Multiple companies have had their FDA reviews put on hold because coronavirus-related travel restrictions at the FDA has kept their manufacturing plants from being inspected.
On Oct. 26, Spectrum Pharmaceuticals Inc., of Henderson, Nev., said the FDA was delaying a decision on the BLA for Rolontis (eflapegrastim) because the agency wasn't able to inspect the manufacturing plant of its contract manufacturer, Hanmi Pharmaceutical Co. Ltd., in South Korea. Spectrum is looking to get Rolontis approved as a treatment for chemotherapy-induced neutropenia.
"We want to make sure investors realize that this is not a CRL but a deferral, so there is no need to refile; this is just a delay," H.C. Wainwright & Co. analyst Edward White wrote in a note to clients after the delay was announced.
On Spectrum's conference call to discuss the company's third-quarter financial results on Nov. 4, Francois Lebel, Spectrum's chief medical officer, noted that the company was "exploring ways to expedite the inspection, possibly using alternative methods to ensure the earliest completion of the review of our BLA during this COVID-19 pandemic."
New York-based Bristol Myers Squibb Co. is the latest victim of FDA delays, announcing on Nov. 16 that the agency wouldn't meet its PDUFA action date for lisocabtagene maraleucel (liso-cel) due to the inability of the agency to inspect a third-party manufacturing facility in Texas. BMS has applied for approval of liso-cel, an anti-CD19 CAR T therapy, for relapsed or refractory large B-cell lymphoma after at least two prior therapies.
In addition to BMS, the delay has repercussions for former Celgene Corp. investors who have held onto their contingent value rights (CVR) that were part of BMS' acquisition of Celgene. BMS is obligated to pay $9 to holders of the CVR if three drugs were approved by certain dates: now-approved multiple sclerosis drug Zeposia (ozanimod), liso-cel, and another CAR T, idecabtagene vicleucel (ide-cel). Liso-cel's deadline is Dec. 31, a little over a month away. Ide-cel's deadline is March 31, 2021, just four days after its PDUFA date on March 27, 2021.
The CVR (BMY-RT) closed at 79 cents on Monday, Nov 23, suggesting investors think there's less than a 10% chance of BMS meeting the deadlines.
The FDA has discussed the possibility of doing virtual video inspections of manufacturing sites to complete the required inspections. Executives from both Spectrum and BMS have said they're open to virtual inspections.
"I don't know if they've started any of those, but there's certainly been a lot of discussion about FDA proceeding that way, at least in the near term as they're trying to deal with these issues," Chad Landmon, chair of the intellectual property and FDA practice groups at Axinn, Veltrop & Harkrider LLP, told BioWorld.
Landmon advises companies to start preparing now for the technical challenges with video virtual inspections. "It kind of sounds simple, but have good wi-fi set throughout your facility," Landmon said, noting that in large manufacturing facilities "you wouldn't necessarily have great wi-fi in certain areas because they don't need it."
While the FDA has decided to require inspections for some drugs, it’s using remote reviews of requested records for other drugs. "FDA is utilizing its authority under section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act to request records in advance of or in lieu of drug inspections," FDA Commissioner Stephen Hahn told the Senate Health, Education, Labor and Pensions Committee on Sept. 23.
"Companies are already well-positioned to do this because they're used to being inspected by FDA. They're used to having their documents looked at, and by and large, documents now are kept virtually," Landmon said. "The fact that we're in 2020 and this isn't the year 2000 is a huge benefit technology-wise; 20 years ago, I'm not sure we could have done this."
Remote still tough
The FDA allowed Alkermes plc to complete its manufacturing inspection by undergoing a remote inspection of records from its facility in Wilmington, Ohio. Nevertheless the company wasn't able to gain FDA approval for ALKS-3831, its treatment for schizophrenia and bipolar I disorder. On Nov. 17, the company received a CRL related to the tablet coating on certain development batches of ALKS-3831 that resulted in erosion of tablets.
Given how well the review was going with the FDA's division of psychiatry, Alkermes CEO Richard Pops said the company was "quite surprised" to receive the CRL. Leading up to the CRL, the company had "a week of active and productive discussions on the label with the division of psychiatry," Pops noted.
Meanwhile, the FDA's Office of Pharmaceutical Quality (OPQ) was reviewing the manufacturing records, which were received in September. OPQ had no contact with the company after acknowledging receipt of the records, despite multiple requests for feedback.
"If a question arises during the records review process, the FDA is not obligated to reach out to the sponsor until the [PDUFA] action date, even if the sponsor may already have information responsive to FDA's concern," Heather Faulds, senior vice president of regulatory affairs and knowledge management services at Alkermes, explained on a call with investors to review the CRL.
If the FDA had inspected the facility, Dublin-based Alkermes believes the agency would have been convinced that the tablet coating issue was fixed and approved the drug.
"In normal course, we believe the CRL request would have been addressed in the context of a pre-approval inspection," Pops told investors on the call. "We believe that that issue has been resolved for some time and that sufficient data is available to address these observations."
Alkermes has already been in contact with the FDA and expects to be able to submit the information to address the FDA's concerns quickly.
"Essentially, Alkermes just has to resubmit paperwork communicating the resolution of the tablet erosion issue in certain batches. Under a class I resubmission, the FDA will act within two months," J.P. Morgan analyst Cory Kasimov wrote in a note to clients.