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

Jill Wechsler

The termination of the public health emergency (PHE) declared almost three years ago will end various subsidies and flexibilities for healthcare services and treatments. The change, however, will have a less immediate effect on FDA policies governing the approval and marketing of drugs and medical products, as the agency’s authority to utilize Emergency Use Authorizations (EUAs) for vaccines, diagnostic tests, and therapies will remain in place and are not tied directly to the government’s PHE declaration of March 2020 (1).

Even so, FDA is encouraging sponsors to conduct studies and file applications for full approval of products authorized by EUAs, as there is some uncertainty about which drugs and biological products, as well as some vitro diagnostics and devices, authorized under FDA EUAs will remain in effect and for how long. The largest number of such fast authorizations are for some 400 COVID-19 tests and diagnostics, and many manufacturers of these medical devices are expected to end distribution as demand drops. At the same time, many manufacturers of vaccines and medical products approved under the EUA process are conducting additional studies and submitting data to the agency to gain fully approved biologics license applications (BLAs) and official approvals for fast-developed products drugs and devices.

Biopharma companies also are watching how the health emergency phase-out affects telehealth services and patient access to care. During the pandemic, more flexible policies permitted providers to prescribe certain medicines via telehealth visits, including controlled substances. FDA also may retain certain flexibilities for conducting clinical trials, developing generic drugs, meeting certain post-marketing requirements, and holding meetings with sponsors to discuss development programs or manufacturing issues. The agency already has announced plans to conduct more “live” meetings with manufacturers, in addition to continuing online conversations.

Sponsors of clinical trials hope to continue to benefit from added flexibility for clinical research, such as more leeway to conduct informed consent and to track responses and health changes of study participants via remote access methods. Another modified requirement drops Institutional Review Board (IRB) review of very small clinical trials. These approaches have been highly valuable during the pandemic for continuing biomedical research and for providing needed treatment to patients without requiring them to come to
clinics and hospitals.

A main change, though, is the status of multiple FDA guidance documents issued during the health emergency without the usual lengthy comment-and-finalization process. FDA posted a notice on March 13, 2023 addressing which of more than 70 guidance documents issued during the COVID-19 pandemic would be revised and retained, and which will expire with the declared end of the PHE (2).

At the same time, health plans, providers, and patients will notice significant changes with the termination of the broader public health emergency. Since the PHE was declared in January 2020, it has been extended every 90 days to remain in effect. Now, the Department of Health and Human Services (HHS) and state health agencies may halt or reduce coverage and reimbursement for COVID vaccines and treatments, as the federal government stops high-volume purchasing of these products, looking to integrate COVID-19 treatment into health care plans and systems (3).

The omnibus budget bill passed by Congress in December 2022 already allows states to start dropping Medicaid and other health services for millions of patients that were added to state programs to help combat COVID-19. A fact sheet issued by the Centers for Medicare and Medicaid Services (CMS) clarifies that Medicare will continue to provide vaccines and most COVID-19 treatments at no cost, but that Medicaid programs may require some cost sharing for such products. Similarly, Medicare enrollees may continue to see broad access to telehealth services, while many states may limit telehealth flexibilities for local health programs (4). To minimize coverage disruptions, HHS is planning a 16-month special enrollment period for health plans covered by the Affordable Care Act (ACA) to help people losing Medicaid coverage to enroll in a market plans.

Both Republicans and some Democrats in Congress have been pressing for the Biden administration to end the PHE declaration since 2022, as opposition has mounted to continued executive powers, for example, to close ports of entry, waive regulatory requirements, provide emergency funding for certain programs, and, most of all, to require masking and other emergency policies to prevent the spread of disease.

Many of these issues will be discussed and analyzed in the coming months as Congress works to reauthorize the Pandemic and All Hazards Preparedness Act (PAHPA), which governs emergency health programs and expires Sept. 30, 2023. The Senate Health Education, Labor and Pensions (HELP) Committee sought comments in March 2023 on the effectiveness of existing programs, gaps in authorities, and opportunities for enhancement from public health officials, healthcare providers, biopharma companies, and other affected parties (5).

