FDA+ roundup: More than 2 years after a CRL, Lexicon is still battling the decision; UK pharma industry weighs direction of MHRA
Back in March 2019, the FDA made clear to Sanofi and its partner Lexicon Pharmaceuticals that it couldn’t approve the application for their diabetes drug because the data submitted do not show that the drug is safe.
“The data demonstrated that the addition of sotagliflozin to insulin is associated with an increased risk of diabetic ketoacidosis (DKA), a serious and often life-threatening consequence of insulin insufficiency,” the agency said in a rare explanation of the complete response letter. “Time-to-event analyses of the clinical trial data showed earlier development of DKA in sotagliflozin-treated patients than in patients assigned to placebo, without evidence that the risk stopped increasing over time.”
While FDA said the clinical trial data showed that sotagliflozin, which is approved in the EU, reduced HbA1c, a validated surrogate endpoint due to improved glycemic control, the agency also said the effect “was modest.” The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee split 8-8 on whether the overall benefits outweighed the risks.
“Diabetic ketoacidosis is an inherent risk of type 1 diabetes and an increase was seen with sotagliflozin compared to insulin alone,” Lexicon CMO Pablo Lapuerta said in a statement after the adcomm vote. “We believe this can potentially be addressed with proper education and monitoring.”
Typically, companies that receive CRLs try to work with FDA, address the deficiencies outlined, and resubmit their application as quickly as possible for approval.
But Lexicon, after Sanofi handed over control of sotagliflozin and sent its stock shares into a tailspin, appealed the CRL twice, and is now seeking a hearing to further discuss the application. FDA, meanwhile, has to continue to go through the process that’s afforded to drugmakers, despite rejecting both appeals in Nov. 2019 and March 2020 and standing by its determination that the drug’s DKA risk outweighed its benefits.
Most recently, in a letter dated this year, CDER has agreed to postpone its proposal to refuse to approve the NDA until Nov. 26.
New, FDA-funded book on pharma manufacturing lays bare the risks of trying to get innovative
The National Academies of Sciences, Engineering, and Medicine recently published a new FDA-funded book on innovations in pharmaceutical manufacturing, making clear that it can be “a risky proposition.”
The reality constraining the pace of innovation around pharma manufacturing, according to the book, “is the reality that formal regulatory review of technology occurs specifically in the context of individual products.”
What that means is that the FDA doesn’t approve new technologies that can be used for different drugs, but it evaluates the technology with respect to its suitability to deliver a high-quality product consistently. The authors add:
Although that paradigm might be appropriate for the pharmaceutical regulatory regime, it places a large burden on any manufacturer that seeks to bring forward a novel technology in support of product approval for the first time. Even if regulators have had exposure to and generally support a particular manufacturing innovation, only when a product that uses it has been fully subjected to detailed review and approval can an initial understanding of its genuine regulatory status be achieved. It is entirely incumbent on the manufacturer to satisfy all requirements that regulators need to approve the product, which might include unanticipated activities, costs, and time that could affect the financial viability of the product.
The book also calls for much more regulatory harmonization to allow for more global innovation, explaining, “Any progress that can be made to enhance or accelerate regulatory harmonization and consistency will clearly reduce current disincentives for global implementation of innovative manufacturing technology.”
Pharma industry group to MHRA: Don’t make the UK irrelevant
Fresh off the UK drug regulator’s decision to authorize Merck’s new Covid-19 early treatment pill, which was the first authorization in the world, the UK pharma industry’s association is calling on the MHRA to continue to be a strong leader or else companies might skip out on launching new products on the island entirely.
Thanks to Brexit, and the cutting of ties between the UK and the European Medicines Agency, once headquartered in London, the UK’s MHRA now has to find a happy medium between sticking with the international science and shining bright enough as a leader to continue to attract new medicines.
“The UK now can shape its independent regulatory policy strategy in a way that places the MHRA at the forefront of developing ‘gold standard’ regulatory frameworks and innovative practices for new technologies,” the Association of the British Pharmaceutical Industry said in a recent report. “However, this should be done in a way that ensures the UK remains internationally competitive. Drastically diverging from the direction of travel of other world-leading regulators could have negative consequences, such as the UK becoming a late launch market – or no launch market at all – for new treatments.”