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

Jill Wechsler

The possibility of a Supreme Court ruling that overturns Roe v. Wade and ends the national right to abortion also is focusing attention on FDA policies supporting access to the abortifacient mifepristone. What are often referred to as medical abortions have expanded in recent years to account for more than half of pregnancy terminations in the United States, spurred by expanding state restrictions on surgical abortions, as well as more flexible FDA policies that permit prescribing of the drug via telemedicine visits adopted during the COVID-19 pandemic.

Mifepristone, or Mifeprex, was approved by FDA in 2000 for use with a second drug, Misoprostol, to provide a safe and effective method to induce a miscarriage. The first drug blocks progesterone production, and the second, which is taken at home, empties the uterus. Adverse events have been sparse when the drugs are used properly during the first 10 weeks of pregnancy. FDA initially limited prescribing of mifepristone to specially trained health professionals and required a consultation in a clinic or doctors’ office and dispensing only by certified pharmacies. Modifications made during the 

public health emergency permit patients to consult physicians and receive prescriptions via telemedicine visits

 and to obtain the pills through the mail.

Such changes now are prompting those states that have limited surgical abortions to also seek curbs on access to the abortion pill. Approximately 20 states have moved to restrict telehealth prescribing of the medicines and distribution through the mail and to require a real-time patient visit to a doctor. Policies are in flux, though, as legal challenges have blocked state enforcement in many cases.

One troubling result of such state restrictions is that patients and clinics are seeking access to these medicines through foreign online pharmacies. Many of these operators provide generic versions of mifepristone made in India and China that may not be approved by FDA, and delayed shipments can raise issues with safe use of the products.

Patient access to birth control pills has also emerged as another concern related to a Court decision eliminating the protections provided by Roe v. Wade, as anti-abortion activists signal interest in such a move. These widely used medicines still require a visit to and prescription from a health professional, prompting patient advocates to respond with a push for over-the-counter (OTC) status for the “pill.” Some manufacturers have been conducting studies to support an OTC switch but face regulatory challenges in documenting that patients can use birth control pills safely. And frequent attempts by women to use these drugs to induce an early abortion are sure to prompt opposition to policies that make birth control pills more accessible.

Issues related to mifepristone prescribing and dispensing already are 

emerging in the debate over legislation to reauthorize FDA user fees for drugs and medical products. 

A rollback of the agency’s more liberal prescribing policy was proposed during the debate, and states continue to consider policies that override FDA regulation of this area.

Articles

Issues related to mifepristone prescribing and dispensing are emerging in the debate over legislation to reauthorize FDA user fees for drugs and medical products.

Escalating Abortion Battle Threatens FDA Authority

FDA officials have faced a range of tough questions on Capitol Hill in recent weeks as part of the process for gaining timely agreement on legislation to reauthorize user fees for the agency’s medical product regulatory programs. On April 26, 2022, members of the Senate Health, Education, Labor & Pensions (HELP) Committee quizzed Center directors for drugs, biologics, and medical devices on multiple contentious issues—expedited approvals, vaccines for young children, orphan drug exclusivity, access to medical abortions, conflicts of interest, and hiring initiatives, to name a few.

Less was said by most members of the HELP Committee about the specific provisions in the new user fee packages for drugs (PDUFA), generic drugs (GDUFA), and biosimilars (BsUFA), which were 

 by Center for Drug Evaluation and Research (CDER) Director Patrizia Cavazzoni and Center for Biologics Evaluation and Research (CBER) Director Peter Marks. A delay in finalizing the agreement on medical device user fees (MDUFA), however, drew sharp criticism from the committee’s ranking Republican, Sen. Richard Burr (R-NC). And Burr questioned whether added fee payments really will enable these key FDA operations to actually reduce sizeable staff vacancies, as new hires have failed to offset even larger attrition rates at the agency.

Several senators challenged FDA’s approval of Aduhelm to treat Alzheimer’s disease and the equally controversial decision by the Centers for Medicare and Medicaid Services (CMS) to limit access to the drug to those Medicare beneficiaries enrolled in postapproval clinical trials. Cavazzoni was adamant about the validity of FDA’s approval of the drug, while also seeking Congressional support for legislation enabling FDA to require manufacturers to start confirmatory trials at time of drug approval, to meet agreed on timelines and milestones for such studies, and for authority to expedite the market withdrawal of drugs that fail to show benefit in postapproval trials.

