FDA’s high bar for breakthrough therapy designations

Sanofi gaining breakthrough designation for its phase II project olipudase alfa underscores the risks and benefits of seeking this regulatory accolade for major scientific advances.

The FDA has been approving roughly one out of every three requests it receives, but the payoff appears worth the effort, with these products achieving approval in less than six months, on average, after submission of a new drug or biologics application (see table below). Meanwhile, the sector is starting to see signs that this policy is maturing and sparking competition to address underserved diseases.

16 OK’d, dozens awaiting

To date, 16 projects with breakthrough status have achieved FDA approval and have done so in an average of 5.7 months from submission – if Roche's Esbriet is excluded from the analysis. Esbriet was initially submitted in 2009 and rejected by the agency the following year, before the breakthrough programme existed. It was subsequently awarded the designation and granted approval, taking nearly five years in total to get regulatory blessing.

Including Esbriet brings the average approval time to nine months, but a truer picture of the benefit of breakthrough status is painted if Roche's drug is omitted.

Breakthrough designations ranked by 2020 US sales forecast
US sales ($m)
Product Company Approval time (mths) 2014 2020
Opdivo Bristol-Myers Squibb 4.8 1 5,023
Harvoni Gilead Sciences 8.0 2,001 3,729
Imbruvica Pharmacyclics 4.5 492 3,501
Keytruda Merck & Co 6.2 48 3,114
Ibrance Pfizer 5.7 2,084
Sovaldi Gilead Sciences 8.0 8,507 1,322
Viekira Pak AbbVie 8.0 48 1,253
Ofev Boehringer Ingelheim 5.5 5 1,143
Esbriet Roche 59.4 5 937
Kalydeco Vertex Pharmaceuticals 3.5 262 627
Gazyva Roche 6.3 47 426
Trumenba Pfizer 4.4 30 348
Xalkori Pfizer 4.9 195 286
Zykadia Novartis 4.1 27 231
Blincyto Amgen 2.5 162
Arzerra Novartis 8.8 92
Average approval time 9.0
Average minus Esbriet 5.7
Source: EvaluatePharma  

Taking the smaller number as an average, Vertex Pharmaceuticals’ Orkambi is already overdue for approval and Alexion’s Strensiq is due any day.

The swiftness of many of these reviews is astounding – less than four months for Kalydeco, the active ingredient of which is also in Orkambi, and less than five for cancer drugs like Zykadia and Pfizer’s meningitis vaccine Trumenba. This shows how earning the designation reduces regulatory risk and explains why so many designations have been sought in the first four years of the programme; in total, the FDA has rendered decisions on 259 requests.

It should not be too surprising that the FDA’s standard is high – just 90 have earned it through the end of May, according to agency data, mostly through the Centre for Drug Evaluation and Research (CDER) and very few through the Centre for Biologics Evaluation and Research (CBER). This is in keeping with the stated goals of the programme: only the projects thought to represent a true advance over existing treatment strategies ought to qualify for the enhanced assistance in trial design and regulatory review offered by achieving designation. 

Thus the list of breakthrough drugs includes: the three hepatitis C treatments that achieve cure rates above 90%, Harvoni, Sovaldi and Viekira Pak; the checkpoint inhibition agents Opdivo and Keytruda in oncology; and Kalydeco, the first-ever disease-modifying treatment for cystic fibrosis.

Time period/agency division Received Granted Denied
1 October 2014 – 29 May 2015 (CDER) 68 15 28
1 October 2014 – 31 May 2015 (CBER) 13 4 8
1 October 2013 – 30 September 2014 (CDER) 96 31 51
1 October 2013 – 30 September 2014 (CBER) 26 7 19
1 October 2012 – 30 September 2013 (CDER) 92 31 52
1 October 2012 – 30 September 2013 (CBER) 11 1 10
9 July 2012 – 31 September 2012 (CDER) 2 1 1
Total 90 169

Despite the attraction, there is no sign that pharma companies are accelerating their efforts to put forward breakthrough-eligible candidates. The eight-month period spanning October 2014 until the end of May 2015 saw 10 breakthrough applications per month, the same monthly rate as that recorded between October 2013 and September 2014.

And the proportion of breakthrough designations actually granted by the FDA has also remained similar. In 2014 31% of applications were greenlighted, while 57% were denied. So far this year 23% have made it through, while 44% have been blocked – but currently, there are more applications pending versus last year. 

Breakthrough not a given, can be taken

In the meantime, the FDA is reporting that it has rescinded designations for the first time ever – four since the beginning of the US government’s fiscal year on October 1. An FDA spokesman would not identify which designations had been revoked, but Merck & Co and Bristol-Myers Squibb have reported that the FDA informed them that their hep C candidates would no longer qualify.

This should be a sign of caution for developers in highly competitive areas like immuno-oncology. If they are basing a strategy on achieving breakthrough status, they will need to show a significant improvement over more advanced projects to hope to achieve and also to hold their designation.

With Novartis and Juno Therapeutics having hoovered up the first two designations in the CD19 CAR-T space, it will make the work of Kite Pharma and Cellectis that much more interesting.

To contact the writers of this story email Jonathan Gardner or Madeleine Armstrong in London at [email protected] or follow @ByJonGardner or @medtech_ma on Twitter

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