Orphan Insights, Part 3: Breakthrough Therapy Designation

Orphan Insights is a short series of Q&A assembled from the many discussions I have with companies developing medicines and therapies for rare diseases and who are seeking regulatory advice. These questions are related to when, why and how to engage with the regulators, and take advantage of the various designations applicable to their orphan programs. Each “Part” in this series will pose questions and offer strategic and thought-provoking responses. By no means are these straight forward answers, I hope however that you find the considerations helpful. I encourage you to reach out should you want to discuss anything further.

A Breakthrough Therapy (BTD) is an FDA designation that was introduced in 2012 as a means to permit the FDA to grant priority review to a drug candidate under development for a serious or life-threatening disease, when clinical evidence indicates the therapy offers substantial treatment advantages over existing therapies for patients.

Since inception, the FDA has approved 61* breakthrough therapy designated products out of 505 total requests for the designation with about 33% of those designations granted.

On average CDER receives 100 applications each year, while CBER receives less than 30 applications for BTD each year.

In 2017, the FDA approved 17 Breakthrough Therapy drugs.

Question #1 – What are the benefits of a BTD?

(Copied and pasted from Section 902 of FDASIA)

1. Holding meetings with the sponsor and the review team throughout the development of the drug
2. Providing timely advice to, and interactive communication with, the sponsor regarding the development of the drug to ensure that the development program to gather the nonclinical and clinical data necessary for approval is as efficient as practicable
3. Taking steps to ensure that the design of the clinical trials is as efficient as practicable, when scientifically appropriate, such as by minimizing the number of patients exposed to a potentially less efficacious treatment
4. Assigning a cross-disciplinary project lead for the FDA review team to facilitate an efficient review of the development program and to serve as a scientific liaison between the cross-discipline members of the review team (i.e., clinical, pharmacology-toxicology, chemistry, manufacturing and control, compliance) for coordinated internal interactions and communications with the sponsor through the review division’s Regulatory Health Project Manager
5. Involving senior managers and experienced review staff, as appropriate, in a collaborative, cross-disciplinary review

What does all that REALLY mean?

1. As soon as you receive your designation (within 6 months) the FDA will actually request a Type B meeting with the Sponsor to receive a clear picture of the program and development plans. This is a good time to discuss CMC, any newly acquired clinical data, and pivotal trial plans.
2. Your questions, meetings, and requests, get moved to the top of the pile.
3. Ensuring efficient study designs using the rule of “flexibility” therapies under development
4. Your very own Regulatory Project Manager
5. The A-Team made up of Senior-level reviewers
6. Eligible for Accelerated Approval, Priority Review and/or Rolling Review

And lastly, although the term “breakthrough” is not representative of how the FDA deems the medicine in consideration, it is representative of what the industry thinks. The success rate alone is indicative of the challenging criteria and review of these applications. If one receives a Breakthrough Therapy Designation, wouldn’t you think “it must be a breakthrough in medicine”?

Question #2 – When should I apply?

Timing-wise, post IND (and ideally prior to end-of-Phase-2). Data-wise, as soon as you have preliminary clinical evidence that meets the criteria of “substantial improvement over existing therapies on 1 or more clinically significant endpoints.”

Note, while “preliminary” clinical evidence is used for submission purposes, demonstration of the drug development program to continue to meet the criteria for breakthrough therapy designation will be required moving forward to maintain the designation.

Question #3 – Does the EMA have a Breakthrough Therapy Program?

Yes, the EMA has a similar program. This program is referred to as the PRIME scheme or PRIority MEDicines.

The criteria of the PRIME designation is a bit different, and the timing is slightly more definitive. However, the benefits are much the same as including appointment of a dedicated RPM, in this case “a CHMP rapporteur (or CAT), continuous support, organized kick-off meeting (similar to FDA Type B) with the CHMP/CAT rapporteur and a multidisciplinary group, development plan and regulatory strategy guidance along with scientific advice at development milestones, and eligibility for accelerated assessment.

If you would like to some advice on your candidacy for either the BTD or PRIME, call us and we can have a discussion.

Summary

A successful regulatory affairs program requires careful, calculated and creative solutions. There are some regulations you cannot get around. And there are some regulations that you don’t want to miss out on. Every case is unique and for this, I encourage you to consider some of these points and questions.