A Year in Review: Important Intel Gleaned from CDER Report on New Drug Approvals

By James E. Valentine & David B. Clissold – 

In an annual update presented at the FDA/CMS Summit on December 14, 2015, Dr. John Jenkins, Director, Office of New Drugs, the Center for Drug Evaluation and Research (CDER or the Center), provided metrics and insights into the Center’s drug reviews and approvals for 2015, including PDUFA goals, IND activity, new molecular entity (NME) submissions and approvals, and utilization of expedited programs. These bloggers will discuss the topics we found most noteworthy. Several of Dr. Jenkins’ slides are presented below and the full presentation can be found here.

First Cycle Review Rates are at Historic Highs

The first action approval rate for CDER’s NME NDAs and BLAs is currently sitting at 95% with 25 applications pending of those received in Fiscal Year (FY) 2015. This comes after a sharp increase since FY 2010, when first action approvals were at 56%.

When further broken down, Priority Review NME applications in 2015 were approved at a rate of 93% in the first cycle, and have been consistently above 80% since FY 2011. Meanwhile Standard Review NME applications in 2015 are at 100% after hovering between 58% and 85% since FY 2011. However, the median time to approval has increased slightly, likely because under “the Program” (previously discussed here), a filing review takes place over the first two months after an NDA/BLA is submitted, and that time is “off the clock” with respect to the PDUFA timelines.

Why are first cycle approvals so high? Dr. Jenkins made clear in his presentation that “CDER has not changed its interpretation of the statutory standard for approval” and that the Center is “not a ‘rubber stamp.’” Since the standard has not changed, then we must ask: what has? This is likely a multifactorial answer.

First, let’s consider “the Program,” which is designed to improve planning before application submission, increase the number of complete applications at the time of submission, enhance communication and transparency between the applicant and review team during review, and allow for additional review time when amendments are made. One important component of “the Program” is the pre-NDA/BLA Meeting (Pre-Submission Meeting). The purpose of this meeting is to discuss the format and content of the anticipated application, including labeling, presentation of data, dataset structure, and acceptability of data for submission. As a result, CDER likely informed some number of applicants that their information would not be accepted for review because of certain deficiencies (e.g., the need for another pivotal trial, or unresolved manufacturing issues). Thus, applications that may have been submitted in the past were not, and those that were submitted were better positioned to meet FDA’s expectations at the time of the filing decision. Deficiencies that had previously been relegated to Complete Response letters (or Refusal to File letters) could be addressed before submission or, the FDA agreed during the Pre-Submission Meeting, through amendments during the review itself, which could extend the time of that first cycle review.

Now let’s take a closer look at some key characteristics of the 41 NME approvals in Calendar Year 2015; all but five of these drugs were approved on the first cycle (88%).

*Repatha was counted as half because its application was submitted with two indications, of which only one received Orphan Drug Designation.

The first four rows of the table above represent FDA’s four expedited programs for serious conditions. FDA clarified in modifications to the CDER Desk Reference Guide in Fall 2014, that “the Program” can accommodate expedited review times for drugs in one of its expedited programs while still meeting its program commitments, and Dr. Jenkins’ data appears to support that conclusion. Drugs approved on the first cycle utilized at least one of those programs at a higher rate than drugs approved, but not on the first cycle (69% vs. 20%, respectively). These programs, especially the “all-hands-on-deck” Breakthrough Therapy program, provide additional attention and interactions with FDA. These interactions provided sponsors with the opportunity to obtain additional input from FDA regarding drug development programs and the ultimate content of the application, as well as the opportunity to discuss with or “sensitize” FDA to issues that could make the review of an application particularly challenging.

The final two rows in the table above represent two factors that may have affected FDA’s benefit/risk analysis. A greater proportion of drugs approved on their first cycle were first in their class, increasing the likelihood that they are for diseases with treatments that have less favorable benefit-risk profiles or have no available treatment options. Lastly, about half of all drugs approved on their first cycle were for rare conditions while no drugs approved on a subsequent cycle were. As analyses conducted by HP&M attorneys have found, FDA demonstrates extraordinarily reasonable flexibility in its review of applications for orphan drugs.

Orphan NME and New Biologic Approvals are at an All Time High

Not only are orphan drugs playing a role in first cycle review approvals, but orphan drug approvals themselves are at an all time high. As of December 9, 2015, CDER has already approved 19 orphan NME and New Biologics in the calendar year. CDER approved 17 NDA/BLA for orphan drugs in calendar year 2014. Together, this may signal a jump in the number of orphan NME and New Biologic Approvals relative to past years. This is very promising for rare disease patients and the companies that are investing in developing drugs for these diseases, which are often severe and/or life-threatening, but poses a series of unique challenges, such as small patient populations to enroll in clinical trials and large information gaps in the understanding of the underlying science (e.g., pathophysiology, natural history).

NDA Review Times Vary by Division

When it comes to review times, review division matters. The chart below plots each division’s median NDA review time against the percentage of NDAs that qualified for Priority Review. As might be expected, the divisions with the most Priority Review applications (Oncology and Anti-Viral) have the shortest review times. Somewhat surprising is the number of review divisions with median NDA review times in excess of 350 days, even after factoring in a number of Priority Review NDAs for most of those divisions. Only three divisions (Bone, Reproductive and Urologic; Psychiatry; and Dental and Dermatologic) received no Priority Review NDAs.

Breakthrough Therapy Designation Program Metrics Indicate Continued Strong Interest but Low Success in Getting Designated

The Breakthrough Therapy Designation (BTD) program has suffered from a lack of clarity due to subjective criteria, even with the issuance of a final guidance in May 2014 and a MAPP in March 2015. Purportedly, the pace of requests and percentage of applications granted designation have remained steady. From the start of the BTD program in December 2012 through November 2015, CDER received 307 requests for BTD, of which 95 (31%) have been granted. So far 20 of the applications that received BTD have been approved.

However, of the 307 requests, 48% have been denied, 14% withdrawn, and 7% are pending. Dr. Jenkins’s presentation provided some common reasons for denial of BTD requests:

• Evidence does not include clinical data;
• Evidence is too preliminary to be considered reliable (e.g., small numbers of patients or inadequate duration of follow up);
• Failure to demonstrate “substantial” improvement over available therapy vs. “expected” incremental benefit of development programs;
• Reliance on a novel biomarker or surrogate endpoint without sufficient evidence to support benefit to patients;
• Post-hoc analyses of failed studies.

The number of BTD requests and granted designations is highest in the oncology, antiviral, and hematology divisions (see chart below).