The notice highlights how the program supports medical countermeasures development and deployment, including the strategic national stockpile, Project BioShield, activities of the Biomedical Advanced Research and Development Authority, EUAs, and other activities designed to better coordinate and prepare for public health emergencies. While there is bipartisan support for continuing PAHPA funding and programs, the reauthorization process will provide a forum for discussing both curbs and benefits of public health flexibilities.

FDA. FAQs: What Happens to EUAs When a Public Health Emergency Ends? 

FDA. Guidance Documents Related to Coronavirus Disease 2019 (COVID-19). 

HHS. Fact Sheet: COVID-19 Public Health Emergency Transition Roadmap. Press Release. Feb. 9, 2023.

CMS. CMS Waivers, Flexibilities, and the Transition Forward from the COVID-19 Public Health Emergency. Press Release. Feb. 27, 2023.

US Senate Committee on Health, Education, Labor & Pensions. Ranking Member Cassidy, Chair Sanders, Romney, Casey Seek Information from Stakeholders on PAHPA Reauthorization. Press Release. March 15, 2023.

Jill Wechsler is Washington editor for Pharmaceutical Technology.

When referring to this article, please cite it as Wechsler, J. FDA and Industry Prepare for End to COVID-19 Emergency. 

Articles

FDA is encouraging sponsors to conduct studies and file applications for full approval of products authorized by Emergency Use Authorizations.

FDA and Industry Prepare for End to COVID-19 Emergency

While it is critically important for the nation’s healthcare system and for biomedical research that the Supreme Court’s recent ruling preserved access to mifepristone (Mifeprex) for now, the emergency action fails to ensure FDA’s long-standing regulatory authority and legal status for evaluating and approving new drugs and medical products. In sending the case back to the Fifth Circuit Court of Appeals for further review, the high court’s April 21, 2023 action leaves open the prospect of further rulings that could undermine FDA’s approval process. States where abortion remains legal are stocking up on the pills, and biopharma companies are filing briefs to support FDA’s authority to regulate the development of safe and effective medicines.

The case arises from a ruling by Texas federal judge Matthew Kacsmaryk that supports a lawsuit from abortion opponents claiming that FDA’s approval of mifepristone ignored demonstrated safety concerns and relied on “unsound reasoning and studies” in the face of “significant political pressure” to increase access to chemical abortions. The lawsuit also states that FDA overstepped its authority in expanding access to mifepristone in 2016 and January 2023 by moderating distribution restrictions imposed by a Risk Evaluation and Mitigation Strategy (REMS).

The Justice Department, acting for FDA, and manufacturer Danco Laboratories appealed the Texas case to the Fifth Circuit Court of Appeals, which ruled more narrowly that mifepristone could remain on the market, but only under its more limited original prescribing and dispensing conditions in effect until 2016. That decision also threatened access to a recently approved generic alternative from GenBioPro, raising tricky questions about whether a generic drug can remain on the market under conditions that differ from the original brand.

Complicating the situation was a decision in another case from a federal judge in Washington state that mifepristone is safe and effective and that FDA must maintain access to the drug in the 17 states and the District of Columbia backing the lawsuit. Here the 

in imposing REMS limits on prescribing and dispensing of the treatment and ordered federal authorities not to make any changes to restrict access to the drug.

In response to the circuit court ruling on the Texas case, the Biden administration and Danco 

with the Supreme Court on April 14, 2023 to maintain approval of the drug while the case proceeds. The plaintiffs argued that FDA approval of the drug is based on studies demonstrating that mifepristone is safe and effective and that halting its distribution would harm patients. Multiple interested parties filed amicus briefs, including members of Congress, physicians, abortion rights groups, and opponents. 

 railed against this “unprecedented assault on FDA’s approval decisions.”

In a declaration accompanying the FDA appeal to the Supreme Court, Deputy Commissioner Janet Woodcock attested to the harm and difficulties that would arise from a court decision that rescinds the conditions of use for mifepristone approved by the agency in 2016. Such a move would “create significant chaos” for FDA and manufacturers, Woodcock stated, emphasizing that it was a mistake to think that the agency “could simply snap back” to a prior approval situation. Manufacturers would need to revise product labeling, prescribing information, and other documents to reflect new dosing, which now would be out of date.

arguing in a four-page dissent that the high court should have left in place the pre-2016 restrictions on access to mifepristone as ordered by the appeals court. Alito claims that it would not cause “irreparable harm,” as FDA predicts, to limit the drug’s distribution to rules adopted in 2000 because, as he remarkably says, the agency could use its “enforcement discretion” to permit continued marketing of the drug even with outdated labeling while the legal appeals proceeded.

