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|
|*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.