Breakthrough Successes Create Manufacturing Challenges

The breakthrough drug initiative has accelerated the development and approval of highly effective therapies, enabling important new medicines to reach patients sooner, according to Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER). Twelve breakthrough drugs have been approved over the past two years for several critical conditions in addition to cancer, and dozens more are in the pipeline, Woodcock reported in mid-November at a conference sponsored by the Friends of Cancer Research and the Bookings Institution. The response to the breakthrough program by sponsors has “exceeded expectations” and is “good news for patients,” she added. But it also puts pressure on manufacturers to address formulation, stability and quality production issues very early in development, she said.

The program’s success has been noted on Capitol Hill, where Congressional leaders are looking to enact legislation next year to further speed the development of drugs, biologics and medical devices to treat unmet medical needs. House Energy & Commerce Committee chairman Fred Upton (R-Mich) plans to issue a “discussion draft” in mid-January of a bipartisan bill to promote 21st Century Cures, and to finalize legislation in February, he said at the conference on cancer research. Upton’s  timetable calls for moving the bill through the E&C Committee in March so the House can vote on it before Memorial Day. Then it will be up to the Republican-controlled Senate to approve similar legislation as quickly. The goal is to finalize a bill in 2015 that modernizes clinical trials, promotes digital medicine, attracts more young scientists into biomedical research, and provides added incentives for developing innovative therapies. 

Efficacy key
The breakthrough drug program, which was established by the FDA Safety & Innovation Act of 2012 (FDASIA), should encourage such legislative action. Not only is the program a boon for industry and for patients, but it has brought about a change in culture at FDA, Woodcock commented. She noted that the importance attached to streamlining research and review of highly effective treatments sends a signal to review staff that health promotion is equally important as ensuring safety. And reviewers involved in drug quality assessment, moreover, are an important part of the team.

An agency analysis indicates that FDA grants a breakthrough designation to about one-third of requests, and denies it about half the time. The magnitude of clinical effect for a new treatment is the main factor in gaining the breakthrough designation, a bar that is met clearly by new compounds presenting clinical data showing 50% reduced risk of disease progression. Targeted therapies with some genetic component are more likely to be designated; denials occur most often for drugs demonstrating limited efficacy, tested in very few patients, or containing flaws in trial design.

The program’s success, though, means considerable work for FDA. CDER and the Center for Biologics Evaluation and Research (CBER) have vetted more than 200 requests for designation since January 2013 and have granted nearly 70, a process that involves dozens of meetings with sponsors and within the agency. Those products designated as breakthroughs get “focused attention” from FDA on development programs, which may involve advice on streamlined clinical trial designs or use of innovative statistical methods.

Accelerating production
Equally important is FDA assistance in addressing options for accelerating the manufacturing process and scheduling timely plant inspections for a drug likely to come to market much faster than expected. CMC reviewers in CDER work with manufacturers to clarify clinically relevant specifications and to determine what quality testing can be addressed post-approval, Woodcock observed, noting that reviewers in CDER’s Office of New Drug Products (ONDP), which will be part of the new Office of Pharmaceutical Quality, are integral to providing an overall assessment of benefits and risks related to bringing a breakthrough candidate to market based on limited information, such as only six months of stability data.

So far, CMC issues, stability and quality have not been “deal breakers” for breakthroughs, said Richard Pazdur, director of CDER’s Office of Hematology & Oncology Products, in discussing manufacturing challenges related to developing breakthroughs at the FDA/PQRI conference in September 2014. He encouraged manufacturers to get CMC people involved very early in examining accelerated production options, even before submitting a request for breakthrough designation. FDA will use “appropriate flexibility” to be able to release clinical study materials early, but he noted that there are limits to how much regulatory “contortionism” is possible.

Main concerns for CMC reviewers include inadequate characterization of the drug substance, inadequate analytical procedures, and a poor understanding of formulation and critical quality attributes, noted ONDP acting director Sarah Pope-Miksinski. There also may be questions about whether a manufacturing site is ready for pre-approval inspection and if the commercial process is sufficiently understood. Manufacturers should acknowledge up-front where data is limited related to dosage form, facility capabilities and methods and process validation in order to have a “robust discussion” with FDA about innovative risk-mitigation strategies and new technologies that may be useful.

A critical drug can be approved based on calculation of “reasonable shelf life,” a plan for commercial scale-up, and agreement on provisional narrow specifications and formulation, with an understanding that these parameters can be revised later. FDA is open to accepting less stability data at submission and allowing sponsors to submit additional information during review. And reviewers will work with manufacturers to develop post-marketing commitments that can address residual risk. 

No let-up
Meanwhile, FDA is looking to clarify standards for what is and what is not a breakthrough to reduce the volume of inappropriate requests and moderate its added workload. Woodcock is pleased to report a high level of concurrence between CDER new drug review divisions and the agency’s Medical Policy Council, which oversees the breakthrough designation process. But she noted that an abbreviated process for writing up rejection reports on “obvious non-starters” could reduce some less critical tasks.
The agency also would gain from filling some of the 650 staff vacancies in CDER, many of them for review positions. FDA officials hope that Congress will provide additional funding to support the breakthrough program and other new initiatives that over extend its staff.

The regulators and researchers anticipate that some promising breakthrough drugs may turn out to have safety problems or more limited efficacy than seen in early studies. But early approval of such products does not mean that FDA is lowering its standards, Woodcock maintains. She notes that CDER delayed approval for one breakthrough drug when problems emerged in a clinical trial. And she reports no let-up in applications seeking breakthrough status, setting the stage for continued growth and benefits from the program.