The US Food and Drug Administration's (FDA) is now approving more new drugs and biologics during their first review cycles than at any time since at least 2008, a new FDA-commissioned report shows.
The report, conducted by the Eastern Research Group (ERG) on behalf of FDA, is focused on the fifth iteration of the Prescription Drug User Fee Act (PDUFA), which was passed in 2012 under the Food and Drug Administration Safety and Innovation Act (FDASIA).
PDUFA, which was first passed into law in 1992, created FDA's first-ever user fee programs. The programs require drug companies to pay FDA user fees each time they submit a new drug product for review. In return for those fees, FDA is able to hire additional review staff and has promised to review drug products according to set timeframes. Most traditional drugs are reviewed on a 10-month timeframe, for example.
The PDUFA program has proven popular, and has been reauthorized—with changes—every five years since it was first signed into law. With its 2012 reauthorization under FDASIA, the PDUFA program underwent some significant changes meant to accelerate the review and potential approval of drugs without compromising safety or efficacy standards.
Those efficiencies focused on the quality of new drug and biologic applications. When FDA receives an application, it is first judged on the completeness of the application (are all of the required sections there?) before FDA staff begin reviewing it. After an application is accepted for review, staff will then assess the content of the regulatory submission, including the safety, efficacy and manufacturing data provided within the submission.
In the past, the problem has been that manufacturers often had to guess which data FDA might want to see in a submission. While a company might think one particular trial endpoint was acceptable for use in a trial, FDA might go on to reject the application (known as a "complete response letter") if it felt that endpoint didn't prove adequate assurances of safety or efficacy.
This could lead to otherwise safe and effective drugs being denied during their first review cycle, all because the manufacturer and FDA didn't agree on the suitability of the evidence collected.
So under FDASIA, FDA committed to some major changes meant to increase the approval rates of drugs submitted for the first time.
Specifically, FDA committed to better communication between drug sponsors and regulators, as well as other changes meant to make amending a regulatory application an easier process.
These changes, collectively referred to as "The Program," were intended "to improve the efficiency and effectiveness of the first cycle review process and decrease the number of review cycles necessary for approval, ensuring that patients have timely access to safe, effective and high quality new drugs and biologics," FDA explained in a commitment letter to the pharmaceutical and biopharmaceutical industries.
Under The Program, companies would have access to pre-submission meetings meant to establish expectations for a specific application, "Day 74 Letters" outlining issues with a drug application early on in the submission process, predictable review timelines, mid-and late-cycle review communications from FDA and more.
The Need for Review
Another major change under The Program has to do with the performance of FDA. In past years, pharmaceutical companies have explained that they lacked conclusive data about how FDA was faring under PDUFA until late in the review cycle, making it difficult for them to ask for mid-course corrections.
If companies were being asked to fund a large portion of FDA's operating budget, the companies said, they should at least have assurances that FDA was meeting its review commitments.
So in 2013, FDA announced it had contracted with the Eastern Research Group to conduct an assessment of The Program. The assessment, they said, would be published by the end of March 2015.
Sure enough, ERG has now published that report, Assessment of the Program for Enhanced Review Transparency and Communication for NME NDAs and Original BLAs in PDUFA V.
The report has mostly good news for both FDA and industry.
"FDA-applicant communications have been excellent and constructive, with a spirit of cooperation, for both Program milestone meetings and regular contact outside these meetings," the report notes. Some Program participants interviewed by ERG characterized their interactions with FDA as being "the best" they had ever been.
That said, the report found that the increased meetings had served to burden FDA reviewers, especially for applications already subject to a compressed review timeline (such as drugs given priority review designation). However, the report did not find any instances of this impacting the quality or timing of reviews or review decisions.
Both FDA and industry said they thought the increased communication had allowed them to resolve issues quickly and efficiently, find "mutually agreeable solutions to issues," and form "productive working relationships."
Those changes have resulted in major improvements in first-cycle review approvals, the report found. Drug applications filed between 2008 and 2012 were approved during the first review cycle 54.8% of the time, the report found. Under PDUFA V, 71.9% of drugs have been approved during the first review cycle.
Some of this improvement may be due to changes in the review process, the report notes. Under PDUFA V, an additional two months were built into the review process. FDA review times have therefore been slower than in previous years, but it has only missed the review goal date for a single drug so far under PDUFA V, the report found. In addition, many more drugs are now being approved in advance of their PDUFA date than in past years, ERG said.
The Black Box of Inspections
Perhaps the only area FDA needs to improve in, the report found, is with respect to pre-approval inspections of manufacturing facilities and clinical trial sites.
"Inspections represented a 'black box' to many FDA reviewers and applicants," ERG wrote in its report. "This was in stark contrast to the high levels of transparency and open communication associated with other aspects of the review process."
ERG noted that inspections can single-handedly derail reviews, and that improvements in this area could result in more timely review decisions. Many of these inspections are not conducted until late in the review cycle, meaning any problems could result in a complete response letter (CRL) being issued. The report observed that some inspections were complicated by logistical challenges, a shortage of staff with the appropriate technical expertise and technical constraints specific to the manufacture of a drug.
The extensive, 196-page report can be found on FDA's website here.