By Harsh Sancheti, MSPS, MSRS, Ph.D., Medical Writer at Cato Research
Looking for a FDA Breakthrough Therapy Designation (BTD)? Utilizing the Preliminary BTD Advice System Might be USEFUL – or NOT
The Breakthrough Therapy Designation (BTD) process implemented by the US FDA facilitates expedited regulatory review of a drug candidate intended to treat a serious or life-threatening condition. To be designated BTD, the sponsor must share preliminary clinical evidence indicating that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. The program has been largely popular with the pharmaceutical/biotech industry since its introduction in July 2012 with the Food and Drug Administration Safety and Innovation Act (FDASIA) approval. By the end of March 31, 2016, the Center for Drug Evaluation and Research (CDER) had received 342 BTD requests (BTDR) of which 111 were designated BTD. Getting a BTD designation is hugely beneficial to the sponsor and according to some estimates can result in approximately 3.5 years less development time than a drug not granted any of the other expedited statuses by the FDA. So why does the FDA want to bring some changes to the BTD process/program? It is because the increasing BTDRs are putting a burden on the FDA and its ability to handle these requests. Thus, enters FDA’s ‘preliminary BTDR Advice’ system.
Although, there are not many details available from the FDA publicly about the preliminary BTDR Advice system, its primary goal is to allow the FDA to carry out a preliminary review (without using extensive resources) and give nonbinding advice on whether a formal BTDR submission by the sponsor would be appropriate. The FDA advises that, ‘A sponsor can contact the regulatory project manager (RPM) in the division to which the active IND is assigned and request the “Preliminary Breakthrough Therapy Designation Request Advice” template. This template should then be submitted as a formal amendment to the IND and a subsequent teleconference between the sponsor and the review division will be set up by the RPM. The review division will make a recommendation as to whether a request for a BTD is appropriate, may be too preliminary, or does not currently meet the criteria for a BTD. The Agency’s recommendation is advisory and is not to be interpreted to predict the Agency’s decision on the BTD request’.
Additionally, a sample BTDR Advice template found online recommends submission of the following:
- Details about the eligibility for a condition being serious and life-threatening along with indication details
- Candidate drug’s mechanism of action and its relation to existing therapies
- Describe the currently available therapies
- Information on the preliminary clinical evidence along with clinical trial details
The FDA’s response to a preliminary BTDR Advice:
- The Division’s preliminary advice is nonbinding and will not preclude you from submitting an official BTDR in the future.
- Even if you 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 this determination.
- The Division will schedule a 15 minute teleconference to discuss this information.
- No written documentation of the advice provided by the Division or minutes of the teleconference will be issued to the sponsor.
The preliminary BTDR Advice system is an interesting initiative by the FDA to perhaps eliminate BTDRs that clearly lack basis for a possible BTD. It must be understood that an official BTD requires a multi-level evaluation by the FDA. The BTDRs are first evaluated by the division who make a recommendation; this is followed by an evaluation by senior FDA officials comprising the CDER Medical Policy Council who make the final decision about granting the designation or not. Clearly, this multi-level review process would be more burdensome for the FDA than the sponsor; additionally, the FDA currently does not charge any fees for BTDR evaluation. Early on, it was estimated that the FDA would get as few as two or three BTDRs per year but the actual requests went up quite steeply by 30- to 40-fold from initial estimates after a guidance on expedited review programs that includes BTD was published by the FDA in 2014. Thus, perhaps trying to streamline the process, especially for sponsors that do not clearly understand the requirements for a BTD would assist the FDA in utilizing its limited resources more efficiently.
But is it more advantageous for the sponsor to submit a ‘preliminary BTDR Advice’ vs. an ‘official BTDR’? Drafting an official BTDR is fairly straightforward and does not require extensive resources. Sponsors submitting an official BTDR would get a definite reply from the FDA (as opposed to a nonbinding reply after submitting a preliminary BTDR Advice). The response to an official BTDR is fairly quick: less than 60 calendar days of FDA receiving the official BTDR. Sponsors are also allowed to resubmit an official BTDR that was initially denied or withdrawn by the FDA. Whereas, sponsors submitting a preliminary BTDR Advice may not even get any FDA advice if the FDA determines that an official BTDR would be required for making any determination. In this scenario, would it be really useful for the sponsor to submit a preliminary BTDR request? This remains to be seen.