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

Jill Wechsler

In the coming months, public health officials and biopharmaceutical companies face the task of addressing and mitigating the ongoing effects of COVID-19, while also continuing to develop and produce vital new vaccines and therapies. To maintain smooth operations, FDA is relying on swift reauthorization of industry-paid user fee programs, as well as Congressional action on policies affecting the agency and biomedical R&D. These ongoing imperatives, however, may be sidelined by mid-term elections in November 2022, where the pandemic response and access to medicines and healthcare services will be prominent issues. Drug pricing will remain a highly charged topic, as the debate continues over patent protections and the need for global vaccination efforts to control COVID-19.

A notable change at FDA will be the appointment of Robert Califf as commissioner. The Senate Health, Education, Labor and Pensions (HELP) Committee held a confirmation hearing for Califf in December 2021, setting the stage for his return to FDA after holding the top job at the end of the Obama administration. Califf will provide much-needed permanent leadership at the agency, where many experienced but exhausted staffers have struggled with uncertainty over FDA’s future and resources. A prime order of business for Califf is to advance a major staff hiring program to ensure the quality and stability of the agency’s workforce.

FDA benefitted in 2021 from the expert leadership of Acting Commissioner Janet Woodcock, but her temporary status limited the launch of new programs and policies. There are signs that Woodcock may stay at FDA under Califf to further implement reforms of the agency’s IT and management systems and other long-debated research and manufacturing initiatives. FDA and industry face ongoing difficulties managing clinical trials and supply chain disruptions that limit manufacturer access to necessary ingredients and supplies. The fast expansion of research on gene and cellular therapies has taxed biotech scientists and reviewers, as has mounting requests from sponsors for meetings to discuss the accelerated approval of cutting-edge therapies. FDA managed to maintain timely review and approval programs for new drugs and biologics during the pandemic, but it will be a challenge to continue those gains.

In addition to addressing difficulties related to medical product development and marketing, Califf will need to deal with a range of critical regulatory and policy issues. Misuse and abuse of opioids continues to escalate, while appropriate oversight of e-cigarettes and vaping products are in the spotlight. FDA needs to ensure the safety of much of the nation’s food supply, while also dealing with Congressional concerns about the regulation of cannabis-derived compounds in foods and dietary supplements.

Effective FDA oversight of new medical products requires timely reauthorization of user fee programs that are critical for maintaining FDA’s efficient regulatory processes for drugs and biologics (the Prescription Drug User Fee Act–PDUFA VII), for generic drugs (Generic Drug User Fee Amendments–GDUFA III), and for biosimilars (Biosimilar User Fee Act–BsUFA III). FDA officials have collaborated with industry representatives in crafting new “commitment letters” for implementing program and fee updates linked to product development, application vetting, and manufacturing oversight (1–3).

The need for Congress to approve these and other fee programs by Sept. 30, 2022, sets the stage for the legislators to enact additional measures affecting FDA, including the new Cures 2.0 measure that has been circulating on Capitol Hill. Building on the initial Cures program approved in 2016, the new bill aims to enhance biomedical research and FDA approval of new therapies, particularly those for serious and orphan diseases. The proposal also advances the use of real-world evidence and patient reported outcomes in drug development and supports efforts to approve more complex generic drugs and biosimilars.

During the past two years, biopharma companies adopted innovations in research and manufacturing to enable the quick scale up and expanded production of vital vaccines and therapies, in the United States and abroad. FDA has advanced these efforts with ongoing support for modern manufacturing systems and quality initiatives able to reduce the need for agency oversight and inspections. The pandemic greatly limited the agency’s field inspection process, and many of the resulting changes will continue, as FDA relies more on manufacturer records, inspection reports and regulatory decisions by trusted foreign regulatory agencies, and on remote facility assessments instead of on-site inspections.

These efforts further speak to the need for global harmonization in regulatory policies and for agreement on regulatory standards as the pandemic continues to highlight the need for the testing and production of medical treatments around the world. The International Council for Harmonisation provides support for such efforts as it further advances new guidelines to modernize the conduct of clinical trials, regulation of generic medicines, control of impurities in drugs, and quality risk
assessment by manufacturers.

