Deficiencies in Manufacturing Derail CDER Approvals in 2016

FDA’s Center for Drug Evaluation and Research (CDER) approved 22 new molecular entities (NMEs) in 2016, according to a January 4, 2016 release from the agency. Of the 22 NMEs, 12 were large-molecule therapeutics. Of CDER’s 45 novel drug approvals in 2015, 17 were considered large-molecule therapeutics (larger than 900 Daltons).

In 2016, 11 of the 12 large-molecule drugs that were approved were biologics. This includes seven monoclonal antibodies (mAbs), one hormone, and three DNA-derived medications. The remaining large-molecule medication was a diagnostic agent.

Although the overall number of drugs approved by CDER in 2016 was lower than it was in 2015, FDA officials said the medical value of the medications that were approved was high. The 2016 approvals included the first-ever treatments for spinal muscular atrophy and Duchenne muscular dystrophy. Approximately 37% of the novel drugs approved were the first in their class (as of Dec. 9, 2016).

The agency also said that CDER approved five novel drugs in 2015 that had Prescription Drug User Fee Act (PDUFA) dates in 2016, which affected overall numbers for 2016. "While the number of novel new drug applications received for review in 2015 was similar to our most recent 10-year average of 35 applications per year, the natural fluctuation of the timing of application submissions and their PDUFA goal dates, meant there was a smaller pool of novel drug applications to target action on than in recent years," wrote John K. Jenkins, MD, director of CDER’s Office of New Drugs, in a FDA blog post.

Manufacturers should take note, however, as Jenkins asserted that many of the issues listed in the complete response (CR) letters to manufacturers were related to quality. “In examining the deficiencies cited in the CR letters issued to novel drugs in 2016, it is notable that the primary deficiency for several of the applications was failure to comply with FDA’s current good manufacturing practice (cGMPs) regulations.” Jenkins added, “The number of CR letters that cited failure to comply with cGMP regulations was unusually high for a single year.”

It’s difficult to know exactly what the most common cGMP deficiencies were in 2016, as FDA does not disclose all information in CRs-and even if a sponsor chooses to post about receiving a CR letter, the company does not often elaborate on what the specific deficiencies are or the sponsor redacts certain offenses in official documents.

In 2016, Sanofi and Regeneron disclosed they received a CR letter for sarilumab (an investigational drug to treat rheumatoid arthritis). The fill/finish of sarilumab was the root of the problem in that instance. Biopharmaceutical company Chiasma had a problem with one of its suppliers; this issue was revealed after a site inspection. Drug manufacturer Opko received a CR letter because of an issue with one of its third-party manufacturers. Valeant received a CR letter centered around cGMP practices at its Florida facility for an eye drug candidate.

Sandoz received a complete response letter from FDA for biosimilar pegfilgrastim candidate (Neulasta), although the company did not disclose the reasons for the letter. Amgen, AstraZeneca, Vertex, Teva, Dynavax, Novo Nordisk, and Takeda were a few of the other pharmaceutical manufacturers that received CR letters in 2016, although the letters were not necessarily issued because of cGMP issues. According to documents from a meeting led by Jenkins, as of Dec. 9, 2016, there were 12 new molecular entity/biologics license applications that received a CR letter in 2016, compared with only two in 2015.

Sources: FDA meeting notes, FDA Blog