In response to queries about a recent court decision involving the Orphan Drug Act, Cavazzoni warned that the ruling “will send a chill” into the development of rare disease treatments, especially for children. That discussion involves the finding in the case of Catalyst vs. FDA by the US Court of Appeals in October 2021 that FDA cannot approve a pediatric version of a drug that has obtained orphan drug exclusivity for the adult version. That ruling, said the CDER director, enables a company to develop a drug for a very narrow patient population and then use the exclusivity for the initial approval to block further research on the therapy for other conditions and patients. The controversy may prompt legislative action or end up for review by the Supreme Court.

The increasingly contentious debate over FDA regulation of access to the abortion pill mifepristone also gained a hearing, as Sen. Roger Marshall (R-Kan) warned that patients will be harmed by recent changes in FDA rules that permit access to the drug through telemedicine, as opposed to requiring a visit to a doctor’s office. Marshall cited the potential for severe complications if women take the pills too late in pregnancy, which he said is more likely without an in-office ultrasound examination. Cavazzoni responded that FDA’s “exhaustive review” of the drug indicates that current procedures ensure its safe use, and that an ultrasound examination is not required. Requests for pills to terminate pregnancy have risen recently as states enact increasingly severe limits on abortions, despite parallel efforts to discourage mifepristone use. FDA’s more flexible position on the issue is expected to be a target for legislation backed by anti-abortion groups.

And in response to a query from Committee chair Sen. Patty Murray (D-Wash) about delays in access to vaccines for children under six, Marks of CBER said that FDA action on such a vaccine was a “top priority”, that the agency was waiting for manufacturers to file EUA applications, and that CBER would discuss such preventives at a public advisory committee meeting; a highly transparent discussion, said Marks, was important for building public trust in the safety and effectiveness of any preventive for very young patients. CBER’s subsequent announcement that such committee review would not occur until June 2022, however, prompted loud protests about FDA delaying access to vaccines important for keeping very young patients healthy.

The tone and scope of the questioning of FDA officials here and at earlier hearings by the House Committee on Energy and Commerce provide a glimpse of what measures Congress may tag on to the user fee reauthorization package. The outcome of months of discussion will emerge more visibly this month as the process moves forward to “mark up” a legislative proposal that includes all the user fee packages and leading add-on measures. All parties would like to see Congress vote on user fee legislation before its annual recess in August, but the schedule is tight, and the scope of pet initiatives expands every day.

Members of Congress asked FDA about multiple contentious issues, including expedited approvals, vaccines for young children, orphan drug exclusivity, access to medical abortions, conflicts of interest, and hiring initiatives. 

Congress Presses FDA on Key Policies and Operations 

As the COVID-19 pandemic shows signs of becoming less widespread and lethal, federal agencies and medical product manufacturers are assessing the potential impact on the development and distribution of drugs and diagnostics made available under FDA’s Emergency Use Authorization (EUA) policy. That program has allowed FDA to approve medical countermeasures based on more limited clinical and manufacturing data to facilitate earlier patient access to treatments and preventives during the health emergency (1).

Although the Biden administration recently extended the current COVID-19 Public Health Emergency (PHE) declaration past its mid-April 2022 expiration date (2), government agencies and the biomedical industry anticipate an end to emergency status in the near future. That prospect is prompting all parties to consider likely changes in R&D processes as well as in coverage and reimbursement for pandemic therapies, vaccines, diagnostics, and other medical products. FDA recently posted an information page on the topic, aptly titled “What happens to EUAs when a public health emergency ends?” (3).

FDA’s process for approving drugs, vaccines, and diagnostics under a health emergency is governed by section 564 of the Food, Drug, and Cosmetic Act and differs from the rules affecting federal health coverage and reimbursement under the Public Health Service Act (4). FDA initially gained EUA authority in 2004 to facilitate access to drugs, biologics, and diagnostics needed for emergency use, as in the case of an anthrax attack, the emergence of a deadly virus such as Ebola or Zika, and other bioterrorism events. EUAs related to those conditions have not been terminated and remain in effect, largely for several in vitro diagnostics (IVDs) and added uses for some therapeutics.