At the same time, FDA’s process for quickly authorizing access to new COVID-19 vaccines and treatments through the Emergency Use Authorization (EUA) process will face added scrutiny, as the US and the world look to shift to a post-pandemic phase. FDA will urge sponsors to seek permanent approval of EUA products or phase out their production. At the same time, policy makers see a strong need to improve planning for future health emergencies, building on the lessons learned from COVID-19 at home and abroad.

Many of these regulatory and R&D goals may be sidelined, however, if the political debate over Biden administration proposals for expanding social and health programs delays approval of new user fee legislation, and other measures affecting FDA and its programs. As the midterm elections grow near, action on major legislation will face an unofficial deadline of enactment by mid-year or risk being left by the political wayside.

, FDA.gov, accessed Dec. 8, 2021.
2. FDA, 

, accessed Dec. 8, 2021.
3. FDA, BsUFA III: Fiscal Years 2023-2027, FDA.gov, accessed Dec. 8, 2021.


Vol. 46, No. 1
January 2022
Pages: 13–14

When referring to this article, please cite it as J. Wechsler, “Major Challenges Ahead for FDA and Pharma,” 

Articles

To maintain smooth operations, FDA is relying on swift reauthorization of industry-paid user fee programs.

Major Challenges Ahead for FDA and Pharma

As the nation awaits further decisions from the Supreme court on the legality of restricted abortion policies adopted by certain states, FDA has become embroiled in the debate over access to “chemical” or “medication” abortions through the prescribing and distribution of the abortifacient mifepristone. The two-dose treatment to bring on a miscarriage of an early pregnancy was approved by FDA in 2000 with the requirement that patients receive the pill directly from a physician, with administration of the initial dose in the doctors’ office. That physician-dispensing requirement has been contested by reproductive rights groups and state officials since 2017. In 2020, the in-person prescribing and dispensing requirement was lifted as part of efforts to reduce the need for patients to go to healthcare facilities during the pandemic.

Under pressure to determine whether to continue the use of telemedicine and remote office visits for prescribing mifepristone, FDA disclosed on Dec. 16, 2021 that it would retain its more flexible prescribing policy, reflecting the broader adoption of telemedicine by public health programs. In this controversial decision, officials at the Center for Drug Evaluation and Research (CDER) 

said they would modify the Risk Evaluation and Mitigation Strategy

 (REMS) for mifepristone to remove the requirement for physicians to physically hand the drug to a patient [see]. However, the agency retained the requirement that patients sign a special form to be prescribed the drug and that clinicians pre-register and receive training under the REMS program. The 

 is that prescribing physicians should be able to date pregnancies accurately and provide any necessary surgical intervention or other treatment if needed.

At his Senate confirmation hearing this week, Robert Califf sidestepped a query on how he would prevent policies that permit abortifacient pills to be casually dispensed to patients, responding that he would rely on FDA staffers to “make good decisions.” Anti-abortion activists already are predicting that Califf will collaborate with Democrats and abortion advocates to speed the drugs to patients through the mail. Conversely, abortion rights groups plan campaigns to better inform patients of the availability of the drugs, their safety, and proper use. In fact, medical abortions have risen in popularity, accounting in 2019 for 44% of pregnancy terminations by women who sought abortions in clinics before 10 weeks of pregnancy, according to data from the Centers for Disease Control and Prevention.

Meanwhile, states are acting on this issue. In October 2021, Texas added to its controversial six-week limit on surgical abortions another law that limits medication abortions to the first seven weeks of pregnancy, even though mifepristone is considered effective for up to 10 weeks after conception. The Texas law also blocks sending the pills through the mail or prescribing the treatment through telemedicine.

FDA has become embroiled in the debate over access to “chemical” or “medication” abortions through the prescribing and distribution of the abortifacient mifepristone.

FDA Caught in Abortion Battles

The Biden administration’s choice to lead FDA successfully navigated a Senate confirmation hearing on December 14, setting the stage for full Senate approval early next year. The leading Republican on the Senate Health, Education, Labor and Pensions (HELP) committee, Sen. Richard Burr, praised the stellar academic and medical research credentials of his fellow North Carolinian, eliciting support from other Republicans on the panel. HELP Committee Chair Patty Murray (D-Wash.) set the stage for a speedy conclusion to the vetting process and votes on Califf’s confirmation in early January.

