Examining Breakthrough Designation Labeling

Boston—For new drugs to treat serious and often life-threatening conditions, 4 expedited FDA-approval pathways are available: (1) fast-track designation; (2) accelerated-approval pathway; (3) priority-review designation; and (4) breakthrough therapy designation. During a session at the AMCP meeting, Saurabh Aggarwal, BS, MS, PhD, principal, cofounder, Novel Health Strategies, Chevy Chase, Maryland, gave an overview of breakthrough therapy designation.

The breakthrough therapy designation was established as part of the FDA Safety and Innovation Act of 2012, and includes 2 important criteria: (1) the designation can be applied only within the context of a serious or life-threatening disease or condition; and (2) it must be predicated on preliminary clinical evidence demonstrating substantial improvement over existing therapies on ≥1 clinically significant end point.

Dr. Aggarwal noted that potential advantages of a breakthrough therapy designation include a relatively fast regulatory approval process and there is a potential premium pricing opportunity, noting that the median price premium for these drugs is 30%, which is beneficial for manufacturers but poses challenges for payers. Conversely, Dr. Aggarwal said a potential disadvantage of breakthrough therapy designation is the risk of approving a product that has not been fully tested for safety.
In just over 2 years, >217 breakthrough therapy applications have been submitted to the FDA. Of those applications, 62 products have been granted the designation and 117 have been denied.

In terms of trends in breakthrough designation, 68% of approvals are for small molecule drugs and 58% have been granted orphan status. Breakthrough designation is most commonly indicated for oncology medications, comprising 42% of the drugs approved. Hepatitis C virus (HCV) is another top indication for breakthrough designation, comprising 16% of the drugs approved. According to Express Scripts, the estimated cost of treating all HCV patients using approved breakthrough designated products would be $300 billion. Dr. Aggarwal continued the session by highlighting breakthrough designations for these 2 disease states.

Ibrutinib has received 3 breakthrough therapy designations for mantle cell lymphoma (MCL), Waldenström’s macroglobulinaemia, and chronic lymphocytic lymphoma (CLL). Ibrutinib was approved for MCL based on the findings of a phase 2/3 trial that observed a response rate of 68%, with complete response found in 21% of patients and partial response found in 47% of patients. The overall rate of survival at 18 months was 58% for patients with MCL receiving ibrutinib. The drug was also approved for the treatment of CLL based on the findings of a phase 2/3 trial that observed a response rate of 43% in patients receiving ibrutinib compared with 4% of patients receiving ofatumumab.

Pembrolizumab was granted breakthrough designation for the treatment of melanoma based on the results from a phase 1/2 trial. According to the study, 24% of patients who received the recommended dose of 2 mg/kg had their tumors shrink.

Dr. Aggarwal noted that pembrolizumab is expected to be combined with certinib to test for other oncology treatment indications. “This will be worrisome for managed care to have a combination breakthrough therapy designation in terms of cost,” he said.

Following the recent approval of the 2-drug combination therapy ledipasvir/sofosbuvir for the treatment of HCV, Dr. Aggarwal discussed a triple combination therapy granted breakthrough designation—daclatasvir, asunaprevir, BMS-791325. The combination was granted breakthrough designation following the results of a phase 2 trial, though the drug is currently in a phase 3 trial.  

Another 2-drug combination therapy granted breakthrough designation for the treatment of HCV is daclatasvir/asunaprevir, which was granted designation based on a phase 3 trial; the drug is currently pending approval. In the trial, 87.4% of interferon-ineligible or intolerant patients achieved sustained virologic response at 24 weeks. The rates were similar in patients with and without cirrhosis (90.9% vs 84%, respectively).—Kerri Fitzgerald