "As a result, patients, physicians and other health care providers have no objective information about the long-term safety or effectiveness of those products."
DeLauro's concerns are more than plausible. FDA has taken some products approved based on surrogate endpoints, such as Roche's Avastin (indication for breast cancer), off the market based on safety concerns that were only fully realized with the benefit of complete data.
DeLauro said that compassionate use exemptions, made through Investigational New Drug (IND) amendments and protocols, might instead be a better choice for extremely small patient populations until complete data could be obtained.
Devices Also Targeted
Devices were also highlighted in the congresswoman's letter. She took note of FDA's reclassification of many so-called "pre-amendment" devices from Class III to Class II. Pre-amendment devices are defined as those which were on the market prior to the 1976 Medical Device Amendments to the Federal Food, Drug and Cosmetic Act. All such devices were immediately classified as Class III "high risk" devices.
In the intervening years, FDA has reclassified many of those devices, making many of them Class II devices able to be approved through FDA's 510(k) premarket notification process. Class III devices must undergo review through FDA's more rigorous Premarket Application (PMA) process, which requires substantial clinical data.
In 2012, FDA received new authority under the Food and Drug Administration Safety and Innovation Act (FDASIA) to expedite the classification of all remaining pre-amendment devices, which it has started to do.
The problem, DeLauro wrote, is that FDA appears to be classifying many devices as Class II improperly. She noted concerns raised by some cardiologists about two life-saving devices that were now Class II, allowing them to bypass the PMA process. "Cardiologists have pointed out that this could be life-threatening," she wrote.
DeLauro's letter goes on to press Hamburg for a number of other pieces of information, such as the enforcement mechanisms it uses against manufacturers who fail to provide FDA with the required postmarketing studies in a timely manner, and its rationale for creating a new approval pathway instead of just relying upon the compassionate use exemptions in the IND regulation.
FDA was asked to respond to DeLauro's concerns, but was not given a respond-by date.