The broader issue for industry, policy makers, and legal experts is whether FDA approval and marketing decisions can be overturned by private lawsuits on the basis of alleged safety issues that surface post-approval. If such a ruling is successful, it could open the drug regulatory process to allegations of violative behavior on all sides—faulty preclinical and clinical studies, newly detected side effects, and errors in FDA decisions. In the past, courts have shied away from making such rulings based on their recognition that the technical and scientific aspects of drug regulation are complex and need to be decided by experts.

The Fifth Circuit Court has scheduled an expedited hearing on the case for May 17, 2023 to review the merits of the Texas district court decision, particularly on-line and mail-order access to the drug. Many legal experts say the case should be tossed because the antiabortion doctors challenging FDA’s approval of mifepristone lack standing to bring the case. But whoever loses will appeal to the high court, where the outcome remains uncertain.

The Supreme Court’s action leaves open the prospect of further rulings that could undermine FDA’s approval process.

Court Ruling Leaves FDA Authority in Limbo

In an unprecedented ruling, last week a federal judge in Texas 

suspended FDA’s approval of mifepristone (Mifeprex)

, declaring that the agency had not sufficiently assessed the safety and efficacy of this widely used abortifacient. Judge Matthew Kacsmaryk stated that FDA ignored demonstrated safety concerns and relied on “unsound reasoning and studies” in the face of “significant political pressure” to increase access to chemical abortions. FDA approved the drug 20 years ago.

If the decision is not overturned, it not only would lead to the removal of the drug from the market across the nation, but it would also raise uncertainties about the continued marketing of any authorized medical product that raises social, cultural, or political issues.

At the same time, a federal judge in Washington state ruled in another case that mifepristone is safe and effective and ordered FDA to maintain access to the drug in the 17 states and the District of Columbia backing the lawsuit. Here Judge Thomas Rice 

not to make any changes to restrict access to the drug in response to claims filed by that state’s attorney general and colleagues that FDA had imposed too many restrictions on patient use of mifepristone.

Similarly, Biden administration lawyers maintain that FDA approval of the drug is based on studies demonstrating that mifepristone is safe and effective and that halting its distribution would harm patients. The Justice Department and drug manufacturer Danco Laboratories filed a notice of appeal, with Attorney General Merrick Garland indicating plans to ask the US Court of Appeals for the 5th circuit to allow FDA to maintain approval of the drug while the case proceeds. Implementation of the Texas ruling was delayed for seven days to accommodate such anticipated challenges and court-ordered delays.

 that it “stands behind its determination that mifepristone is safe and effective under its approved conditions for use for medical termination of early pregnancy, and believes patients should have access to FDA-approved medications that FDA has determined to be safe and effective for their intended uses." The agency adds that the drug was approved based on the “best available science and done in accordance with the laws that govern our work.”

The broader issue for industry, policy makers, and legal experts is whether FDA approval and marketing decisions can be overturned by private lawsuits on the basis of alleged safety issues that surface post-approval. If such a ruling is successful, it could open up the drug regulatory process to allegations of violative behavior related to a range of perceived situations—faulty preclinical and clinical studies, newly detected side effects, and violations in the FDA decision-making process. In the past, courts have shied away from making such rulings based on their recognition that the technical and scientific aspects of drug regulation are complex and need to be decided by experts.

The Texas lawsuit also claims that FDA overstepped its authority in expanding access to mifepristone in January 2023 by moderating distribution restrictions imposed by a Risk Evaluation and Mitigation Strategy (REMS). Conversely, the 

is that FDA erred in imposing REMS limits on prescribing and dispensing the treatment.

