Jill Wechsler is BioPharm International's Washington Editor, jillwechsler7@gmail.com.

Jill Wechsler

	A surge in applications to test and develop new cellular and gene therapies is overwhelming staff at FDA’s Center for Biologics Evaluation and Research (CBER) and prompting calls from manufacturers and research organizations to increase funding for these programs. At the public meeting to kick off negotiations for renewing the Prescription Drug User Fee Act (PDUFA) before the current program expires in September 2022, patient advocates, research experts, and industry similarly called for more user fee revenues to support CBER programs to advance these innovative therapies.

	User fee payments now fund more than 70% of the cost of FDA’s new drug review program, up from about 7% of its budget in 1993. Manufacturers pay more than $1 billion a year, primarily through annual program fees. The Center for Drug Evaluation and Research (CDER) is 

 this year to support its new drug review program, while CBER gets $135 million; smaller amounts fund the review of medical devices combined with drugs and inspections by FDA’s field force, while a hefty portion supports a wide range of agency activities, services, and facilities.

	The smaller amount for CBER reflects the relatively few biologics license applications (BLAs) it has reviewed under PDUFA-only three applications by the Office of Tissues and Advanced Therapies (OTAT) in 2019, compared to more than 100 new drug applications (NDAs) and BLAs vetted by CDER (PDUFA does not support CBER regulation of vaccines and blood products). But now CBER is overseeing more than 900 active investigational new drug applications (INDs) for cellular and gene therapies, with some 200 new submissions anticipated this year. In addition, OTAT manages FDA’s high-profile program for vetting regenerative medicines advanced therapies (RMATs) and awarding the RMAT designation to products meeting set standards.

	In June, OTAT director Wilson Bryan reported at the Biotechnology Innovation Organization’s (BIO) digital annual conference a “huge escalation” in his office’s workload prior to the pandemic, with a tripling of INDs for gene therapies in the past three years. And while research in these new treatments has slowed in recent months, that has been supplanted, he noted, by more interest in using cellular therapies and intravenous immunoglobulin to treat COVID-19.

	CBER Director Peter Marks similarly noted at BIO that CBER was meeting user fee goal dates overall, despite the need to shift personnel and resources to deal with the pandemic. Some early meetings intended to assist sponsors in designing research programs for new therapies had to be delayed or cancelled, he acknowledged, but most regulatory activities were moving forward.

	At the PDUFA public meeting, Rachel Sher, vice-president of the National Organization for Rare Disorders (NORD), noted that CBER officials expect to be called on to review and approve some 40–60 innovative gene and tissue-based therapies over the next 10 years. Jeff Allen, president of Friends of Cancer Research, similarly called for added support for the review of cell and gene therapies, as did Robert Falb, head of the Alliance for Regenerative Medicine. Cartier Esham, executive vice president of BIO, cited the greater demand on CBER personnel and requests for added meetings with sponsors in backing increased resources for CBER. The funds also would help clarify expedited pathways and expand standards for advanced manufacturing processes and technologies for gene therapies.

 kicks off a year-long process for FDA and industry to negotiate program goals and fee structure for PDUFA VII well before the current program expires. FDA also will regularly meet with representatives of consumer and patient organizations, research entities, and healthcare organizations to hear their concerns and priorities for changes in current PDUFA programs and new fee-supported initiatives. The aim is to present Congress with a user fee agreement by the middle of next year so that the legislators can write and approve authorizing legislation by early 2022 and avoid any lapse in FDA user fee collections.

	A main goal for both CDER and CBER is to recruit and train additional staff to assess its wide array of innovative products, building on provisions in the current PDUFA program for filling more than 200 agency positions over five years and for retaining experts at the agency. FDA has found it very difficult to expand staff in a very tight job market and through the agency’s cumbersome hiring process. The initial hiring goals for CBER were one-fifth that for CDER, but few new recruits have come on board.