Specific authority for FDA to approve EUAs related to SARS-CoV-2 was issued by the secretary of Health and Human Services (HHS) in February 2020 to facilitate the availability and use of qualifying treatments lacking full market approval. This authority does not expire automatically as with other Public Health Service emergency policies; it has enabled FDA to speed critical anti-COVID vaccines to the nation, while also issuing hundreds of EUAs for IVDs, ventilators, personal protective equipment, and other medical devices—most recently for a breath test COVID-19 diagnostic test.

EUAs have been more controversial for the handful of antivirals and monoclonal antibodies (mAbs) seeking that status. FDA has revoked emergency use for certain therapeutics later found less safe or effective than initially claimed, notably for hydroxychloroquine/chloroquine. More recently, the spread of the new Omicron BA.2 subvariant led to the revocation of the EUA for the mAb sotrovimab (Xevudy) produced by GlaxoSmithKline and Vir Biotechnology, based on its reduced effectiveness against the new strain (5). Similarly, in January 2022 FDA ended emergency use of Regeneron’s mAb REGEN-COV as a preventive and treatment for COVID-19 due to lack of effectiveness against new variants. Regeneron meanwhile applied for full FDA approval of the therapy for preventing and treating COVID-19, but FDA recently extended its review of the application for three months (until July 13, 2022) to assess additional
information to support a biologics
license application (6).

These regulatory actions illustrate the importance of manufacturers anticipating and planning for the conduct of studies needed for the eventual conversion of EUA’s to full approvals. That process will tax FDA resources particularly for the vast number of EUAs for medical devices; FDA recently proposed a 180-day period for manufacturers to either discontinue EUA product distribution or seek permanent marketing authorization for diagnostics and other products (7).

Vaccine makers have taken the lead in filing for full FDA approval
of COVID-19 preventives, starting with Moderna and Pfizer shots for adults. Vaccines for younger age groups and booster shots continue to be provided under EUAs, although manufacturers have begun to seek permanent approval of added uses and indications. And while EUAs largely cover the full use of a medical product related to the pandemic, some already-approved therapies and medical products that gained expanded indications and uses under the emergency program will need to weigh whether to seek full approval of such added uses.

Although manufacturers may continue to produce and market drugs and vaccines under EUAs, an end to the broader HHS Public Health Emergency will alter emergency coverage and reimbursement for numerous medical services, testing, and treatments. This will affect payment and access to therapies and vaccines through Medicaid and Medicare and state and local health programs and alter important flexibilities that now apply to private insurance and health care providers such as hospitals and clinics. Of particular importance will be the impact on the broader emergency use of telehealth programs, increased coverage for in-home care, the availability of free vaccinations and testing, and subsidies to access therapies at lower cost, as outlined in an issue brief from the Kaiser
Family Foundation (8).

In addition, a separate HHS declaration provides liability immunity for activities related to COVID-19 countermeasure development and use. It protects pharmacists, physicians, nurses, and other providers who administer COVID-19 vaccines, as well manufacturers and distributors involved in providing countermeasures to the nation. The end to that added immunity could affect access to treatments and diagnostics from biopharma companies and have notable implications for further development of medical countermeasures.

, accessed April 18, 2022.
2. X. Becerra, Renewal of Determination that a Public Health Emergency Exists, 

 April 12, 2022.
3. FDA, FAQs: What happens to EUAs when a public health emergency ends?, 

, accessed April 18, 2022.
4. FDA, Emergency Use Authorization, FDA.gov, accessed April 25, 2022.
5. FDA, FDA Updates Sotrovimab Emergency Use Authorization, 

,
April 5, 2022.
6. Regeneron, “US FDA Extends Review of Biologics License Application for Regen-COV (Casirivimab and Imdevimab) for Treatment and Prophylaxis of COVID-19,” Press Release, April 14, 2022.
7. FDA, 

Transition Plan for Medical Devices Issued Emergency Use Authorizations (EUAs) During the Coronavirus Disease 2019 (COVID-19) Public Health Emergency, Draft Guidance for Industry 

(CDRH, December 2021).
8. J. Cubanski et al., “What Happens When COVID-19 Emergency Declarations End? Implications for Coverage, Costs, and Access,” 


Volume 46, Number 5
May 2022
Pages: 14–15

When referring to this article, please cite it as J. Wechsler, “FDA and Industry Prepare for Transition from Emergency Use Authorizations,” 

What are the next steps for permanent authorization of COVID-19 vaccines, treatments, and diagnostics?