The main opposition to Califf came from Democrat Sen. Bernie Sanders (I-Vt), who questioned the nominee’s long ties to the drug industry and involvement in industry research that has generated high-priced medicines. At the same time, Califf received letters of support from six former FDA commissioners and a long list of academic, public health, and patient organizations. The nominee, who headed FDA in 2016, said he would hit the ground running and noted the importance of working closely with Congress and other federal health agencies.

The main point of controversy during the two-hour hearing centered on FDA approval of opioids leading to the addiction and hundreds of thousands of deaths from drug overdoses. Califf promised irate Senators from New Mexico and New Hampshire that he would take a “very aggressive approach” toward opioids and conduct a “comprehensive review” of their status and labeling as a first order of business.

In a brief statement, Califf outlined his top priorities as building on the lessons learned from this pandemic to ensure readiness for future health emergencies; ensuring the safety and effectiveness of regulated products, including tobacco and opioids; and ensuring that FDA stays current with the latest advances in science and technology. During the hearing, Califf highlighted his aim of working with sponsors to make better use of health records and real-world data to gain evidence able to support regulatory decisions and track medical conditions. He noted his long-time work to develop better systems for generating reliable evidence to support regulatory decisions. He and his supporters have emphasized that Califf’s experience in managing clinical trials for sponsors of new therapies enhances his ability to modernize practices and policies for developing and overseeing new, advanced treatments.

General agreement that FDA needs a confirmed commissioner is slated to speed Califf’s appointment. Both the nominee and Senate HELP leaders also praised the strong leadership at FDA provided by Janet Woodcock this past year and are waiting to see how and whether she remains at the agency under Califf.

General agreement that FDA needs a confirmed commissioner may speed Califf’s appointment.

Califf Gains Bipartisan Support for FDA Confirmation

As Congress struggles to reach agreement on major legislation to fund leading administration social and spending initiatives and to raise the debt limit to avoid default on government borrowing, the White House is emphasizing that reduced spending on prescription drugs can help offset some of the steep costs. President Joe Biden highlighted how current proposals for curbing outlays on pharmaceuticals will help protect patients’ health and save the government billions in a 

 on strategies for controlling drug costs.

Even though Biden applauded the efforts by pharmaceutical companies in developing life-saving vaccines and treatments for fight COVID-19, he criticized industry for jacking up prices on medicines that have been on the market for years. This leaves Americans paying “the highest prescription drug prices of any developed nation in the world,” he stated, lamenting that many patients struggle to afford needed therapies as a result.

Biden pointed to provisions in the Build Back Better (BBB) bill, which is pending before the Senate, that would change the equation. To help all consumers afford medicines, the legislation would set a $35-a-month cap on cost-sharing for insulin for all patients, impose a stiff tax on manufacturers that raise prices faster than inflation, and expand access to health insurance and Medicaid.

And to reduce Medicare drug expenditures, the legislation would open the door to government negotiation of prices on certain older drugs, while also capping annual outlays for seniors at $2000 a year. These provisions were approved by the House following lengthy negotiations with moderates anxious to protect incentives for biopharmaceutical R&D. One result is that the current measure limits Medicare price negotiations to only 20 drugs that have been on the market enough years to have lost exclusivity.

Even so, there’s strong opposition to the drug pricing proposals from Republicans, and the provisions may need to be revised and narrowed to avoid violating Senate budget rules that limit the type of legislative changes eligible for consideration in spending bills. At the same time, a calculation by the Congressional Budget Office (CBO) that the drug pricing provisions would save the government about $160 billion over 10 years has built support for the package from Senate moderates who object to excessive federal spending. Senate majority leader Charles Schumer (D-NY) has set a goal of enacting the $1.7–$2 trillion BBB social-spending and climate change legislation by Christmas, but there’s a lot of skepticism on Capitol Hill about meeting that time frame. A more immediate deadline is for Congress to authorize an increase in the federal debt ceiling before it expires next week, a situation that continues to muddy the broader negotiations on spending and revenues.

President Joe Biden highlighted how current proposals for curbing outlays on pharmaceuticals will help protect patients’ health and save the government billions.