	Stakeholders at the public meeting also supported broader use of real-world evidence and innovative clinical trial methods to advance new therapies and for FDA to expand electronic communications systems in research and regulatory programs. A prominent theme is for the agency to incorporate innovations and changes adopted for dealing with the COVID-19 pandemic into ongoing research policies and regulatory programs. Manufacturers and other stakeholders have until August 23 to submit comments on the process to a public docket, which will provide the basis for the ongoing discussions.   

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Patient advocates, research experts, and industry are calling for more user fee revenues to support CBER programs to advance innovative therapies. 

Stakeholders Seek Increased User Fee Support for Biologics

	As the world waits anxiously for more effective COVID-19 treatments and for a vaccine to halt the pandemic, analysts on all sides are examining appropriate pricing models for these critical products. Gilead’s $3000 price tag on remdesivir ($2300 for US public health programs), set in late June 2020, came in lower than financial analysts expected, but still outraged consumer advocates and liberal politicians. Skepticism has greeted promises from some vaccine makers pledging to offer preventives on a no-profit basis due to uncertainty about what that promise means and the timeframe for free or low-cost programs. Meanwhile, Congressional leaders are adding modest drug pricing provisions to new legislative proposals; consumer groups are complaining about annual pharma price hikes; and the White House still signals plans for administrative action to link US drug prices to international rates.

	The debate over access to and pricing of safe and effective COVID-19 vaccines has heated up as several candidates move into later-stage clinical trials. If based on estimated cost savings to healthcare systems and to the global economy, the value of successful vaccines would be multi-billions of dollars. But few believe that most of those benefits should go to the manufacturer.

	Leading vaccine makers Johnson & Johnson and AstraZeneca have stated they plan to offer their treatments on a no-profit basis, but it’s not clear what “no profit” means here. Pfizer, one of the few Big Pharma companies not receiving public R&D support, has waffled on the issue. Congressional leaders are insisting that COVID-19 vaccines be available at no cost to Americans, as outlined in a recent 

 from Senate Democrats that maps out policies for “Getting a Safe and Effective Vaccine to All”.

	A related issue is to what extent support from the National Institutes of Health (NIH) or the Biomedical Advanced Research and Development Authority (BARDA) should affect product prices. Analysts put federal government support for Gilead’s remdesivir at around $6.5 billion. The Institute for Clinical and Economic Review (ICER) initially said that the drug’s announced price was in line with its earlier cost-benefit analysis that supported a price of $2800 for treatment, but only if the therapy actually saves lives (which Gilead now says it does).

	These and other issues related to prices for COVID-19 drugs and vaccines were the subject of a recent 

hosted by the National Pharmaceutical Council (NPC). Is there something unique about a pandemic that alters how one looks at drug pricing, and should that translate into paying more-or less-for remedies? asked NPC chief scientific officer Robert Dubois. Would too-low prices curb future innovation, as industry and investors insist, or does more profit block equitable public access to drugs and vaccines?

	The drug pricing conversation is different in a pandemic, where everyone’s goal is to “get back to normal,” observed ICER Executive Vice-President Sarah Emond. And that outcome should be rewarded, according to Craig Garthwaite of the Kellogg School of Management at Northwestern University. At the same time, the system needs to ensure public access to drugs and vaccines, noted Peter Neumann of Tufts University Medical Center. Instead of focusing on cost and profit and future innovation, Peter Bach of Memorial Sloan Kettering’s Center for Health Policy & Outcomes urged industry to invest in obtaining sound data from randomized, placebo-controlled clinical trials to ensure appropriate use of a new therapy and to fully understand its value.