FDA and Industry Prepare for Transition from Emergency Use Authorizations

FDA recently issued a new guidance on how to make clinical research more inclusive, building on earlier, broader advisories on the topic. At the same time, Congress is looking to advance legislation promoting clinical trial diversity in pre- and post-market studies, while the latest revision to drug user fee programs includes provisions for advancing clinical trial diversity in sponsors’ R&D programs. These initiatives fit the Biden administration’s broader goal of addressing racial and ethnic health care disparities through a range of public research and coverage programs.

This latest FDA draft guidance follows its advisory on 

Enhancing the Diversity of Clinical Trial Populations

 supported efforts to expand eligibility criteria and improve enrollment practices and trial designs so that clinical studies would better reflect the population most likely to use the drug if approved.

 is to clarify how sponsors should submit a “Race and Ethnicity Diversity Plan” with applications proposing clinical research or continuing with trials to support the approval of drugs, biologics, and medical devices. The draft guidance encourages early submission of such plans to present strategies for enrolling and retaining diverse patient populations in trials. FDA 

o discuss such research proposals as early as possible during the investigational new drug (IND) stage, and certainly before launching pivotal Phase III studies.

FDA defines a “diverse population” as including demographic factors such as race, ethnicity, sex, gender identity, age, pregnancy or lactation status, and the presence of additional comorbidities. Sponsors should set enrollment goals for a full range of populations in order to obtain relevant pharmacological and genomic data that can help design larger studies appropriately. The guidance also outlines patient retention strategies, which may involve collaboration with community health workers and patient advocates and reimbursement for expenses to participants in need. FDA advises sponsors to consider the location and accessibility of research sites as part of diversity planning and to design programs for reaching out to patients often reluctant to participate in medical research.

Efforts to achieve greater diversity in research “will be a key focus throughout the FDA,” stated FDA Commissioner Robert Califf, noting the importance of effectively fighting diseases that often disproportionately impact minority communities in announcing the new proposal. These regulatory efforts support the Biden administration’s Cancer Moonshot initiative, which aims to address inequities in access to cancer screening, diagnostics, and treatment across race, gender, region, and resources. The new guidance was developed by staff of Project Equity at FDA’s Oncology Center of Excellence (OCE), which seeks data supporting the approval of oncology therapies that fully represent all patients in need of treatment.

Congress also is likely to consider legislation on this issue as part of a broader measure to reauthorize FDA user fees that is moving forward on Capitol Hill. A bipartisan bill supported by leading members of the House Energy & Commerce Committee aims to enhance FDA’s authority to require that drug and device applications include demographic information on the population to be treated and to enroll such groups in clinical research programs. The Diverse & Equitable Participation in Clinical Trials (DEPICT) Act further authorizes FDA to require sponsors that fail to meet diversity enrollment targets to obtain that data in post-marketing studies.

The 2.0 update to the 21st Century Cures Act similarly calls for FDA and other federal health agencies to advance diversity in clinical trials through added research and policy-making activities. And the latest version of the Prescription Drug User Fee Act (PDUFA VII) sets goals for sponsors to enhance clinical trial diversity, particularly in the development of new cancer therapies.

FDA aims to further encourage diverse clinical trials through research projects to explore best practices for achieving these goals. One proposal is to learn more about which populations are most affected by research that fails to address diversity issues. Others look to better define “health diversity” and how to determine when a specific population or group is most adversely affected by inequities in treatment and research. Sponsors would like more advice from FDA on how to respond when unable to enroll fully representative populations in studies, and what data is most important to collect. Goals may differ for research programs that involve very few patients, as seen in efforts to extrapolate race and ethnicity data from limited studies. An important issue is how FDA and sponsors should consider clinical data from research sites outside the United States. FDA has requested that stakeholders submit comments by June 13, 2022 on these and other topics raised in the guidance document.

New guidance from FDA and legislation from Congress promote clinical trial diversity.

Clinical Trial Diversity Advances in Regulatory Agenda

To further encourage pharmaceutical companies to invest in the reliable production of higher quality products, FDA is reviving efforts to establish a Quality Management Maturity (QMM) program. An updated version of this approach is spelled out in a new 

White Paper from the Office of Pharmaceutical Quality

 (OPQ) in the Center for Drug Evaluation and Research (CDER) and will be addressed further at two workshops in May 2022.