Analysts on all sides expect the issue to be addressed by the Supreme Court, which now faces two conflicting federal court rulings. But how quickly and on what grounds the high court will move on these cases remains to be seen. Meanwhile, legal authorities and public health experts will be examining the court decisions closely as well as the details raised related to the history of FDA approval decisions. A 

summary of the issues and options are outlined in a brief 

developed by health policy experts at the Kaiser Family Foundation.

One immediate effect of these legal developments may be a shift to less safe and effective medical abortions. Clinics that provide such services may be forced to shift to chemical procedures that use only the second drug, misoprostol, a widely available stomach ulcer drug that is currently prescribed to be taken after mifepristone to fully expel the embryo or fetus from the patient. Medical abortions are considered more safe and effective with the two-drug regimen, but clinics in many part of the world have long used only misoprostol, despite its more harmful side effects.

Experts familiar with the drug approval process fear that such court challenges to FDA’s oversight authority could open the door for multiple lawsuits to block agency decisions on all sides (i.e., new drug approvals, perhaps by competitor firms; limits on access to vaccines; curbs on blood donor requirements; approval of therapies that raise social, cultural, or economic issues). The situation speaks to the need for the biomedical research community and developers of critical medical products to question such threats to future access to treatment and voice support for science-based regulation.

Will court challenges to FDA’s oversight authority open the door for multiple lawsuits to block agency decisions on all sides?

FDA Regulatory Authority Under Attack

A top priority this year for dealing with the surge in development of new gene and cellular therapies is for the Center for Biologics Evaluation and Research (CBER) to attract hundreds of talented and experienced scientists to the agency. CBER Director Peter Marks recognizes the difficulties in recruiting and retaining staff with limited salary levels and relatively flat funding expected from Congress. While CBER increased staff by 126 new hires in 2022 in its cell and gene therapy office, it also suffered from “the great retirement” that has plagued FDA overall, plus high demand in industry for employees with the experience and skills also sought by FDA.

CBER’s new super Office of Therapeutic Products (OTP) is up and running, featuring a broader structure and room for additional staff, particularly individuals with experience in biotech manufacturing, statistics, and epidemiology, as well as medical reviewers. A “key need,” Marks explained 

in a webinar sponsored by the Alliance for a Stronger FDA on April 4, 2023

, is to attract more seasoned people, particularly those with expertise in manufacturing, to provide the kind of timely, accurate information that industry needs. Such mid-career people with knowledge of manufacturing issues, moreover, are particularly critical for CBER to help train more junior staffers, he explained.

Marks observed that the “new economy,” which permits employees to take new jobs without relocating, has been helpful to FDA in attracting new hires from other areas. But at the same time, this shift enables industry to lure away experienced FDA staffers by offering similar flexibilities. In response, Marks recognizes that FDA has to look beyond salaries and to highlight the diversity and opportunities of the workplace to attract people to FDA.

Meanwhile, FDA’s drug review office is making visible progress in filling empty jobs, reported Patrizia Cavazzoni, director of the Center for Drug Evaluation and Review (CDER), in another 

. A main factor is CDER’s success in reducing attrition in current staff to achieve net gains. Compared to last year, CDER has hired more than 270 staffers (vs. 140 the previous year) and lost only 150 employees, compared to a loss of around 180 at this time last year—for a net gain of about 120 staffers through February of this year. Cavazzoni noted important increases in challenging areas such as medical officers, as well as individuals with experience in quantitative sciences.

CDER still has a considerable pay gap in hiring compared to the private sector, Cavazzoni said, acknowledging that “everyone is competing for talent.” Both Marks and Cavazzoni cited the importance of provisions in the 21st Century Cures Act and recently renewed user fee legislation for providing added resources and authority for FDA to offer higher salaries to individuals with needed experience and qualifications. Even so, the agency struggles to compete with the private sector for “really good people,” Marks said.

FDA also needs more field inspectors, in the United States and overseas, Cavazzoni noted, as the agency looks to restart foreign inspections and to catch up on the many surveillance inspections that were not done over the past three years. While FDA has sufficient resources in this area, she acknowledged visible attrition in the field force. We “really have to ramp up hiring for investigators,” Cavazzoni observed, particularly for drug products. “So, here’s my advertisement,” she said. “If you want to be an investigator at FDA, please come and talk to us because we need more staff.”

