Jill Wechsler is Pharmaceutical Technology's Washington Editor, jillwechsler7@gmail.com.

Jill Wechsler

that it planned to resume “prioritized domestic inspections” for certain regulated products that had been put on hold by COVID-19 since March. The agency also would continue to conduct “mission critical” inspections, utilizing methods to ensure the safety of all involved personnel. But it was unclear to biopharma companies from the July 10, 2020 press release which products and situations would warrant on-site visits and how the agency would respond where the pandemic made an inspection unsafe or unfeasible.

 from FDA, published on August 19, 2020, provides answers to such questions about when the agency will seek to visit a site and how it will respond when a needed inspection cannot be conducted safely. FDA explains that it may delay approval of new products in situations where travel restrictions and other concerns block a preapproval inspection that the agency considers necessary.

Breakthrough therapies and regenerative medicine advanced therapies may gain approval even without a desired inspection. This policy also applies to other “mission critical” therapies used to diagnose, treat, or prevent a serious disease where no treatment alternative is available.

However, if an application involves a less critical medicine, and FDA has concerns about the adequacy of the facility but cannot conduct a site visit before the application’s “action date,” then FDA will issue a complete response letter that explains the reasons for delaying approval.

The agency will try to avoid such situations by utilizing other methods to access needed information on a manufacturing operation without an actual site visit. FDA will review earlier inspection reports, request records and information from the applicant and from the facility, and seek to obtain inspection reports from other trusted foreign regulatory partners. And for drugs made overseas where inspections continue to remain on hold, the agency will review product quality through sampling and testing at border control sites.

Similar assessments will apply to bioresearch monitoring (BIMO) surveillance of research sites, conducted to ensure that investigators follow policies to protect research subjects and to ensure the accuracy of clinical trial data. Here, FDA will continue to follow risk-based approaches that consider the nature of the application and site-specific factors.

The new guidance also provides flexibility for manufacturers looking to make changes in a facility or production process for an approved product affected by supply chain disruptions due to the pandemic. FDA will expedite such requests for drugs and biologics used in treating COVID-19 patients and for critical products in shortage situations. This will involve weighing the impact of postapproval changes and a firm’s efforts to mitigate the risk to product quality associated with a change. For critical products, FDA may permit a manufacturer to use a lower reporting category to facilitate the change and avoid pre-approval review and inspection of the changes. In such situations, firms should consult relevant FDA review offices on the most appropriate way to proceed.

Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-19 Public Health Emergency

is temporary, in effect only for the duration of the current health emergency. However, it goes into effect immediately, without the usual delay for stakeholder comment. 

Articles

A new FDA guidance provides answers to questions about when the agency will seek to visit a site during the COVID-19 pandemic and how it will respond when a needed inspection cannot be conducted safely. 

FDA May Delay Approval of Drugs Where Necessary Inspection Is Not Feasible

The White House initiative to encourage production of essential medicines in the United States calls on FDA to set the parameters for and implement main aspects of the program. Under the 

issued by President Trump on August 6, 2020, FDA first will determine which medicines fall under the program’s requirements. In addition, the agency will collect additional information from manufacturers on drug and ingredient origins and accelerate approval of qualifying products and their production facilities.

FDA has 30 days to draw up a list of “essential medicines, medical countermeasures, and their critical inputs” (i.e., APIs and other components) and another 60 days to finalize it. The list will cover therapies and medical products that the US “must have available” at all times, particularly treatments for infectious diseases and to protect against chemical, biological, radiological, and nuclear (CBRN) threats.

To ensure demand for domestically made medicines, federal agencies that purchase drugs, including the Department of Health and Human Services (HHS), the Department of Defense, and the Department of Veterans Affairs, will develop plans in 90 days for steering procurement and contracts to those essential medicines produced at home. Those agencies will have to submit annual reports in 2021 on where they source these critical products. The US Trade Representative, moreover, will exclude those listed products from free trade agreements, while federal agencies will look to revise environmental and other regulations likely to inhibit construction of new pharmaceutical facilities in the US.

