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

Jill Wechsler

One lesson of the COVID-19 pandemic is the importance of being able to assess potential new therapies and vaccines quickly and reliably and in ways that can adapt to changing scientific evidence and public health needs. FDA has responded to these pressures by generating multiple guidance documents and policy initiatives for updating and advancing the clinical research process, including the incorporation of master protocols in research programs to facilitate the development of safety and effectiveness information for multiple test therapies in a compressed time period.

FDA Acting Commissioner Janet Woodcock has long supported wider use of master protocols for such purposes and has worked to advance this approach in the face of greater urgency during the pandemic to ensure that a promising drug is safe and effective. Clearer FDA policies for utilizing master protocols can help advance “best practices in the design and execution of clinical trials” to better evaluate drugs for the treatment or prevention of COVID-19, Woodcock commented in 

The guidance aims to overcome fairly limited use of master protocols in the United States by clarifying for sponsors FDA’s recommendations for evaluating coronavirus treatments or preventives through a coordinated research approach. The 

the design, conduct, and statistical considerations of such studies, along with procedures and recommendations for sponsors to follow.

FDA explains the differences and uses of master protocols for umbrella trials (evaluate multiple products simultaneously for a single disease) and for platform trials (evaluate multiple therapies in a perpetual manner, with test products entering and leaving the study based on results). By coordinating multiple studies, this approach can address multiple scientific questions for several test therapies and help avoid confounding, which is more likely for studies conducted during a public health emergency. An important efficiency is to utilize a common randomized comparator arm.

On the downside, this more complex research approach can require more up-front planning and coordination, FDA concedes, advising research sponsors to consult agency experts early in product development to assess these considerations and study options. In some situations, both stand-alone and platform studies may be appropriate for a drug development program. And while FDA recommends subject blinding, the guidance acknowledges that blinding is not always possible or practical. Master protocols should be reviewed by a central institutional review board, and sponsors should use independent data monitoring committees to ensure objective review of safety and efficacy.

While this latest guidance specifically applies to biopharmaceutical research conducted during the current public health emergency, FDA notes that it aims to provide a basis for ongoing use of master protocols in the future. The agency says that it plans to revise the guidance going forward based on the experience gained during the pandemic.

Well-designed master protocols are important in accelerating drug development, Woodcock noted, “by maximizing the amount of information obtained from the research effort.” Such trials can be updated to incorporate new scientific information and can reduce administrative costs and time involved with starting up new study sites for each investigational therapy. And this approach can increase data quality and efficiency through shared and reusable infrastructure.

Woodcock cites the public-private initiative organized by the Foundation for the National Institutes of Health, the Accelerating COVID-19 Therapeutics Interventions and Vaccines (ACTIV) study, as an “excellent example of master protocols being used to simultaneously study a number of promising drugs.” The potential for well-designed master protocols to accelerate drug development compared to stand-alone studies signals that this research approach will “continue to play an important role in addressing the public health needs created by the pandemic and in generating clinical evidence in general,” Woodcock concluded.

Articles

The agency has published multiple guidance documents and policy initiatives for updating and advancing the clinical research process. 

FDA Promotes Master Protocols to Modernize Clinical Trials

Efforts to return to a more consistent and timely federal field inspection program will take considerable time, as FDA expects to conduct only a small portion of scheduled facility visits in 2021 due to continued limitations on travel imposed by the COVID-19 pandemic. With a huge backlog built up since March 2020, it’s not clear when the agency’s inspection program for drugs and medical products will fully recover. These challenges are acknowledged in the recently issued “

Resiliency Roadmap for FDA Inspectional Oversight

,” which details how the pandemic has delayed all but the most important “mission critical” and high priority inspections this past year, leaving thousands of site visits that will need attention in the coming months—and years. 

The Roadmap reports that FDA was able to carry out approximately 1600 mission critical and high-priority inspections for all regulated products from March 2020 to March 2021, including 29 in foreign countries. However, that is far short of the more than 20,000 inspections normally conducted each year for food, tobacco, and medical products. About half of all the completed inspections (741) involve drugs and medical products. If one combines mission-critical and priority inspections, the totals come to 155 inspections of establishments producing human drugs, 80 for medical devices, and 63 for biologics; the largest portion of audits include more than 400 for clinical data and research sites.

One result is that 68 of more than 13,500 applications for new medical products had approvals delayed largely due to the agency’s inability to conduct inspections.

