Big pharma tightens its grip on breakthrough designations

Data Insights

Four years seems ample time to judge the progress of a new regulatory procedure, and approvals of drugs blessed with US breakthrough status since this accolade was introduced in July 2012 have shown striking reductions in average FDA review time.

If this is one clear trend, another has emerged more slowly: breakthrough therapy designations (BTDs) are accruing mainly to big pharma. And now an analysis by EvaluatePharma links the two, showing how reduced review times have also largely favoured big pharma over smaller groups with BTDs under their belts (see tables below).

True, the sample size is small; only six of the 31 drugs with BTD that were approved between July 2012 and the 2016 half-year point are solely in the hands of small or mid-cap companies. Indeed, of the 145 granted BTD applications just 39 are known to belong to non-big pharmas – though there could be more that have not been disclosed, of course.

But the trend is there: small company drugs with BTD have got to market in an average 8.2 months, seemingly much longer than the 5.5-month average it has taken big pharmas. 

BTD products that have secured US approval*
US sales ($m)
Product Company 2015 2022e FDA approval Approval time (mth)
Opdivo Bristol-Myers Squibb 823 7,123 22 Dec 2014 4.8
Imbruvica AbbVie 659 3,683 13 Nov 2013 4.5
Darzalex Johnson & Johnson 9 3,497 16 Nov 2015 4.3
Tecentriq Roche - 3,456 18 May 2016 4.2
Ibrance Pfizer 718 3,111 03 Feb 2015 5.7
Keytruda Merck & Co 393 2,783 04 Sep 2014 6.2
Harvoni Gilead Sciences 10,090 2,515 10 Oct 2014 8.0
Orkambi Vertex 351 2,152 02 Jul 2015 7.9
Gazyva Roche 79 1,736 01 Nov 2013 6.3
Zepatier Merck & Co - 1,378 28 Jan 2016 8.1
Ofev Boehringer Ingelheim 244 1,286 15 Oct 2014 5.5
Empliciti Bristol-Myers Squibb 3 1,253 30 Nov 2015 5.1
Venclexta Roche - 1,146 11 Apr 2016 5.4
Alecensa Roche 67 1,108 11 Dec 2015 3.1
Viekira Pak Abbvie 1,639 1,034 19 Dec 2014 8.0
Nuplazid Ipsen/Acadia - 1,018 29 Apr 2016 7.9
Sovaldi Gilead Sciences 2,388 863 06 Dec 2013 8.0
Tagrisso AstraZeneca 15 817 13 Nov 2015 5.3
Esbriet Roche 401 781 15 Oct 2014 59.4
Epclusa Gilead Sciences - 560 28 Jun 2016 8.0
Kalydeco Vertex 372 515 21 Feb 2014 4.7
Strensiq Alexion 4 420 23 Oct 2015 10.0
Trumenba Pfizer 19 326 29 Oct 2014 4.4
Zykadia Novartis 75 314 29 Apr 2014 4.1
Kanuma Alexion - 307 08 Dec 2015 11.0
Xalkori Pfizer 231 307 11 Mar 2016 2.8
Bexsero GlaxoSmithKline 26 292 23 Jan 2015 6.0
Blincyto Amgen 45 225 03 Dec 2014 2.5
Arzerra GSK/Novartis 89 158 17 Apr 2014 4.9
Praxbind Boehringer Ingelheim - - 16 Oct 2015 7.9
Xuriden Wellstat Group - - 04 Sep 2015 7.9
*between 9 Jul 2012 and 30 Jun 2016.

As before, this calculation excludes the anomaly of the Roche drug Esbriet. This had been filed in 2009 before being subjected to a five-year delay, and only after Roche applied for the newly introduced breakthrough designation did it get approved.

Across all 31 approvals the average review time is 6.1 months, or 7.8 if Esbriet is included; a year ago average review time for BTD drugs was 5.7 months (FDA’s high bar for breakthrough therapy designations, June 8, 2015).

Either way this shows how BTD can speed a drug’s path, since US review times overall are running at between nine and 10 months. So it might be surprising that BTD applications have been holding steady over time, and at present 145 have been granted, with the US agency giving the OK to about 40% of those submitted.

BTD applications to date*
Time period/agency division Received Granted Denied
1 Oct 2015 - 30 Jun 2016 (CDER) 82 29 31
1 Oct 2015 - 30 Jun 2016 (CBER) 18 5 9
1 Oct 2014 – 30 Sep 2015 (CDER) 93 32 43
1 Oct 2014 – 30 Sep 2015 (CBER) 20 8 9
1 Oct 2013 – 30 Sep 2014 (CDER) 96 31 51
1 Oct 2013 – 30 Sep 2014 (CBER) 26 7 19
1 Oct 2012 – 30 Sep 2013 (CDER) 92 31 52
1 Oct 2012 – 30 Sep 2013 (CBER) 11 1 10
9 Jul 2012 – 31 Sep 2012 (CDER) 2 1 1
Total 145 225
*between 9 Jul 2012 and 30 Jun 2016.

That said, one obvious question is whether the FDA would in any case have fast-tracked a drug that is clearly highly promising, or is showing efficacy in an unmet need – with or without the existence of BTD.

This has long been an imponderable, but a new analysis seems to support this hypothesis. The trick is to look at two drugs – Vertex’s Kalydeco and Pfizer’s Xalkori – whose approved BTD uses were not their first registered indications.

Kalydeco was approved in 4.7 months for treating cystic fibrosis patients with non-G551D gating mutations, having first been approved for the non-BTD use of G551D-mutated cystic fibrosis. For Xalkori, BTD approval in Ros1-mutated lung cancer came in just 2.8 months, after first being approved in Alk-mutated tumours.

But how long did these to drugs take to negotiate the regulatory pathway in their initial uses, which both occurred before the BTD pathway was in effect? The answer is just 3.5 and 4.9 months respectively.

This is not to deny the benefit to an applicant that BTD brings in terms of interacting with the regulator and planning a robust pivotal programme. But the FDA clearly does not need to have its hand held, and smaller companies still need to work harder to turn breakthrough designation into faster approval.

To contact the writers of this story email Jacob Plieth or Edwin Elmhirst in London at news@epvantage.com or follow @JacobPlieth or @EPVantage on Twitter

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