QMM encourages drug and biotech firms to develop manufacturing systems and measures that indicate the quality performance of production and marketing systems in ways to avoid drug shortages. The program aims to reward companies that achieve certain standards by supporting premium prices from drug purchasers and other stakeholders for medical products from manufacturers with high QMM measures ensure reliable, high-quality supplies. Thus, “good actors” in the pharmaceutical industry that earn high quality ratings from public health programs would gain a competitive advantage in the market.

This announcement comes on the heels of FDA’s renewed effort to update its drug Quality Metrics program, as 

 The QMM program aims to establish a flexible approach for manufacturers to report on a range of quality measures for facilities, operations, and products.

QMM is “Essential for Stable US Supply Chains of Quality Pharmaceuticals,” the 

, and can be achieved through a framework for FDA and purchasers to “objectively rate” manufacturing sites.

The initiative sets a framework for how companies can collect information for assessing and rating manufacturing sites on their quality operations. CDER will define the scope and meaning of QMM scores with an aim to establishing objective, consistent, and validated assessment tools across manufacturing sites. This latest proposal builds on two pilot programs that engaged manufacturers in the process for developing QMM criteria at domestic and foreign sites. A takeaway message from participating firms is the importance of minimizing the burden on sites from the QMM process.

The development of a valid QMM rating program fits current efforts by the Biden administration and members of Congress to encourage more drug production in the United States as one way to address pharmaceutical industry supply chain vulnerabilities. For healthcare systems to pay more for US-made medical products, manufacturers should be able to demonstrate their higher value and to provide greater assurance of reliability in supply. Quality ratings would be available to the public as a way to drive manufacturer participation and improvement and to encourage the market to reward investment in reliable operations.

. The program will address the potential for QMM to improve supply chain purchasing decisions, its relation to international quality standards and advanced manufacturing operations, as well as FDA quality rating systems for medical devices and other industries.

FDA is reviving efforts to establish a Quality Management Maturity program.

FDA Revives Initiative to Identify and Reward Quality Drug Operations 

With Congressional reformers stymied in efforts to impose curbs on prescription drug prices and reimbursement, some legislators are taking a more targeted strategy by looking to lower the cost of clinical research and drug development. Leading Democrats in the House and Senate have proposed a measure to facilitate access to less costly comparator drugs needed in clinical trials, while another bill aims to increase transparency in the costs of clinical trials to better assess whether high R&D expenses justify high launch prices for new treatments.

The “Discounted Drugs for Clinical Trials Act” addresses complaints that biopharmaceutical companies make it difficult and expensive for competitors to obtain marketed drugs needed to conduct subsequent clinical trials. This includes cancer treatments approved as standards of care that often provide an efficient and informative way to test new cancer therapies. Even more common are the difficulties faced by manufacturers of generic drugs and biosimilars in obtaining brand drugs needed for comparative bioequivalency testing.

 for ensuring that eligible firms and investigators can access approved drugs or biologics for research purposes. The manufacturer of the reference product would have to sell a specific quantity of the requested drug to a firm at a price comparable to its cost of production. 

Another measure calls for more accurate calculation of outlays for clinical trials and overall R&D expenditures 

to better assess industry spending on drug development and claims that high R&D costs justify high launch prices. For this purpose, annual data on costs incurred from a clinical trial would be added to the ClinicalTrials.gov website, as well as disclosed by biopharma companies in R&D expenditures submitted to the Securities & Exchange Commission.

Sponsored by the chair of the House Oversight & Reform Committee Carolyn Maloney (D-NY) and Sen. Debbie Stabenow (D-Mich), chair of the Senate Finance health care subcommittee, the measures have gained attention on Capitol Hill and in the research community. The House Oversight panel cites its three-year investigation into pharma R&D spending and company practices allegedly designed to suppress competition from generics. These claims fit a range of efforts by Democrats to enact legislation designed to curb industry practices accused of supporting monopolies able to maintain high list prices.

Democrats have proposed a measure to facilitate access to less costly comparator drugs needed in clinical trials, while another bill aims to increase transparency in the costs of clinical trials.