FDA Corner – Interview with Amy Mckee, MD

BY Erik J. Maclaren, PhD

Breakthrough Therapy Designation and Mechanisms of Expedited Review

The U.S. Food and Drug Administration (FDA) is responsible for reviewing the evidence of safety and efficacy for all new drugs before they can be made available to patients. Increasing the efficiency and speed of the approval process for drugs that treat serious diseases, including lung cancer, is an important part of improving patient access to lifesaving medications. The FDA currently employs 4 distinct mechanisms to expedite the review of potentially important drugs:

1. Fast Track Designation can be granted to promote the development and approval of drugs to treat serious conditions with unmet clinical need. This designation provides for more frequent communications and meetings between the drug company and the FDA to support the approval process, as well as eligibility for Accelerated Approval, Priority Review, and Rolling Review.

2. Breakthrough Therapy Designation may be applied to drugs that have preliminary clinical evidence of being a substantial improvement over existing treatments in the management of serious conditions. The manufacturers of Breakthrough Therapies receive all Fast Track benefits plus intensive guidance and organizational commitment from the FDA for creating an efficient drug development program. Examples of recently approved thoracic oncology agents with recent Breakthrough Therapy designation include pembrolizumab for the first-line treatment of metastatic PD-L1-expressing non-small cell lung cancer (NSCLC) and crizotinib for ROS-1 positive NSCLC.

3. Accelerated Approval regulations allow drugs for serious conditions with unmet clinical need to be approved based on a surrogate endpoint, such as tumor size or response, rather than on more traditional clinical endpoints like patient survival. This process can significantly decrease the amount of time required to gather the necessary data on efficacy to gain approval. Accelerated approval is conditional; to retain approval, drug companies are required to conduct phase 4 confirmatory trials to confirm the clinical benefits of these agents. Examples of recent accelerated approvals in thoracic oncology include alectinib for patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib, and osimertinib for patients with EGFR T790M mutation-positive NSCLC who have progressed on or after EGFR TKI therapy.

4. Priority Review is granted to drugs for serious conditions that would offer significant improvements in safety or efficacy over standard treatments. The FDA strives to take action on applications under Priority Review within 6 months, as opposed to 10 months under Standard Review.

The Breakthrough Therapy designation is important for increasing the availability of oncology drugs that demonstrate large early clinical effects. The early involvement and coordination of experienced, senior FDA personnel can significantly reduce the time necessary for development and approval. Criteria for this designation include the following: (1) the drug is intended to treat a serious condition, and (2) preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over currently available therapy. Although the Breakthrough Therapy designation is often used for oncology agents, drugs treating any serious or life-threatening conditions, including non-oncologic illnesses, are also candidates for this designation.

IASLC Lung Cancer News spoke with Amy McKee, MD, acting deputy director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, about the details and benefits of the Breakthrough Therapy designation.

Q: Are different criteria used to apply the Breakthrough Therapy designation to oncology agents vs other agents for other diseases?

A: No. Every product is evaluated within the context of the specific disease and available therapy for that specific disease.

Q: Are toxicity issues assessed differently since the stakes are higher in oncology with different risk-benefit expectations?

A: All the products eligible for Breakthrough Therapy designation are to treat serious or life-threatening conditions. The risk-benefit calculus may change between diseases and even within a disease. For example, the risk-benefit evaluation for a product to treat newly diagnosed breast cancer in the curative setting is different than that for recurrent metastatic breast cancer.

Q: What are the expectations once an agent has achieved Breakthrough Therapy status? Does the paradigm change for conditional or full approval?

A: If a product receives Breakthrough Therapy designation, the FDA will provide intensive guidance on efficient drug development. Additionally, the drug’s marketing application, either a New Drug Application or a Biologics License Application, may be able to obtain rolling submission and review, as well as other actions to expedite a marketing application review. However, the approval standards for both accelerated approval and regular approval are not altered for a product with Breakthrough Therapy designation status.

Q: What percentage of agents achieving Breakthrough Therapy status go on to full approval?

A: As of January 1, 2017, the Office of Hematology and Oncology Products has approved 22 products with Breakthrough Therapy designation in 30 indications. Of these 22 products, 13 to date have received full (regular) approval.