Drug Costs Central Issue in Budget Battles

The challenges in developing gene and cellular therapies have made headlines over the past year, as biotech companies have launched a wave of development programs despite ongoing concerns about treatment safety and efficacy plus unknown long-term effects. High price tags on these breakthrough treatments, moreover, threaten to block patient access to potentially life-saving cures and treatments. FDA scientists and reviewers are working to advance the field, with new guidances and advice for manufacturers on appropriate testing of treatments to minimize risks to patients and fill gaps in data.

New gene therapies for debilitating rare conditions stand to advance from an 

FDA collaboration with the National Institutes of Health (NIH) and a cadre of pharma companies, small biotechs, and patient groups

, formally announced Oct. 27, 2021. The Bespoke Gene Therapy Consortium (BGTC) will be managed by NIH’s Accelerating Medicines Partnership program and the Foundation for the NIH and will provide public and private resources to support the development of gene therapies to treat rare diseases.

To start, the BGTC plans to initiate preclinical and clinical trials for four to six monogenetic rare diseases that currently lack any treatment. Such advances will facilitate a better understanding of the biology and production of adeno-associated virus (AAV) vectors utilized to deliver gene therapies to individual patients. The consortium will provide $76 million over five years from NIH and private partners to fund a range of research, such as establishing standardized analytical test methods to improve AAV production and use and to advance toxicology testing for preclinical development. The term “bespoke” reflects the need for efficient methods for developing highly individualized therapies to fit the genetic specifics of one or two patients.

The BGTC initiative has been under development for several months, as seen in remarks at the September 2021 PDA/FDA conference by Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), on how the program could standardize methods for developing and manufacturing bespoke therapeutics. Marks outlined efforts to leverage methods and data from one application to another to reduce prohibitive R&D costs that threaten product development and patient access. In advancing the development of gene therapies for very rare disorders, he noted the importance of collecting baseline natural history data on target diseases and of public-private partnerships to enable streamlined production through a “cookbook” for developing bespoke therapeutics.

This public-private collaboration is particularly timely in the wake of recent patient deaths and safety issues linked to experimental gene therapies involving AAV delivery. 

FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee met in early September

 to discuss these concerns, noting the limitations of preclinical animal models in predicting potential risks from viral vectors. Panel members cited the need for clearer standards related to gene therapy development, for more comprehensive patient screening, and for longer assessment of patients following treatment to better track side effects that may emerge later.

Even though the experts stopped short of recommending specifics curbs on developing these advanced treatments, 

FDA put a clinical hold on an early study for gene therapy from BioMarin.

Pfizer halted studies on two experimental gene therapies

 following reports of adverse events in early studies.

Meanwhile, CBER seeks to expand the resources and expertise for its Office of Tissues & Advanced Therapies (OTAT) to better oversee and provide advice on developing genetic and other advanced products. Despite a slowdown in biopharmaceutical research due to the pandemic, CBER officials continue to see a strong flow of applications to test experimental cell and gene therapies, many requesting meetings with OTAT staff to discuss research plans. OTAT director Wilson Bryan noted the importance of transparency on safety issues related to gene therapy in a Nov. 12, 2021, presentation at a meeting sponsored by Prevision Policy. One critical issue to explore is whether the effectiveness of gene therapy treatment wears off over time, warranting re-administration. To address these unknown and continuing safety concerns, Bryan emphasized the importance of long-term follow-up of all gene therapy patients—maybe following gene therapy patients “forever,” he commented.

High price tags threaten to block patient access to potentially life-saving cures and treatments.

FDA Grapples with the Promise and Perils of Gene Therapy

Drug development and regulation will never be the same following the momentous changes in healthcare delivery and biomedical research over the past year. The desperate need for new vaccines and therapies to tame the deadly COVID-19 virus required new policies and procedures for how biopharma companies select, test, and manufacture medical products—and revised regulatory practices for evaluating clinical data, manufacturing operations, and procedures for submitting and
analyzing information.

Most visible have been the many changes in the conduct of preclinical and clinical studies for new vaccines, drugs, and medical products. The shutdown of many clinical sites and difficulties in visiting medical facilities required researchers to use virtual and remote methods for identifying potential trial participants, obtaining informed consent, and tracking clinical data. Sponsors looked to deliver experimental treatments directly to patients and to record symptoms and treatment effects at home. Interest rose in innovative clinical research methods, such as master protocols, adaptive trial designs, and Bayesian analytical methods to reduce study size and duration. Digital technology was adopted to track novel endpoints, and the value of utilizing real-world data and real-world evidence from healthcare systems and disease registries gained acceptance for supporting pre- and post-approval
research requirements.