The prospects for catching up are dim because the agency must address all those site visits missed this past year, while striving to deal with continued growth in its oversight responsibilities. FDA should inspect more than 23,000 establishments across all commodities in the current fiscal year (ends Sept. 30, 2021), the number expanded by those rolled over from last year. About 4000 of these audits cover establishments producing drugs, biologics, and other medical products. But even with a return to standard operations by mid-summer, the agency expects to conduct only 851 mission critical and priority site visits for medical products. If all travel restrictions are lifted and no other emergencies occur, FDA’s best-case scenario calculates that it might be able to conduct 1600 domestic inspections this year—about half of the to-do list.

Moreover, there’s always the possibility the situation could get worse—if new variants emerge, travel remains restricted, or FDA staff appears at risk in visiting manufacturing facilities. Then the agency will have to revert to utilizing alternatives to on-site visits, such as virtual inspections, sample testing, and reliance on reports from trusted foreign regulatory partners—all considered less effective than real-time inspections.

FDA’s continued focus on mission-critical and high-priority inspections in the coming months means that it will postpone most routine surveillance activity. Mission-critical inspections include important products previously involved in recalls or serious adverse events, plus preapproval audits for breakthrough therapies, regenerative medicines, treatments for serious conditions, and products related to COVID-19. The ongoing delays in inspections for lower-risk facilities means that for some time there will be wider intervals of time between inspections for sites subject to routine post-approval surveillance, as compared to emergency use authorizations, emergency situations, or critical medicines.

For the longer term, FDA looks to modernize its inspection program as part of a multi-year effort to transform data enterprise platforms and enhance cross-program interoperability. This IT modernization initiative will review approaches to regulatory oversight using next-generation assessment technologies, while also reviewing the need for potential legislative action to enhance regulatory oversight. A new agency-wide Inspectional Affairs Council will plan and coordinate inspection activities.

FDA expects to conduct only a small portion of scheduled facility visits in 2021 due to continued limitations on travel imposed by the COVID-19 pandemic. 

FDA Inspection “Roadmap” Acknowledges Continued Delays and Challenges Ahead 

against a clinical trial sponsor that has ignored requirements to post study results on the ClinicalTrials.gov website. 

 warns Acceleron Pharma that it faces a $10,000 penalty if it continues to ignore requirements to disclose summary results information related to a study done years ago for a combination cancer treatment.

The FDA notice marks the first time the agency has publicly threatened fines and possible criminal prosecution for such a violation since the clinical trial disclosure rule went into effect in 2017. FDA 

 on how sponsors should meet the disclosure requirements and what action it will take with entities that fail to comply. The guidance explains that FDA will first send the sponsor a pre-notice of noncompliance, which allows 30 days for voluntary action. That would be followed by a final notice allowing another 30 days before levying penalties, as has occurred now with Acceleron. Although the company has published articles on this Phase II study of dalantercept with axitinib for patients with advanced renal cell carcinoma, which turned out to be unsuccessful, the company failed to post results on the ClinicalTrials.gov website managed by the National Library of Medicine at the National Institutes of Health (NIH).

FDA emphasizes that it encourages voluntary compliance with requirements for registering clinical trials for drugs, biological products, and medical devices on the ClinicalTrials.gov website and for submitting required summary results to the clinical trials data bank no later than one year after study completion date. To enforce this policy, FDA now has sent more than 40 pre-notices of noncompliance as part of the agency’s effort to promote greater transparency related to clinical trials and to allow the broader scientific community to access and build on the submitted data. The overarching goal is to enhance public support and participation in the clinical research process.

While continuing to urge sponsors to meet the disclosure policy voluntarily, Acting Commissioner Janet Woodcock stated that FDA takes enforcement of the clinical trials registration and results information requirement “extremely seriously.” FDA will take “appropriate actions,” Woodcock said, to ensure that required information in available “for the benefit of clinical trial participants and public health.”

Advocates for greater transparency in clinical research applauded FDA’s action, but still harped that it was too slow in enforcing penalties for delayed disclosure, which some analysts regard as widespread among researchers. Sponsors have appeared most reluctant to post study outcomes data for failed clinical trials, as was the case for the Acceleron therapy, partly to avoid acknowledging research disappointments.

FDA is threatening enforcement action against a clinical trial sponsor that has ignored requirements to post study results on the ClinicalTrials.gov website.

 FDA Gets Tough on Sponsors Not Reporting Clinical Trial Results 

As pressure mounts on Capitol Hill to enact legislation designed to reduce federal outlays for prescription drugs, the drive for “vaccine equity” around the world is bolstering efforts to limit patent protections on innovative medicines and vaccines to combat the global pandemic. In a surprise move, the Biden administration has announced support for waiving international protections on intellectual property (IP) under the World Trade Organization (WTO) to expand access to COVID-19 vaccines. US Trade Representative Katherine Tai 

stated that a limited waiver on IP protections for certain products would be negotiated by WTO

 to help end the worldwide pandemic and block the emergence of new viral variants.

