It's hard to imagine 2017 could get worse for CRLs tied to manufacturing

FDA logo
The FDA sent 5 CRLs tied to manufacturing problems in 2016 out of the 12 CRL's issued.

There are trends that portend good things for the industry, and then there are others. If 2016 is an indicator, manufacturing problems could see more bad news about drug approvals in 2017, delivered in the form of a complete response letters or delayed PDUFA dates.  

The FDA this year so far has issued a dozen complete response letters raising questions about the readiness of drug candidates. Five of those, an astonishing 40%, were specifically tied to questions the agency raised about the manufacturing capabilities of a drugmaker or its contractor. In 2014 and 2015, there was one CRL each year tied to manufacturing questions from the FDA. On top of that, Roche announced this week that its PDUFA date for its treatment for relapsing multiple sclerosis Ocrevus had been pushed three months into next year while the agency reviewed additional data on its commercial manufacturing processes.

In one of the 5 cases involving CRLs, the drugmaker and its contractor were able to respond quickly and get the drug approved yet this year, but the other four have led to delayed approvals and launches. That group includes Sanofi and Regeneron’s experimental IL-6 inhibitor sarilumab, an expected blockbuster that will compete with AbbVie’s Humira. 

So what’s up? The FDA spokesman Kristofer Baumgartner says there is nothing the agency is doing differently that accounts for the huge spike.   

“Although the number of CRs related to manufacturing is higher than in recent years, we have not conducted a more formal analysis of this issue,” Baumgartner said. Rather, he said, the increase “is related to the types of applications and their complexities rather than a change in FDA’s approach to reviewing applications.”

Maybe so, but it is an increase that means that the FDA approved far fewer drugs this year, that patients have been deprived of new treatments and drugmakers, well they have had potential sales and profits put off into the future. 

Starting it all off this year was the CRL that Miami-based OPKO received because of issues the FDA had with the manufacturing plant in Florida where its drugs are being manufactured by Catalent. But in that case, the company won approval weeks later for its chronic kidney disease drug Rayaldee after Catalent worked with the FDA to quickly get the issues resolved.

Others have not been so fortunate. Take AstraZeneca, which had plunked down $2.7 billion buyout of ZS Pharma to get its hands on its investigational treatment for hyperkalemia, only to have approval stalled by a CRL for issues the FDA found during a pre-approval inspection at the ZS Pharma unit.  

Then there was Valeant Pharmaceuticals, which could use any kind of boost these days. It had a its latanoprostene bunod ophthalmic solution, turned away by the FDA because of deficiencies at a plant operated by Valeant’s Bausch + Lomb unit. Valeant has said the candidate therapy for ocular hypertension could be $1 billion seller. A few days later, Ocular Therapeutix, also received a manufacturing related CRL for an for Dextenza, a treatment for post-ophthalmic surgery pain.

Portola had consideration of AndexXa, its breakthrough anticoagulant reversal agent, delayed in August, a problem that also affects Bristol-Myers Squibb and Pfizer which market the anticoagulant Eliquis for which AndexXa would serve as a bleeding antidote. Just days ago, Portola announced it was borrowing $50 million from BMS and Pfizer to help it deal with the FDA's concerns. 

Finally in late October, on the day that Sanofi and Regeneron had expected to win approval for sarilumab, they had to tell investors they had gotten a CRL instead. This for a drug that had in one trial had out performed Humira, the biggest-selling med in the world with about $14 billion in sales last year.

The problem the FDA said was issues at a Sanofi fill/finish facility in France. But this is not just any fill/finish facility. It also is the facility that is set to handle another of the drug candidates being developed by Sanofi and Regeneron, dupilumab, an experimental, first-in-class treatment for eczema that also could be a multi-billion dollar seller.  Sanofi has indicated it has other manufacturing sites to turn to and that there should be no problem getting dupilumab to market as expected.

All of the drugmakers say they are working with the FDA and expect to get things turned around quickly, but in some past cases, drug launches have been postponed for years.