Sponsors gained important advice from FDA on conducting clinical trials during the pandemic from a steady stream of new guidance documents addressing the need for flexibility while maintaining study integrity. Multiple advisories discussed new analytic approaches, protocol management, and dealing with missing data, among other critical issues. At the same time, important guidance documents advised manufacturers on strategies for testing and producing new vaccines and therapies to treat COVID patients.

An important innovation was FDA’s expanded use of the Emergency Use Authorization (EUA) process to speed successful products to patients during the health emergency. At the same time, the regulators required vaccine trials to test thousands of patients to assure the public of the safety and viability of these new preventives. Vaccine experts at the Center for Biologics Evaluation and Research (CBER) worked overtime to clarify the size and diversity of efficacy trials and key analytical assessments needed to gain EUA status and later full approval, establishing standards and procedures that will shape research for health emergencies to come.

The need to quickly produce millions of doses of new vaccines and therapies spurred industry adoption of innovative testing and production methods. Biopharma companies invested resources to update facilities and establish new modular, flexible line operations. Competitors formed partnerships and licensing arrangements to meet production goals at home and for other regions. FDA continued to promote industry adoption of modern manufacturing methods and advanced quality assurance programs to expand biopharma operations in the United States and overseas.

Broader investment in efficient manufacturing systems for generics as well as brand-name medicines was critical to head off drug shortages and ensure reliable production of widely used medicines needed to treat patients in emergency rooms as well as those relying on established therapies for serious diseases. FDA used its expanded authority to respond quickly to shortage situations to prevent gaps in the medical product supply chain for multiple vital medicines.

At the same time, curbs on FDA inspections to evaluate manufacturing sites during the pandemic prompted regulators to expand their use of alternative oversight methods. FDA officials relied more on past inspection reports, current documents from manufacturing sites, and inspection reports prepared by trusted foreign regulatory authorities and shared under mutual recognition agreements. In some cases, FDA “visited” a site through remote online systems. Officials at FDA’s Office of Regulatory Affairs (ORA) indicate that the agency will continue to utilize many of these strategies for streamlining oversight of manufacturing operations, even as on-site visits increase overseas and at home, leading to a more “hybrid” inspection process going forward.

In addition to remote field inspections, FDA review staff organized virtual meetings with medical product sponsors to assess and devise appropriate, yet more flexible R&D programs. Even with most agency staffers working off site, reviewers for drugs, biologics, and generics formed multi-disciplinary teams to assess research proposals remotely to clarify what data and analysis were needed for a product to gain market approval. Such team efforts have been particularly effective for analyzing new COVID-19 vaccines and therapies, as well as for timely review of the steady stream of new drug applications (NDAs), biologics license applications (BLAs), and supplements to treat multiple conditions.

One result is that drug approval processes for fiscal year 2021 remained
strong, with 53 novel drugs approved by the Center for Drug Evaluation and Research (CDER) as of Sept. 30, 2021. That includes multiple treatments for cancer and rare diseases, many utilizing expedited and accelerated approval pathways. CDER also maintained steady review rates for generic drugs as seen in the approval of more than 800 abbreviated new drug applications (ANDAs), including more than 90 first generics and complex generic therapies. There were important advances in biosimilars, moreover, with the approval of the first two interchangeable products (1).

Despite these accomplishments, FDA officials had to contend with public criticism that the review process was taking too long to save dying patients, or that the agency was speeding experimental products through the review process, threatening public health and safety. The highly pressured atmosphere exhausted many FDA employees, as seen in recent announced departures of several agency officials and experienced staffers, and such departures are likely to pick up in the coming months. Changes in agency leadership, in regulatory strategies, and in decisions by researchers and manufacturers on where and how to plan future investments are slated to alter drug development and oversight for years to come.

1. FDA, Generic Drugs Program Activities Report–Monthly Performance, 


Volume 45, Number 12
December 2021
Page: 14–15

When referring to this article, please cite it as J. Wechsler, “Pandemic Alters Policies and Practices for Drug Development and Regulation,” 

The need for medicines to combat COVID-19 has impacted the way regulatory agencies carry out their operations.