Biopharma leaders countered that even with patent waivers, the new vaccines will be difficult for foreign manufacturers to produce quickly and safely [see note below]. Instead, US and European manufacturers seek to maintain IP protections by ramping up vaccine donations and supplies of production materials for India and other countries with capable vaccine production facilities to increase local production. Moderna recently promised to send 500 million doses of its COVID vaccine to COVAX, the vaccine supply program for the World Health Organization (WHO), while Pfizer earlier donated $70 million in medicines to India to help treat the surge in coronavirus infections and deaths. Moderna had previously said that it would not enforce IP protections for its mRNA-based vaccine, but that has not led to new production overseas. And AstraZeneca and Johnson & Johnson already have licensed their vaccines to foreign manufacturers.

Industry’s main message is that patents drive biomedical innovation, which has been responsible this past year for remarkably fast action in developing new vaccines and treatments to combat COVID-19. Loss of IP protection would open the door to drug developers in China and Russia to tap confidential information held by western firms and would do little to help manufacturers in developing nations move into vaccine production.

Meanwhile, Congressional leaders are proposing legislation to drive down drug costs at home to finance expanded social and educational benefits under the Biden administration’s American Families Plan. So far, the White House appears willing for Congress to take the lead on the drug pricing debate, with President Biden omitting specific price reform provisions from this latest legislative package.

The main arguments for and against drug pricing proposals were aired at recent hearings before 

subcommittees representatives, consumer advocates, financial analysts, and leading academics made their cases for legislative proposals to shape drug development and patient care; reformers claimed that costly therapies limit patient access to life-saving treatments, while heavy spending on medicines drives up health care costs for all. Industry analysts maintained that the free market for medicines in the United States benefits all by supporting hefty investment in high-risk biomedical R&D. They argue that actual drug prices are tricky to assess; patient out-of-pocket costs are driven more by hospitals and insurance practices; and greatly expanding competition from Chinese and other subsidized manufacturers is challenging innovation in the US and Europe.

The lead House proposal, HR 3, seeks to authorize price negotiations for drugs reimbursed by Medicare Part D drug plans. While that move is strongly opposed by industry, there’s more bipartisan support for limits on annual drug price hikes, caps on out-of-pocket costs for patients, added price transparency, and revisions in drug reimbursement for treatments delivered in clinics under Medicare Part B.

Senate leaders also are looking to revise earlier pharma pricing measures to gain sufficient support from Republicans to move forward. Earlier legislative efforts by the Senate Finance Committee were blocked by the GOP leadership, and moderates could still shy away from proposals strongly opposed by industry and certain patient groups.

Meanwhile, Democrats disagree on how the administration should use the savings generated by drug price reductions. Moderates look for added revenues to strengthen coverage under the Affordable Care Act and to bolster biomedical research and drug oversight. Progressive reformers, however, want to use the gains to expand Medicare and Medicaid as next steps towards a universal healthcare system.

Up until now, the White House had signaled that it wants to avoid a major confrontation with the biopharmaceutical industry, which has earned plaudits for record development and production of critical COVID vaccines and therapies. President Biden recently signed into law two bills designed to enhance approval of new generic drugs and to encourage prescribing of biosimilars, and other more targeted reform measures may gain support if broader pricing measures fall off.

At the same time, financial reports reveal huge increases in revenues and profits for the makers of pandemic vaccines and therapies. Pfizer recently predicted $26 billion in COVID-19 vaccine sales this year, likely its biggest source of revenue. Analysts also are documenting a broad increase in global spending on drugs and vaccines last year, and the rise is projected to continue. A WTO resolution waiving IP protections only for COVID-19 vaccines in itself is unlikely to erode sales for existing products, as it is expected to take weeks or months to negotiate. The larger danger is that it could set a precedent for similar action on treatments for other critical diseases and further encourage political attacks on pharma operations and profits.

Note: the complexities of mRNA-based vaccine production are clearly illustrated by the New York Times article on Pfizer’s vaccine process:see 

How Pfizer Makes Its Covid-19 Vaccine - The New York Times (nytimes.com)

Combating COVID-19 is bolstering efforts to limit patent protections on innovative medicines and vaccines.

