Will the Breakthrough Designation Shorten Development Times for Oncology Agents Currently in the Pipeline?

This blog is a short version of the full length companion article which can be accessed here.

During the year and a half since the Food and Drug Administration Safety and Innovation Act (FDASIA) was signed into law, there has been much excitement and conversation about this new program.

In November 2013, Gazyva® (obinutuzumab, Roche/Genentech) and Imbruvica® (ibrutinib, Pharmacyclics/Johnson & Johnson) became the first FDA approved oncology agents with Breakthrough Therapy status. Gazyva was approved in combination with chlorambucil in patients with chronic lymphocytic leukemia (CLL); Imbruvica was approved as monotherapy in patients with mantle cell lymphoma (MCL). These approvals may provide the backdrop to ascertain whether and to what degree the Breakthrough Therapy designation can accelerate time to market.

Imbruvica experienced a fast time to market and a quick regulatory review, with the FDA approving the drug about three months before its PDUFA date.  However, will agents with Breakthrough Therapy status consistently and repeatedly experience a speedy time to market or will Imbruvica’s fast time to market turn out to be a unique situation?

With a number of Breakthrough Therapies currently in the oncology pipeline, this question will hopefully be able to be addressed in the relatively near future. According to the FDA website, a total of 34 Breakthrough Therapy designations covering all indications, had been granted as of November 22, 2013 (note that this does not appear to represent the number of agents but rather the number of requests for the designation that have been granted).1

The applications and decisions for Breakthrough Therapies are currently confidential, and the sponsoring companies have not yet disclosed the identities of a minority of these granted Breakthrough designations. Of the 26 different Breakthrough Therapy agents that have been disclosed to date, one-half are in oncology indications.

Of the oncology agents currently in development that have been granted Breakthrough Therapy status, a number of them received the designation early in clinical development, some after the completion of Phase I trials (see Table 1). Considering the faster time to approval for Imbruvica compared with Gazyva, the pipeline agents that received Breakthrough Therapy status earlier in development are theoretically more likely to have a shorter length of clinical development and time to approval due to the greater opportunities to take advantage of the benefits of increased FDA interactions, advice and organizational commitment.

Indeed, there are already some indications that these agents will have compressed development timelines. After receiving Breakthrough Therapy status based on Phase I data, both LDK378 (Novartis) and lambrolizumab (MK-3475, Merck & Co.) initiated Phase III trials without waiting for Phase II data to become available. In addition, some of these agents will likely apply for accelerated approval based on Phase II data. For example, Novartis is guiding for a regulatory filing for LDK378 in 2014,2 and since the company’s two ongoing Phase III trials of LDK378 just started in the summer of 2013, this timing would have to represent a filing for accelerated approval. In Japan, Chugai recently submitted a marketing application for alectinib based on the results of a Phase I/II trial in Japanese patients, raising the possibility that Roche could follow the same strategy in the United States when the results of the company’s ongoing Phase II trial in U.S. patients become available.

It’s possible that some of these drugs would have sought accelerated approval based on early data even in the absence of Breakthrough Therapy status. Future development will be watched closely over the next few years to see if accelerated approval applications for agents with Breakthrough Therapy status occur with more frequency than has been historically observed, and also to see if the speedy time to market observed with Imbruvica can be repeated consistently for other Breakthrough Therapies.

Table 1. Oncology Agents with Breakthrough Therapy Status

Sources: Various company press releases; Mullard, Nature Reviews Drug Discovery, 2013; Sherman, et al., NEJM, 2013.


  1. U.S. Food and Drug Administration. “Frequently asked questions: Breakthrough Therapies”, http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FDASIA/ucm341027.htm, accessed December 3, 2013.
  2. Novartis, “Third Quarter 2013 Results Presentation”, Appendix, October 22, 2013, http://www.novartis.com/downloads/investors/financial-results/quarterly-results/q3-2013-ir-presentation.pdf

by Cory Blaiss, PhD, Analyst, Clinical and Scientific Assessment, Kantar Health.

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