	The visible commitment of biopharma companies to developing and producing critical therapies and vaccines to combat the pandemic has boosted the public’s regard for the industry. But that could plummet if new treatments prove too costly or unavailable to certain population groups. These issues were raised at recent hearings on Capitol Hill, where some members of Congress continue to call for Medicare to negotiate drug prices and for the feds to exercise “march-in rights” to seize patents from biopharma companies that accept federal funding but then fail to make resulting products available on “reasonable terms” to the public. And to ensure that prices and access are “reasonable,” all parties will be comparing what COVID-19 therapies cost in the United States to the rest of the world and how any differences in the global market affect American patients.

Should therapies and vaccines be cheap or free in a pandemic and would that really dry up innovation? 

Drug Pricing Back in the Spotlight

	FDA announced in July that it plans to resume inspections of some US-regulated facilities this week, but it’s not clear how it will decide which sites to visit and what alternative oversight strategies will apply where on-site inspections are difficult. Yet, the resurgence in COVID-19 cases in the United States looks to limit actual inspections and require FDA to rely more on “virtual” inspections or “paper reviews.” The prospect of further delays in initiating foreign inspections, moreover, raises a host of questions about assuring access to the growing volume of drugs and active ingredients produced overseas and may boost collaboration with foreign inspectorates to vet their local facilities. Overriding all these planning efforts, however, is the expectation that multiple new COVID-19 vaccines and therapeutics will seek regulatory approval in the coming months and will require full FDA vetting of production facilities, operations, and records to allay consumer fears about product safety and quality.

field inspections, citing the need to protect staff overseas and the agency’s ability to block the import of any unsafe products at the borders. FDA officials emphasized that inspections are just one part of FDA’s program for assuring product quality and safety, and that manufacturers ultimately are responsible for ensuring compliance with standards. Although FDA initially indicated that inspections would halt for only a month or so, in May Commissioner Stephen Hahn 

 the need to further delay “routine surveillance inspections” as the pandemic continued.

	During this inspection hiatus, FDA has conducted some “mission critical” site visits but has not provided details as to where such oversight has been warranted and how it was carried out. FDA inspections are particularly important for companies looking to resolve earlier Official Action Indicated (OAI) citations that prevent the filing of new applications and limit business opportunities. And manufacturers looking to bring new drugs to market usually require a pre-approval inspection (PAI) for final approval. But as the recent surge in COVID-19 cases in the US further delays state and local reopening, FDA is under pressure to devise new strategies for meeting application review deadlines set by user fees that increasingly involve drugs and medical products from facilities that were not inspected prior to the pandemic.

	FDA now says it will resume “prioritized” domestic inspections in local areas able to reduce new COVID-19 cases and hospitalizations. Based on a state’s phase of reopening and local trend and intensity of infection, the 

 where the agency can resume mission-critical inspections only, all inspections with measures to protect staff, or all regulatory activities. This approach has raised questions about which localities will qualify for site visits and what fits “mission critical” or “priority” categories:  A new drug nearing its approval deadline? A site able to produce medicines in shortage? Or a firm looking to demonstrate that it has fixed earlier quality problems and wants to resume all operations?

	One surprise is that FDA stated it will pre-announce all prioritized inspections, an approach that is routine overseas, but not at home. The agency explains that providing time to plan for site visits in advance will enhance the safety of both the inspectors and of company staff and also ensure that appropriate personnel are on-site when needed.

	All these challenges raise the prospect that FDA may be conducting fewer on-site inspections in the coming months and will look to tap policies and programs that provide alternative oversight approaches. FDA gained more explicit authority under the FDA Safety and Innovation Act (FDASIA) of 2012 to use new methods to track manufacturing operations in the US and abroad, initially to reduce drug shortages linked to an increasingly global pharmaceutical supply chain. The 

a risk-based approach for determining inspection frequency, strengthened FDA’s authority to take action against manufacturers that refuse or delay an inspection, and authorized the agency to request and access manufacturer records “in lieu of or in advance” of an inspection.