Pharma Prices and Patents Under Attack

Following several months of negotiations involving regulators, industry, and patient and consumer advocates, updated programs supporting the development and review of prescription medicines are being readied for approval by federal agencies and ultimately by Congress. The fee programs so critical to FDA operations for regulating drugs and other medical products must be renewed every five years, this time in 2022, and a range of entities need to sign off on various changes and updates to the programs. The negotiators are finalizing “commitment letters” that spell out what industry will pay and what policies and programs FDA will implement with those funds, to be referenced in implementing legislation.

Although it may seem that there’s plenty of time to finalize new user fee packages and to gain legislative approval before the current authority expires in September 2022, there is pressure to move the proposals forward in the next few months to meet this deadline. The discussions involve separate user fee packages for drugs and biologics (Prescription Drug User Fee Act [PDUFA] VII), generic drugs (Generic Drug User Fee Amendments [GDUFA] III), and biosimilars (Biosimilar User Fee Act[BsUFA] III). The legislators usually look to authorize the new fee packages as part of a broader bill enacting a host of projects and requirements for drug regulation, development, and marketing, possibly including an updated version of the 21st Century Cures Act with provisions governing clinical research and data disclosure.

FDA kicked off the fee negotiating process for renewing PDUFA VII at a public meeting in July 2020. Negotiations have involved subgroups for manufacturing and inspections, digital health and informatics, finance, regulatory decision tools, and pre- and post-market review (1). A main topic has been the need to increase fee revenues allotted to the Center for Biologics Evaluation and Research to provide additional support and resources to oversee a fast-expanding volume of applications for cell and gene therapies, including expedited development of regenerative medicine therapies. And industry continues to press FDA for progress in hiring and retention of a “world-class technical and scientific staff” (1).

PDUFA agreements direct the Center for Drug Evaluation and Research to utilize fee revenues to streamline and manage multiple meetings with sponsors and to advance rare disease therapies and use of real-world evidence, model-informed drug development, and complex clinical trial designs. A new program may test broader use of “split real-time” review of certain innovative drugs.

The program also will continue support for innovative manufacturing technologies and efforts to address more clearly chemistry, manufacturing, and controls issues during development. There is agreement on enhancing oversight of postmarket drug safety and risk evaluation and mitigation strategies, and to utilize more broadly analytics from FDA’s Sentinel Initiative. An important goal is to further implement digital health technologies and bioinformation to streamline drug development and review.

All these initiatives will continue to boost industry fees. Drug application fees are slated to reach $4 million over the five years of the program ending in 2027, up from nearly $3 million today. This increase reflects the steady rise in the portion of FDA operations funded by industry user fees, which now account for about half of the agency’s budget for regulating drugs and biologics. While some observers complain that this arrangement gives industry too much influence over FDA decisions, Congress seems fairly content with the financial arrangement. And FDA officials maintain that increased reliance on fee revenues does not sway approval decisions.

Negotiations also are winding up for reauthorization of GDUFA III, which was launched at a July 2020 public meeting. After making notable changes in fee categories and rates in 2017 revisions, current discussions have focused on plant inspection processes, drug master file use, application review goal dates, and enhancements to the inactive ingredient database (2). Main innovations aim to facilitate the review of complex generics, of the continued rise in supplements seeking post-approval changes, and for controlled correspondence. These and other changes aim to achieve more application approvals in the first review cycle, possibly by assessing facility status earlier in the review process.

Similarly, FDA is considering revisions to BsUFA III to further streamline the approval process and facilitate patient access to less costly biotech therapies. That discussion began with a public meeting in November 2020, where FDA officials presented their goals for updating the program, acknowledging the need for additional guidance on interchangeable biosimilars (3). FDA seeks to better manage meetings with sponsors, who want advisory sessions to begin earlier in product development. Manufacturers emphasized the importance of building a capable staff to manage this program, along with upgrading information technology supporting BsUFA. Consumer advocates would like FDA to address how current reimbursement policies and misinformation stymies biosimilar marketing, but that may lie outside the user fee agreement.

And, separately, FDA is launching its new user fee program for over-the-counter (OTC) drugs, after agreeing to drop levies on manufacturers that jumped in to produce hand sanitizer to combat the spread of COVID-19. FDA included fees for such firms in its December 2020 publication of policies governing the new Over-the-Counter Monograph Drug user fee program (OMUFA), which was authorized by Congress in March 2020 as part of broader pandemic legislation. But an outcry from firms such as liquor distillers forced FDA to drop the fees for companies that only produce hand sanitizer in response to the public health emergency. A new fee schedule was published March 26, 2021 with revised fees for facilities and for OTC products for the current year (4).

