FDA Faulted on Inspection Alternatives
FDA is being criticized for its slow response to the need to find alternatives to physical inspections during the worsening Covid-19 pandemic. The issue is even more critical now as a number of drug submission final review actions have been put on the back burner due to the agency’s lack of a required inspection.
To illustrate the problem, former FDA Office of Compliance and Biologics Quality deputy director and now-Hyman, Phelps & McNamara director Mark I. Schwartz has penned an article at BloombergLaw.com, calling on FDA to find alternatives to a physical inspection to prevent shortages of front-line drugs for treating Covid-19 patients and other lifesaving medications. “Without these inspections, new, cutting-edge therapies are being deferred or rejected, and drug shortages are worsening, including for front-line drugs in the treatment of Covid-19 patients,” he wrote.
As a recent example, the agency 11/16 deferred action on a novel cancer therapy BLA by Bristol Myers Squibb for Liso-cel (lisocabtagene maraleucel) a CAR T-cell therapy for treating adults with relapsed or refractory large B-cell lymphoma after at least two prior therapies. The company said the agency was unable to inspect a third-party manufacturing facility in Texas during the review cycle due to the Covid-19 pandemic. FDA deferred action until the inspection can be completed and did not set a new anticipated action date, BMS said. “The FDA should have been able to determine the facility’s compliance status by other means, particularly since the agency had tacitly acknowledged that the facility met its definition of a ‘mission critical’ inspection, suggesting that the FDA needed to perform the inspection despite the pandemic,” Schwartz said.
An FDA Webview review of recent agency actions found other instances where an inspection requirement blocked final review actions. Last month, FDA deferred its review decision on a Revance Therapeutics BLA for daxibotulinumtoxinA for injection, an investigational neuromodulator for treating moderate to severe glabellar (frown) lines. The agency again said a required inspection could not be conducted at the company’s northern California manufacturing facility due travel restrictions associated with the Covid-19 pandemic. And in October, FDA deferred a review action on a Spectrum Pharmaceuticals BLA for Rolontis (eflapegrastim), indicated for treating neutropenia in patients receiving myelosuppressive anti-cancer drugs, because of the travel restriction blocking an inspection (see story).
Earlier this year, FDA associate commissioner for regulatory affairs Judith McMeekin told the Food and Drug Law Institute’s virtual annual conference (see story) that the agency is evaluating whether it can use live or recorded video to conduct medical product inspections as the Covid-19 pandemic continues to disrupt the agency in its inspection duties. “We are studying how we might incorporate new technologies and tools to support our inspections, including exploring a pilot to assess use of live or recorded video,” she said. Recently, a live video test was conducted during two produce farm investigations to determine acceptability of live technical assistance from headquarters staff and to help with targeted sampling. She said the agency is interested in expanding the pilot to drug and device facilities, and the agency is interested in receiving comments on any challenges this may present.
Schwartz indicated that a “remote inspection” could have been conducted at the Liso-cel manufacturing plant but it was not an option. “Numerous pharmaceutical companies have pleaded with agency officials to conduct such inspections over the past several months in order to resolve manufacturing compliance issues and get critical new drugs approved, and have even offered to obtain the requisite technology, but the FDA has rebuffed such requests,” he said. “The agency has not made public any plans for the adoption of this remote method of inspecting, despite multiple requests from the pharmaceutical industry to do so.”
By contrast, several foreign regulatory bodies, such as the European Medicines Agency (EMA) permit drug plants to be evaluated by remote assessments, including new facilities that have never been inspected by the EMA. “The same is the case for Australia’s Therapeutic Goods Administration, which instructs drug manufacturers to ‘have pre-recorded videos of the site and operations so that the inspectors can be presented with a virtual tour of GMP [good manufacturing practice] relevant areas,’” Schwartz wrote. Additionally, Health Canada and the UK’s Medicines and Healthcare products Regulatory Agency have relied on remote inspections, he added.
“The agency,” Schwartz concluded, “has the statutory authority to replace on-site inspections with a combination of remote inspections, review of the facility’s records, and review of the facility’s recent foreign regulatory reports and supplier/customer reports. The FDA needs to do so immediately. Nothing short of that would be acceptable from a public health perspective. Whether by reason of bureaucratic paralysis or otherwise, FDA drug inspections have slowed to a crawl since the start of the pandemic, with no end in sight. The agency seems incapable of implementing a means of remotely determining the compliance status of facilities whose critical products are needed for treating Covid-19 patients and cancer patients alike. The agency used to be viewed as the world’s gold standard for drug oversight. That designation is currently in doubt.”