The agency is dealing with high demand for staff because of a surge in the development of cell and gene therapies. 

FDA Is Hiring!

In an important update to its policies for conducting clinical trials to support accelerated approval of important oncology and other lifesaving therapies, FDA is articulating a preference for randomized controlled trials (RCTs), as opposed to single-arm studies, to support fast approvals of breakthrough drugs. A new draft guidance, 

Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics

document discusses ways to reduce “clinical uncertainty for patients” 

by encouraging sponsors to conduct RCTs to support accelerated approval. “Building quality and efficiency into the design of oncology clinical trials is a crucial component in providing maximum benefit to those living with cancer,” stated Oncology Center of Excellence (OCE) Director Richard Pazdur.

In moving quickly to outline this research policy, FDA aims to address mounting criticisms of its accelerated approval pathway, which has permitted some therapies to remain on the market for years due to delays in obtaining results from confirmatory studies. Pazdur and colleagues believe that improving the quality and efficiency of initial clinical studies through broader use of RCTs will avoid problems that have delayed confirmation of clinical benefit.

 as “the preferred approach” to support accelerated approval and seeks to limit single-arm studies to specific situations where RCTs present clear difficulties. Sponsors may conduct one RCT to support both accelerated and then full approval or may opt for two RCTs—one for accelerated approval and another to confirm effects for full approval. In both cases, sponsors should pick endpoints appropriate to predicting clinical benefit and consult with FDA on such plans.

In the two-RCT approach, the first study will measure an early response rate, and the second trial will track progression-free survival or overall survival to verify clinical benefit. An important change is that FDA calls for the second study to be well underway at time of accelerated approval. Under recently approved legislation, FDA now can require the launch of confirmatory trials to document clinical benefit at time of awarding an accelerated approval for a new therapy, and here agency officials are moving quickly to clarify how it will implement that new authority. In the draft guidance, FDA advises sponsors to initiate a second or confirmatory study at the time of that approval to verify clinical benefit in a more timely manner. This approach builds on OCE’s Project Confirm, which it launched last year to promote transparency in the accelerated approval process for cancer thereapies and has been adopted more broadly by the Center for Drug Evaluation and Research.

At the same time, the advisory discusses how sponsors still may determine the adequacy of single-arm studies to support an application. If retaining the single-trial approach, sponsors should plan for extending that same study to confirm a longer-term clinical endpoint. Trials should be large enough to detect clinically meaningful and statistically significant improvements in study endpoints as well as to verify longer term benefit. FDA encourages early consultation with the agency on the appropriateness of a planned endpoint for a single trial and its potential to predict benefit to support accelerated approval.

By requiring timely evidence to confirm benefit, the proposal seeks to continue and enhance the benefits of the accelerated approval program, which FDA estimates has advanced patient access to life-saving cancer thereapies by three or more years. This will involve further clarification of appropriate endpoints for oncology and other studies that fall short of documenting increased overall survival.

Comments on the draft guidance are due May 26, 2023.

FDA aims to address mounting criticisms of its accelerated approval pathway.

FDA Backs Randomized Trials for Accelerated Drug Approval

As patients and the public health community mark the 40th anniversary of the Orphan Drug Act of 1983, bio/pharma companies and FDA officials are acknowledging continued challenges in testing, approving, and producing new treatments for critical conditions affecting small patient populations. The program has led to market approval of more than 600 therapies to treat serious diseases affecting fewer than 200,000 patients in the United States. It has also spurred investment by providing grants and tax credits to help fund very small clinical trials, exemptions from hefty user fees, plus seven years added marketing exclusivity for approved orphans, alongside more incentives for developing rare disease treatments for children (1).

FDA notes that orphan therapies accounted for more than half of novel new drugs approved in 2022, and the agency already has approved two notable rare disease treatments this year. At the same time, clinical development and approval of orphan drugs is often difficult, as trial results may be unclear, and the high cost of research and manufacturing can limit industry investment. Tension continues between funding the development of these much-needed therapies and ensuring their affordability for government health programs as well as individuals, particularly with the development of more gene therapies to treat “ultra-rare” diseases and “bespoke” conditions.