1. FDA, “PDUFA VII: Fiscal Years 2023–2027,” 

, accessed April 8, 2021.
2. FDA, “GDUFA III Reauthorization Negotiation Sessions,” 

, accessed April 8, 2021.
3. FDA, “Public Meeting on the Reauthorization of the Biosimilar User Fee Act (BsUFA),” 

, accessed April 8, 2021.
4. FDA, “FDA In Brief: FDA Republishing Fee Rates under the Over-the-Counter Monograph Drug User Fee Program,” 

Washington editor, jillwechsler7@gmail.com.

When referring to this article, please cite it as J. Wechsler, "FDA and Industry Move to Renew New Drug User Fee Programs," 

Updates to user fee programs that fund FDA operations are being finalized by industry stakeholders for approval by Congress.

FDA and Industry Move to Renew New Drug User Fee Programs

In a preview of the administration’s spending priorities for the coming fiscal year, the White House sent Congress a summary of “topline” funding requests this month, which continue efforts to combat the coronavirus pandemic and to restore the nation’s economic health. The 

main initiatives of the administration’s $1.5 trillion budget plan

 would increase outlays for education, climate change, and housing, as well as public health.

To better prepare for the next pandemic, the White House seeks a significant increase in discretionary funding for the Centers for Disease Control and Prevention (CDC), proposing a $1.6 billion increase to an $8.7 billion budget able to modernize data collection and boost support for local health departments. The National Strategic Stockpile would gain almost $1 billion to replenish critical supplies and continue restructuring efforts launched during the pandemic. There’s a mention here of the need to provide “investments to enhance FDA’s organizational capacity,” but more detail will be spelled out in the administration’s formal budget plan for 2022, which is expected next month. FDA may be further affected by initiatives designed to end the opioid crisis and the HIV/AIDS epidemic and the need to vet new treatments in these fields.

In hopes of gaining additional funding, FDA is clarifying how it would use further resources to “enhance” agency operations. In recent comments to the Alliance for a Stronger FDA, Acting Commissioner Janet Woodcock highlighted the need for funds to support further modernization of FDA data and information systems and to step up inspections and surveillance across drugs, biologics, vaccines, and medical devices. These priority initiatives already will benefit from an added $500 million provided to FDA in recently enacted pandemic legislation, but “adequate funding” is needed to keep up with data modernization efforts, Woodcock noted. The pandemic made very clear, she said, that FDA and industry lack insight into the supply chain and need to invest more in this area. For modernizing data systems, FDA is working to establish an enterprise-wide platform with common data standards that will enable systems to talk to each other.

FDA furthermore could be involved in vetting research that arises from the administration’s most prominent initiative, the launch of the Advanced Research Projects Agency for Health (ARPA-H). The Biden plan provides $6.5 billion to establish this new entity within the National Institutes of Health (NIH) as a way to drive “transformational innovation” in health research and speed access to breakthrough treatments. ARPA-H initially would focus on cancer, diabetes, and Alzheimer’s disease and is modeled after the military’s Defense Advanced Research Projects Agency (DARPA), with project funding decisions made by program managers, as opposed to the peer-review process of NIH research institutes. The aim is to be more flexible, with staff able to expand or cancel projects based on results.

While the biomedical research community generally applauded the ARPA-H plan, there is concern that the new initiative would reduce resources available to fund ongoing NIH programs and its main biomedical research mission. The new program would take up most of the $9 billion increase for NIH, which would see its budget rise to $51 billion. It’s not clear how this innovative research agency will be situated within NIH, who will oversee its operations, and how it will interact with biopharmaceutical companies and other agencies such as FDA. President Biden has been a strong advocate for cancer research and has discussed this kind of initiative previously with Congressional leaders. Some research advocates had hoped for a more independent entity that would stand alone within the Department of Health and Human Services (HHS) and will be looking to influence its mission and organization in the coming months of funding debate.

Separately, the White House announced the formation of a new national network to identify and track coronavirus mutations that raise fears of triggering another pandemic. President Biden 

to expand COVID genomic sequencing by CDC and state health departments and to create six “centers of excellence” at leading academic centers to share and analyze data on emerging disease threats. In addition to funding genomic sequencing capacity on the state and federal level, the new program would build a National Bioinformatics Infrastructure throughout the public health system. The White House aims to generate support for this and other public health programs by providing millions in funding to states to expand such efforts locally.

The administration’s full budget plan for fiscal year 2022 is slated to be released in May, later in the year than usual, but often the case with a change in administration. That will launch wide-ranging debate on ARPA-H, pandemic preparedness, and multiple new proposals.

The White House sent Congress a summary of “topline” funding requests that continue efforts to combat the coronavirus pandemic and to restore the nation’s economic health.