FDA’s evaluation of the first two years of the breakthrough therapies program found common threads among designation requests that were granted and denied, which may help sponsors better understand the agency’s criteria for awarding the incentive.
Below are key characteristics of products that have gained and were denied breakthrough designation, as well as reasons why FDA turned down a sponsor’s request for breakthrough status.
Product Characteristics
Category |
Breakthrough Designees |
Breakthrough Denials |
| Average enrollment of trials submitted in request | 184.3 (median: 88) | 114.4 (median: 51) |
| Average number of trials submitted in request | 1.52 | 1.23 |
| Maximum trial phase | 1.94 | 1.73 |
| Request included randomized or blinded trials | 56% randomized/32% blinded | 56% randomized/46% blinded |
| Available therapy for the disease | 64% | 49% |
| Rare and/or orphan | 60% | 55% |
| Genetic/targeted therapy | 38% | 20% |
Note: Based on total of 50 breakthrough designations and 86 denials analyzed
Genetic Component To Therapy
Type of Therapy |
Designees |
Denials |
| With a genetic component in the indication | 19 | 17 |
| No genetic component in the indication | 31 | 69 |
Orphan vs. Non-Orphan
Status |
Designees |
Denials |
| Median enrollment in highest trial phase submitted with orphan status | 69 | 47 |
| Median enrollment in highest trial phase submitted without orphan status | 161 | 56 |
Alternative Therapies Available
Availability of Alternative |
Designees |
Denials |
| Approved and unapproved therapy available | 9 | 10 |
| Only approved therapy available | 23 | 32 |
| Only unapproved therapy available | 14 | 28 |
| No alternative therapy available | 4 | 16 |
Maximum Trial Phase Of Evidence In The Designation Request
Phase |
Designees |
Denials |
| 0 | 2 | 1 |
| 1 | 9 | 27 |
| 2 | 29 | 47 |
| 3 | 10 | 7 |
| No data submitted | 0 | 4 |
Median Trial Enrollment
Phase |
Designees |
Denials |
| 1 | 19 | 28 |
| 2 | 73 | 62 |
| 3 | 161 | 147 |
| Other (requests that included expanded access data) | 16 | 31 |
Reasons for Denial of a Breakthrough Designation
| Total denials reviewed | 86 |
| Lack of efficacy | 57 (66%) |
| Lack of safety | 14 (16%) |
| All data or trial problems | 80 (92%) |
| No clinical data | 5 (6%) |
| Trial design flaws | 22 (43%) |
| Invalid endpoint | 25 (29%) |
| Sample size | 31 (36%) |
| Post hoc analysis | 13 (15%) |
| Trial results too preliminary | 21 (24%) |
| Treatment effects not isolated | 10 (12%) |
| Concomitant treatments | 3 (3%) |
| Miscellaneous or other reasons | 17 (20%) |
Source: Presentation by CDER Director Janet Woodcock during the Nov. 21 Friends of Cancer Research-Brookings Conference on Clinical Cancer Research
https://www.pharmamedtechbi.com/Publications/The-Pink-Sheet/76/48/Break…