Although FDA marked Rare Disease Day in February by approving an important new rare disease drug, the lengthy path to market for Reata Pharmaceuticals’ Skyclarys (omaveloxolone) to treat the neurological disorder Friedreich’s ataxia illustrates both the promises and the challenges in this field. The drug gained approval only after years of development because its initial pivotal clinical trial did not convince FDA of its effectiveness in slowing disease progression. Approval finally came when the agency determined that Reata’s three-year open-label extension, or natural history, study of patients demonstrated notable gains for individuals taking the drug vs. placebo (2). Reata has set the list price for Skyclarys at $370,000 a year, which will be watched closely for its impact on coverage, costs, and patient pushback.

Meanwhile, FDA is moving on several fronts to provide additional assistance to sponsors in designing studies and obtaining needed data to bring rare disease therapies to patients. An initiative from the Center for Biologics Evaluation and Research (CBER) aims to provide increased interactions with agency experts for firms developing promising rare disease gene therapies, an approach that proved highly effective in accelerating the development of critical vaccines during the pandemic. This “Communications Pilot” will aim to answer questions quickly to speed the development and approval of orphan breakthrough therapies or regenerative medicine advanced therapies.

Similarly, the Center for Drug Evaluation and Research (CDER) reports advances in its Accelerating Rare disease Cures (ARC) program—sort of an “operation warp speed” for orphan drugs that coordinates CDER offices in collaborating with industry and patient groups to facilitate product development (3). CDER notes that ARC has formed several consortia to advance treatments for specific rare disorders, and the initiative may support development of new biomarkers and outcomes measures for clinical trials, as well as natural history studies to serve as external controls for developing treatments for less well-known conditions where historical controls may be inadequate.

Both CDER and CBER are involved in the Rare Disease Endpoint Advancement (RDEA) Pilot Program, another initiative offering sponsors more assistance in developing efficacy endpoints for orphan therapies (4).

Supported by recently reauthorized user fees for drugs and biologics, the RDEA pilot will support a handful of sponsors that have initiated rare disease development programs involving novel efficacy endpoints or natural history studies utilizing a proposed endpoint.

And recent legislation has established an initiative to accelerate the development of more effective treatments for Amyotrophic Lateral Sclerosis (ALS) through an FDA Rare Neurodegenerative Disease grants program (5). The awards aim to cover R&D costs of new therapies for ALS and a range of rare neurogenerative diseases in adults and children, as spelled out in an FDA Action Plan issued in June 2022.

Efforts to advance rare disease treatments, however, may be stymied by the ongoing legal battle that has raised challenges to FDA policies governing the scope of orphan drug exclusivity policy. FDA has opposed a recent federal court decision, Catalyst v. Becerra, that granted an orphan drug producer broader exclusivity for treating all aspects of its target condition, and not just the specific uses or indications cited in its application. FDA approved a Catalyst drug for use in adults, but the company sued the agency later for approving another drug for pediatric treatment for the same condition. A federal Court of Appeals supported Catalyst and rejected FDA’s claim that it has authority to make its more limited approval decision.

Despite that court ruling, FDA has insisted that it will continue to tie orphan drug exclusivity only to approved uses or indications (6). The agency has pressed Congress to enact legislation to clarify this stance, but so far has failed to gain action on Capitol Hill. One result is that some manufacturers are delaying investment in orphan drug development, waiting for further clarification on expected exclusivity terms from FDA or the courts.

FDA. Office of Orphan Drug Products Development. 

Reata Pharmaceuticals. Reata Pharmaceuticals Announces FDA Approval of SKYCLARYS (Omavaloxolone), the First and Only Drug Indicated for Patients with Friedreich’s Ataxia. Press Release. Feb. 28, 2023.

FDA. Accelerating Rare disease Cures (ARC) Program. 

FDA. Rare Disease Endpoint Advancement Pilot. 

FDA. Rare Neurodegenerative Disease Grant Program. 

FDA. Clarification of Orphan-Drug Exclusivity Following Catalyst Pharms., Inc. v. Becerra; Notification.

When referring to this article, please cite it as Wechsler, J. Kudos and Hurdles in Tackling Rare Diseases. 

FDA has spurred investment to create and develop 600 therapies.