Big Pharma Tightens Its Grip On Breakthrough Designations

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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 favored 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.

Click to enlarge
Click to enlarge

As before, this calculation excludes the anomaly of the Roche (OTCQX:RHHBY) 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.

Click to enlarge
Click to enlarge

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 (NASDAQ:VRTX) Kalydeco and Pfizer’s (NYSE:PFE) 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 tumors.

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 program. 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.

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