There are some notable exceptions to the program. The Buy American requirements won’t apply to medicines not available in sufficient quantities in the US, to US-made products that are 25% more expensive than imports; or in cases of a national emergency. At the same time, the new policies will aim to combat trade in counterfeit goods and protect intellectual property.

FDA also will seek to reduce supply chain vulnerabilities by collecting information on the sources of and shortages in critical drugs and medical devices and their ingredients, plus information on the date of a facility’s most recent inspection and the results of such inspections. To accomplish these goals, the agency will identify where new regulations or guidance are needed to collect production information and will negotiate with other countries to increase foreign inspections—including unannounced site visits—of firms producing essential medicines. And the government will limit imports from manufacturers that refuse or unreasonably delay an inspection.

At the same time, FDA will encourage pharma manufacturers to shift production to the US by offering accelerated approval of essential medicines made in the US, particularly those needed to counter infectious disease and CBRN threat preparedness. The agency will issue guidance on developing advanced manufacturing techniques for domestic production of essential therapies, while also looking to identify and propose changes in laws and regulations found to erect barriers to domestic production efforts.

A main objection to the “Buy American” policy for pharmaceuticals is that domestically produced critical medicines are likely to be more expensive than those made overseas. Generic-drug makers, in particular, acknowledge that APIs and drugs from China and India are cheaper than those made in the US and that government contracts for pharmaceuticals need to assume higher prices for American-made products.

In this light, the initiative to increase purchases from domestic producers runs counter to an earlier White House announcement advancing four drug price control initiatives, including an international reference pricing scheme for drugs and biologics. President Trump issued 

on July 24 that call for certain health centers to pass on price discounts on insulin and epinephrine

 drug imports from Canada and other countries 

, policies announced previously and already undergoing analysis for impact and implementation. Another proposal would reduce rebates paid to 

“middlemen” managing Medicare drug plans,

 which analysts say would raise premiums for beneficiaries

. Trump again floated the idea of setting an international pricing index, or “most favored nation” policy, to link prices paid for Medicare Part B medicines to those paid overseas.

Manufacturers were livid that the White House was proposing such massive changes in operations with the Buy American plan and a foreign pricing index at a time of great industry focus and investment in developing treatments to combat COVID-19. Big Pharma CEOs rejected Trump’s invitation to come to a White House meeting to discuss these proposals, further escalating tensions between biopharma companies and the administration. Trump has more support for his drug pricing proposals from Democrats, but no further action is expected this year.

The White House initiative to encourage production of essential medicines in the United States calls on FDA to set the parameters for and implement main aspects of the program. 

FDA in Hot Seat on Buy American Drug Policy 

As biopharma companies and research institutes advance the development of promising vaccines against COVID-19, policy makers and health officials have intensified deliberations on strategies for ensuring fair and equitable distribution of anticipated preventives. The issue is important to health authorities across the globe and has emerged as a seminal topic in the United States amidst growing debate over healthcare disparities and whether high costs will limit access to critical treatments.

To build public support for a vaccine distribution plan even before any test product gains market approval, the National Institutes of Health (NIH) and the Centers for Disease Control and Prevention (CDC) have called on a special expert panel to tackle the allocation issue. At the agencies’ request, the National Academy of Sciences, Engineering and Medicine (NASEM) has formed a 

of leading bioethicists, economists, geneticists, and public health authorities to quickly develop a framework for priority vaccine access to assist policymakers in the US and other nations achieve equitable distribution of anticipated vaccines. This project was launched July 24, 2020 with the aim of providing a final report by early October.

The NASEM panel will contribute to similar discussions by the Advisory Committee on Immunization Practices (ACIP), which regularly advises the CDC on overall vaccination policy. An ACIP COVID working group is collecting and analyzing information on pandemic vaccines under development and has held discussions and public meetings to identify high-priority groups for initial vaccination. There will be further open public meetings in August and September, and the ACIP committee will collaborate with the NASEM panel to avoid confusion and build public confidence in their recommendations.

