Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Breakthrough Therapy Designation: Challenges and Opportunities for Innovative Drug Development – A Three-Year Review after PDUFA V ***

Dr. Qian Mao (Abschlußjahr: 2016)

Summary
Language: English

Background: Advances in the science increase significant numbers of drug candidates that show extraordinary effects at early stages of drug development, which challenge the traditional approach to clinical development and FDA`s standards for tolerability and efficacy. The Breakthrough Therapy Designation (BTD) was introduced as part of the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012, to facilitate development and review of drugs and biologics that address unmet medical needs in the treatment of serious or life-threatening conditions.

Objective: Since the inception of BTD program, the number of requests to the FDA has been continuously increased over the years, showing its popularity for pharmaceutical industry. The 22 NMEs with previous BTD have received first-ever approvals by the FDA and have been collected as case studies to represent the impact of BTD program on innovative drug development in the global convergence. Some key measures are pre-defined to evaluate the impact of BTD on drug development, e.g., the grade of combination with other expedited tools, the review time, and the development time and the approval basis. Analyzing the complied post-marketing activities serves to understand the kinds of flexibility that the FDA might commit to BTD approvals. To gain a whole picture of current global convergence of breakthrough therapy, the regulatory status of the 22 case studies in the key ICH region (EU and Japan) are also investigated in this master thesis.

Key findings:

• All of the 22 approved BTD drugs received at least one additional expedited tool by the FDA to maximize the acceleration of development program. As shown in comparison analysis with non-BTD novel drugs, the approved BTD drugs trend to combine more frequently with other expedited tools to accelerate review and pre-market development.
• All of the 22 approved BTD drugs received priority review by the FDA: the average review time of 6.4 months was observed among all indications, which was 3.3 months faster than the average review time of non-BTD drugs under priority review.
• The drugs which were granted as BTD in their early development presented very fast development paths: from IND until approval within 4 years, based on single-arm non-randomized pivotal phase I or phase II trials as accelerated approvals.
• The drugs which the BTD was granted during or after filing could also expect additional benefit from the BTD program, e.g. expedited review, extended resources by the FDA to review additional data, intensive guidance and flexibility by the FDA for CMC readiness.
• A delayed access of 22 BTD drugs to patients underlying serious diseases in the EU as well as the “drug-lag” in Japan were observed, partly due to delayed submission by sponsors and partly due to longer review time and different fundament of decision making by agencies.

Conclusion: The retrospective analysis based on the 22 case studies demonstrates the positive impacts of BTD on innovative drug development, as committed by the FDA. The BTD creates a regulatory environment offering unique benefits from the FDA to expedite access to breakthrough therapy to patients underlying serious diseases with high unmet medical need. It is also important to understand that the BTD is not a guarantee of success but is correlated with certain risks and limitations. It is the sponsor´s own responsibility to overcome all challenges associated with the expedited development pathway. The EMA and PMDA has been developing similar regulatory environment for breakthrough therapies. It will be interesting to analyze the PRIME scheme and Sakigake after two or three years of launch to evaluate this global convergence of BTD program.
Pages: 54, Annexes: 2