FDA Updates Breakthrough Therapy Program: Meet the Preliminary Breakthrough Therapy Designation Request

By Alexander J. Varond

FDA’s breakthrough therapy designation (BTD) program has been, by all accounts, a popular program. Sponsors, looking to gain extra support from the Agency, shorten review times, and signal to investors that FDA views their preliminary clinical evidence favorably, have submitted over 330 breakthrough therapy designation requests (BTDRs) in just under 4 years. Perhaps responding to the program’s popularity, FDA has begun implementing a new procedure, dubbed the “Preliminary BTDR Advice” Request. The new Preliminary BTDR Advice Form is available here.

FDA’s Preliminary BTDR Advice Form states that it is to be used “as a basis for the Division to comment on whether a [BTDR] is appropriate, at this time, may be too preliminary, or does not currently meet the BTD criteria.” Preliminary BTDR Advice Requests must not exceed 2 pages and must be submitted to the IND.

FDA advises further that:

  • The Division’s preliminary advice is nonbinding and will not preclude [Sponsors] from submitting an official BTDR in the future.
  • Even if [Sponsors] request preliminary BTDR advice, the Division may not have enough information to determine if a BTDR is appropriate at this time. An official BTDR may be required to make a determination.
  • The Division will schedule a 15 minute telecon to discuss [the request].
  • No written documentation of the advice provided by the Division or minutes of the telecon will be issued to the Sponsor.

The four categories of information requested in the Preliminary BTDR Advice Form are:

  • Whether the indication is serious and life-threatening;
  • The drug’s mechanism of action and the drug’s relation to existing therapy(ies);
  • Available therapies; and
  • Preliminary clinical evidence, including trial design, trial endpoints, treatment groups, and number of subjects enrolled.

FDA is often asked by Sponsors whether the Agency agrees that the therapy should be designated as a breakthrough therapy. The Preliminary BTDR Advice Request appears to be a way to formalize these inquiries and encourage Sponsors to open a dialogue about BTD eligibility before submitting an official BTDR.

In practice, drafting an official BTDR is fairly straightforward and does not require extensive resources. So, it is unclear that Sponsors will use the Preliminary BTDR Advice Request since they are able to get an actual determination on an official BTDR with fairly limited effort, within 60 days of FDA’s receipt of the request.

On the other hand, FDA has often discussed the burdens that the BTD program puts on the Agency. BTRDs are first handled by the Division and then sent to CDER’s Medical Policy Council, which is staffed by senior FDA officials. The Division is tasked with making a recommendation on BTD eligibility to the MPC, and the MPC makes the final call on whether to grant BTD. Given this multilevel review process, it is not hard to understand that the BTD process is comparatively much more burdensome for FDA than for Sponsors. What’s more, Sponsors may resubmit BTDRs that were initially denied or withdrawn.

FDA had previously responded to this asymmetric resource requirement by educating Sponsors on BTD requirements (see FDA’s presentation from 2015) and requesting that Sponsors discuss the viability of a breakthrough therapy designation request prior to actual submission of a request.