The resulting distribution framework aims to identify first-tier vaccine recipients as well as populations that should be added as more vaccine becomes available. Individuals at higher risk will include those in higher age groups, with underlying health conditions, engaged in high-risk occupations, affected by racial and ethnic disparities, and in hard-hit geographic locations. The experts also will consider how best to communicate the allocation recommendations to promote a sense of equity and to mitigate vaccine hesitancy. The NASEM panel is holding its 

August. 7, moving quickly in order to issue a draft report by early September and then final recommendations by early October. The very tight timeline is designed for the panel to present its framework in time to have an impact.

At the opening meeting of the NASEM expert panel in July, NIH Director Francis Collins directed the group to consider the needs of individuals at highest risk of complications from COVID-19 and of essential workers in setting a distribution policy well in advance of having an approved vaccine. Collins also proposed early access for participants in late-stage vaccine clinical trials who receive a placebo, instead of treatment. Whether there are 10 million or 100 million doses available early on will determine how far down the priority list health authorities can go, he explained, but with taxpayer money funding vaccine manufacturing ahead of time, the aim is to have millions of doses ready to go when authorities determine that one or more vaccines are safe and effective.

Even with an agreed-on plan for equitable access to vaccines, federal and state agencies and industry face a monumental task of transporting, distributing, and administering millions of vaccine doses as fast and as efficiently as possible at the appropriate time. A serious complication is that there may be more than one approved vaccine, with products carrying different indications and dosing protocols. Delivery requirements will vary depending on product temperature, storage, and handling requirements. With some vaccines requiring two doses, it will be important to keep track of who needs a second dose and when and where. Systems also are needed to track and report adverse events, as well as overall immune response.

While the CDC normally manages vaccine distribution to state agencies, especially for children, uncertainty has been generated by talk of the military stepping in to handle main logistics, as proposed by the administration’s Operation Warp Speed initiative. State and public health officials are wary of federal pandemic planning efforts so far, given the lack of coordination and effectiveness in distributing COVID-19 test kits and personal protective equipment to healthcare providers and facilities. Shortages continue in those categories, and in supplies of those medicines that have demonstrated some effectiveness in treating sick patients.

The National Governors Association has advised state officials to start planning now for vaccine administration efforts but acknowledges that uncertainty over who will be in charge complicates such efforts. Meanwhile, vaccine manufacturers will be looking for information on where to ship vaccines when available, initially for emergency use and more widely following product approval. That will require decisions on priority populations and locations to receive early vaccines, which hopefully will emerge in time to support efficient distribution efforts.

As biopharma companies and research institutes work to develop vaccines against COVID-19, policy makers and health officials debate strategies for ensuring fair and equitable distribution of anticipated preventives. 

Debate Accelerates Over Who Gets COVID Vaccine First

The need for treatments to combat the spread of COVID-19 is promoting greater cooperation among drug regulatory authorities around the world. FDA officials are communicating more frequently with their counterparts in Europe, Canada, Japan, and other nations through established programs and agreements. In addition, the International Coalition of Medicines Regulatory Authorities (ICMRA) has expanded its program to facilitate regular discussions among some 30 governmental and international agencies. These efforts seek common approaches to clinical research and biopharmaceutical production needed to wipe out the coronavirus pandemic globally.

Editor's Note: This article was published online on June 29, 2020.

The long-standing collaboration between FDA, the European Commission (EC), and the European Medicines Agency (EMA) has shifted to promote regulatory cooperation to combat COVID-19. A high-level FDA–EMA virtual meeting in mid-June reviewed ongoing efforts to develop new therapeutics and vaccines, as well as the use of real-world data to inform regulatory decisions. A main focus was the challenges related to production and rapid scale-up of potential vaccines and therapeutics (1).

