2018 Complete Response Letters: Efficacy Issues Drove Most Product Rejections
Executive Summary
US FDA issued at least seven rejections to novel products; opioid analgesic sponsors had very little success, while biosimilar developers had a so-so year.
Complete response letters (CRLs) for novel products in 2018 didn't prevent the US FDA's year-end novel approval count from reaching a historic high, but a lack of evidence of efficacy appeared to be the chief culprit for new molecular entities (NMEs) and new biological entities (NBEs) being derailed.
Sponsors publicly announced the receipt of nine CRLs for novel products in 2018, more than half of which appear to have involved inadequate evidence of efficacy.
For Starpharma Holdings Ltd./ITF Pharma's VivaGel BV (astodrimer sodium), Sunovion Pharmaceuticals Inc.'s dasotralin and Achaogen Inc.'s Zemdri (plazomicin), the sponsors all specifically disclosed that the US FDA was looking for additional evidence that the product was effective.
Akcea Therapeutics Inc. and InfaCare Pharmaceutical Corp. did not disclose the content of the CRLs for their respective products Waylivra (volanesorsen) and stannsoporfin. However, efficacy issues were raised at each drug's advisory committee meeting.
One of the issues surrounding Waylivra, designed for the treatment of familial chylomicronemia syndrome (FCS), was the sponsor's use of the percent change in fasting triglyceride (TG) at three months as a surrogate endpoint. The advisory committee narrowly recommended approval by a 12-8 margin. (Also see "Akcea Waylivra's Surrogate Endpoint Gains Support At US FDA Advisory Committee " - Pink Sheet, 10 May, 2018.) However, FDA expressed uncertainty about the magnitude of the clinical benefit in its briefing documents. (Also see "Surrogate Endpoint, Safety Questions May Be Too Much For Waylivra To Overcome At US FDA Panel" - Pink Sheet, 9 May, 2018.)
Stannsoporfin, meanwhile, was shrouded in an even greater degree of concern about its clinical benefit, as an advisory panel voted 17-6, with one abstention, that the jaundice drug did not demonstrate substantial evidence of effectiveness. (Also see "InfaCare’s Stannsoporfin For Jaundice Rebuked By US FDA Panel" - Pink Sheet, 3 May, 2018.)
Trevena Inc.'s opioid Olinvo (oliceridine) was the only rebuffed novel product of the year where the sponsor announced that safety was a concern. According to the company, FDA requested additional clinical data on QT prolongation and indicated that the submitted safety database was not of adequate size for the proposed dosing. The agency also requested additional nonclinical data and validation reports, Trevena added.
Quality issues were cited for Evolus Inc.'s DWP-450 (prabotulinumtoxinA), Acacia Pharma Ltd.'s Barhemsys (amisulpride) and Prometic Life Sciences Inc.'s Ryplazim (plasminogen).
In total, however, the Center for Drug Evaluation and Research (CDER)'s 2018 novel approval count of 59 was shortened by only seven. Although Zemdri was rejected for the treatment of bloodstream infections (BSI), FDA cleared the aminoglycoside antibacterial for the treatment of complicated urinary tract infections (cUTI). (Also see "Achaogen Questioning Whether Others Will Pursue LPAD Pathway After Zemdri Misses Out " - Pink Sheet, 26 Jun, 2018.) Ryplazim, meanwhile, would have been regulated by the Center for Biologics Evaluation and Research (CBER).
Difficulties For Opioid Developers
Sponsors announced at least 34 total CRLs in 2018. Clinical issues (ie, FDA concerns about safety or efficacy) were the most common reason disclosed (present in 18, or 53%, of the letters). Quality issues were the next most common (11, 32%) but precise comparisons are difficult because some CRLs included multiple issues, and for one-fifth of the letters (7, 21%) the sponsor acknowledged the CRL but wouldn't disclose anything about it.
Standing out among the crop of denied applications were opioid analgesics, which received at least five complete response letters versus just one approval. (See sidebar for related story.)
AcelRx Pharmaceuticals Inc.'s Dsuvia (sufentanil) was the one opioid analgesic backed by the agency in 2018. (Also see "Dsuvia Approval May Be Followed By New Opioid Review Paradigm At FDA" - Pink Sheet, 2 Nov, 2018.)
One of the CRLs issued in 2018 went to Braeburn Pharmaceuticals Inc. for an opioid product that is not designed for analgesia: Brixadi (buprenorphine depot, formerly CAM2038) for the treatment of opioid use disorder in adults. (Also see "Braeburn Gets CRL For CAM2038 In Opioid Use Disorder, Yields Ground To Indivior" - Scrip, 23 Jan, 2018.) However, the company refiled the 505(b)(2) new drug application (NDA) in July and announced a tentative approval Dec. 23. (Also see "Keeping Track: US FDA Approvals For Tibsovo, Kisqali And Second Neupogen Biosimilar" - Pink Sheet, 22 Jul, 2018.)
A So-So Regulatory Year For Biosimilars
For their part, biosimilars developers had a roller coaster of a year on the regulatory front, landing seven approvals compared with likely six CRLs.
Amgen Inc./Allergan PLC, Pfizer Inc. and Teva Pharmaceutical Industries Ltd./Celltrion Inc. each ran into FDA stop signs over their copies of Genentech Inc.'s Herceptin (trastuzumab), while Sandoz Inc. and Teva/Celltrion landed CRLs for their biosimilars of Genentech's Rituxan (rituximab).
But Teva and Celltrion ultimately reeled in FDA's blessing for both of their products in the fourth quarter of 2018 after resolving good manufacturing practice (GMP) issues that beleaguered Celltrion's manufacturing plant. (Also see "Keeping Track Of Bad News: Alkermes' Depression Candidate Gets Refuse To File; Teva/Celltrion Biosimilars Land CRLs" - Pink Sheet, 8 Apr, 2018.)
Pfizer also said that FDA raised quality deficiencies in its CRL, while Amgen/Allergan and Sandoz did not cite the reasons for their rejections.
A sixth CRL this year likely went to Adello Biologics LLC's copy of Amgen's Neupogen (filgrastim). Although the company never made an official announcement since the May user fee goal date passed, a spokesperson told the Pink Sheet that, "the filgrastim aBLA filing has been accepted for review by FDA, and the project remains in active development by Kashiv BioSciences."
[Editor's note: The complete response letters chart lists drugs rejected by FDA, including information on the issues raised.]
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Biosimilar Approvals Vs. CRLs |
|||
|
Year |
Approvals |
CRLs |
Approval % |
|
2015 |
1 |
4 |
20% |
|
2016 |
3 |
1 |
75% |
|
2017 |
5 |
3 |
62.5% |
|
2018 |
7 |
6 |
53.8% |
|
Total |
16 |
14 |
53.3% |