‘Breakthrough’ Request Success Tied To Data Reliability

Also, small and private sponsors with less regulatory experience are more likely to see their requests denied than are large pharma companies.

The reliability and persuasiveness of clinical evidence is critical to the success or failure of requests for “breakthrough therapy” designation, an internal FDA analysis found.

At the April 24 Brookings meeting, Center for Drug Evaluation and Research staff presented results from their evaluation of designation decision criteria and characteristics for granted and denied requests. The analysis encompassed breakthrough designation requests, decisions and withdrawals from September 2012 to December 2014.

During that time period, CDER granted 32% of requests and denied 53%; 15% of requests were withdrawn by sponsors.

CDER Analysis Of Breakthrough Program And Decision Characteristics

• Breakthrough is a popular program with many strong candidates, particularly in the oncology, hematology and antiviral classes.
• Most successful breakthrough therapy designation requests (BTDRs) were from large, U.S. sponsors with regulatory experience.
• No pattern was identified in terms of whether a drug had an available therapy or orphan and/or rare status, but trends were observed by therapeutic area.
• BTDRs for indications that had prognostic biomarkers had a higher proportion of grants.
• Breakthrough grants submitted more trials on average and these trials were more likely to be randomized.
• Most BTDR decisions were based on Phase I and Phase II trial data.
• There was no discernible pattern to trial enrollment; appropriate enrollment depended on the specific indication.
• Trial and analysis issues followed by lack of substantial improvement were the top denial rationales.
• Most withdrawals occurred for administrative reasons or because the division indicated to the sponsor the BTDR would be denied.

Source: CDER Office of Program and Strategic Analysis’ slides at the April 24 Brookings meeting on “Breakthrough Therapy Designation: Exploring the Qualifying Criteria.”

Kim Taylor, an FDA operations research analyst, said the review found neither a one-size-fits-all characterization of a breakthrough drug nor a definitive threshold for substantial improvement.

Nevertheless, some preliminary patterns were observed, most notably related to the importance of reliable, persuasive clinical evidence (see box).

Trial and analysis issues were the most common reason why breakthrough requests were denied, having been cited in 72% of cases. This included trial design issues, sample issues, endpoint issues, results that were deemed too preliminary, and flawed post hoc analyses.

Lack of substantial improvement was cited in 53% of denials. Lack of data, including no clinical data or incomplete clinical data, was cited in 17% of denials, and safety concerns were cited in 11% of denials.

In terms of predictors of a successful designation request, the study found that products with a biomarker component in the indication were more likely to receive breakthrough status than those without a biomarker (Also see "FDA Breakthrough Designation Standards Revealed (Kind Of)" - Pink Sheet, 1 Dec, 2014.).

The analysis also showed that large sponsors (defined as more than 15,000 employees) had the highest rate of granted requests at approximately 61%, while small sponsors (fewer than 250 employees) and private firms had the lowest rates, at 19% and 20% respectively.

Sponsor size also appeared to be correlated with regulatory experience.

The agency reported that 83% of medium and large sponsors had prior regulatory experience, meaning they had a drug listed in “The Orange Book,” while only 15% of private and small sponsors had such prior experience.

Industry representatives noted that small companies with limited regulatory experience may benefit the most from the agency’s willingness to provide informal feedback as to whether early clinical data would support breakthrough designation for a given product (see related story, (Also see "Unsure About ‘Breakthrough’-Worthiness? Talk To FDA First" - Pink Sheet, 4 May, 2015.)).

In cases where data from randomized trials and hazard ratios were available, the hazard ratios averaged 0.48 for grants and 0.68 for denials. All but one of the hazard ratios noted in the analysis were in oncology and hematology; the sole outlier was in the cardio-renal division.

In her slides, Taylor noted there is wide variation by therapeutic area in trial characteristics, patient populations and available therapies. “Thus, any characterization of a substantial improvement threshold may be best approximated by therapeutic area. However, the small number of [breakthrough] grants and denials in each area thus far make it difficult to do so this early in the program.”