FDA and European Union efforts to address COVID issues also are advancing through the work of some 30 FDA–EMA technical expert groups that regularly address topics such as vaccine development, pharmacovigilance, blood products, and drug shortages. Now these panels are examining timely topics such as interpretation of data supporting emergency use authorization of experimental treatments, expanded use of real-world data to better understand the natural history of the coronavirus, and the performance of diagnostics. These discussions often include regulatory authorities from Japan, Canada, Australia, and other established agencies.

In addition, FDA and EMA officials have extended the discussion of these and other topics to a broader group of regulatory authorities through ICMRA. Since March 2020, experts representing 25 agencies in 17 countries have participated in regular virtual meetings to gain understanding and convergence of requirements on clinical trials and data standards for COVID-19 vaccines and therapeutics, plus the use of real-world evidence and observational studies to complement evidence from clinical trials (2). ICMRA members have discussed what preclinical data are needed to support proceeding to first-in-human clinical trials and the importance of risk mitigation strategies to better protect research participants. These experts further discussed guiding principles for COVID clinical trials, including the use of master protocols, ethical questions related to human challenge trials, post-approval requirements for vaccines, and the need for regulatory flexibility during the pandemic at a meeting on June 12, 2020, which was moderated by Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), but now on detail to the White House Operation Warp Speed initiative (3).

A main goal of such interactions is for regulators in different regions to understand and accept the study designs and clinical endpoints of early vaccine candidates, pointed out Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), at the annual meeting of the Biotechnology Innovation Organization (BIO) in June. He emphasized that COVID vaccine development “is really a global issue,” and that it’s important for authorities around the world to gain an understanding about “what success will look like” in bringing safe and effective preventives to market. Because these vaccines may be widely used after only months—instead of years—of testing, Marks acknowledged that clinical trials will need to be sufficiently large and widespread and early vaccine subjects will need to be closely monitored to evaluate safety effectively. And multiple vaccines may gain approval, as some populations may benefit from one preventive more than from another. A common understanding of the need to test any emerging vaccine on a sufficient number to establish a strong safety dataset will help avoid later debate among authorities over which assays to consider or the size of studies needed, Marks noted.

Even with a high degree of international collaboration on advancing vaccine development and production, a certain degree of “vaccine nationalism” will affect the distribution of any successful preventive. Research and regulatory authorities recognize that biopharma companies and government health agencies will be under pressure to take care of their home populations first, but they also expect industry to ramp up production and form partnerships with other organizations to fully supply broader regions of the world.

Huge investments by private firms and government agencies are being made to retrofit existing facilities and to secure supplies of key raw materials to be able to produce billions of dosages. At the same time, researchers seek strategies for producing more stable products that can be stored longer and shipped more easily, as well as formulations that can provide needed protection with a smaller dose. To ensure early distribution of COVID vaccines in all regions, the World Health Organization, the Global Alliance Vaccine Initiative, and the Coalition for Epidemic Preparedness and Innovation have formed a vaccine purchasing group that seeks $18 billion for a COVID-19 advanced market commitment.

The research community also is looking to provide strong safety data in order to overcome a visible degree of public skepticism about the value of being vaccinated. If 30% or 40% of the population will not take this vaccine, Marks lamented at BIO, it may not be possible to achieve desired herd immunity on a broad basis. The larger concern for Marks and others, though, is that success in combatting COVID won’t come fast enough to avoid an even more lethal second wave at the end of the year.

1.A. Abram, “Partnering with the European Union and Global Regulators on COVID-19,” 

, July 13, 2020.
3.ICMRA, “Global Regulators Work Towards Alignment on Policy Approaches and Regulatory Flexibility During COVID-19–Update #4,” June 12, 2020.

Washington editor, jillwechsler7@gmail.com.


Volume 44, Number 8
August 2020
Pages: 14–15

When referring to this article, please cite it as J. Wechsler, "Regulatory Collaborations Aim to Speed Access to Drugs," 

Efforts by regulators seek common approaches to clinical research and biopharmaceutical production needed to wipe out the coronavirus pandemic globally. 

Global Regulatory Collaborations Aim to Speed Access to New Vaccines and Drugs

	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.   

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? 