	This “in lieu of” provision for obtaining manufacturing records is considered key to providing a framework for more virtual or “records-only” inspections, according to experts participating in a recent webinar hosted by the Food and Drug Law Institute (FDLI). So far, FDA has been reluctant to conduct full remote inspections, but has accessed records for less formal “assessments” to help determine the need for and timing of a site visit. FDA 

 issued in October 2014 outlines procedures for the agency to request and obtain plant operating records for such purposes. With these provisions in mind, manufacturers should be establishing policies and systems able to evaluate and comply with FDA requests for production records, e-data bases, and relevant documents. At the same time, industry should be seeking more information from FDA on how it will restart its current inspection program, including the time frame for advance notices of planned inspections, how the agency is prioritizing inspections, and how a remote inspection would be conducted.

Industry should be seeking more information from FDA on how it will restart its current inspection program.

Will FDA Inspections Ever Be the Same?

	With more than 100 vaccine research programs looking to address the pandemic, FDA officials are moving to clarify standards and requirements for vetting and approving viable preventives. The agency recently

 outlining recommendations for documenting vaccine quality, safety, and efficacy in order for a product to move forward.

	A main point of discussion is the provision that a vaccine should be at least be 50% more effective than placebo in preventing the disease, a standard that some criticized as much too low to tackle COVID-19 effectively. However, Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), which oversees vaccine production and approval, considers the 50% benchmark as hitting the “perfect spot,” he said in a webinar sponsored by the Alliance for a Stronger FDA on July 8, 2020. Efficacy lower than the 50% level yields a vaccine that may have very little effect, he explained, but if manufacturers had to achieve an 80% effect, there might not be a vaccine for months. “So,” he said, “50% seems the right place.”

	Marks expects that clinical trials for the first COVID vaccines will need to pursue a fairly traditional approval process, with Phase III studies enrolling 10,000–50,000 patients in each arm. Clinical trials for COVID vaccines need to be done efficiently and quickly, but still must be randomized, blinded. and placebo controlled. And adaptive trials need to describe the study plan up front. Studies should aim to enroll a broad spectrum of the population, as it will be important to see the effect of a vaccine on both older individuals and pediatric populations, as well as those with immune compromised systems and specific health conditions.

	FDA also seeks consistent, high-quality manufacture of vaccine candidates to ensure product safety. Safety concerns often link back to manufacturing quality issues, Marks explained, noting that CBER scientists will assess product sterility and potency through lot release requirements and look for consistency in manufacturing processes and controls for scale-up. Early safety studies need to enroll at least several thousand patients, because even a rare adverse event could affect thousands with a vaccine administered to many millions. And post-market surveillance will be important to track vaccine effectiveness in the real world, with manufacturers following up for a year or longer through well-planned pharmacovigilance programs. “We don’t want to skimp here,” stated Marks.

	A main objective for the agency is to instill widespread confidence in any FDA-approved vaccine, a critical factor at a time of considerable vaccine “hesitancy” in the United States. Marks admits to being very scared by polls showing that up to one-third of Americans are hesitant about taking the vaccine. “People need to have confidence that what’s out there will be of high quality and safe and effective, and that we’ll be monitoring for any problem.” And he emphasizes that full transparency on the part of manufacturers is very important to support clear messages about likely vaccine side effects and acceptable risks.

	The vaccine development approach mapped out by FDA is unlikely to produce an approved preventive this fall, Marks acknowledged. It will take weeks or months to enroll the thousands needed in clinical trials. And most of the current candidates will require two doses, which adds to testing timeframes. FDA will support efforts by manufacturers to look for ways to speed production. But “at the end of the day,” Marks stated, “we have to be able to tell the public that these are high quality products, and that corners were not cut.”

FDA officials are moving to clarify standards and requirements for vetting and approving viable preventives. 

Author | Jill Wechsler

Articles

Stakeholders Seek Increased User Fee Support for Biologics

Drug Pricing Back in the Spotlight

Will FDA Inspections Ever Be the Same?

FDA Maps Expectations for COVID Vaccine Proposals