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

Jill Wechsler

Despite a long history of difficulties in this area, FDA once again is taking steps to facilitate the import of less costly prescription drugs from Canada by states, Indian Tribes, and other entities. The Canadian government has objected to the plan, manufacturers challenge the legality of the process, and the complex requirements for establishing state import plans has stymied implementation.

FDA guidance for establishing import programs 

states upfront that its main purpose is to “achieve a significant reduction in the cost of covered products” for Americans, while “posing no additional risk to the public’s health and safety.” At the same time, the program excludes many important and high-cost medicines, including biological products, infused drugs, controlled substances, and drugs subject to risk evaluation and mitigation strategies (REMS), raising questions about realistic expectations for significant cost savings.

 Even so, this latest drug importing effort reflects the widespread belief among US policy makers and consumers that Americans can reduce drug costs by importing cheaper, but legitimate products from Canada or other industrialized nations. Federal laws require that all drugs sold and distributed in the United States meet FDA requirements for safety and efficacy, and the cost of medicines traditionally does not factor into those decisions. Even though countless studies document that many therapies are less expensive in Europe and other regions, efforts to legalize the import of such products from advanced nations have faltered in the past due to difficulties for FDA in ensuring that drugs made abroad are legitimate and meet regulatory requirements. Border states such as Maine and Vermont have authorized consumer purchasing from Canadian pharmacies in the past, but these efforts have been cumbersome and limited. Numerous drug websites claim they can provide US consumers with quality products from abroad, but those operators often prove to be unreliable and even fraudulent.

Despite these problems, the Trump administration unveiled a Safe Importation Action Plan in 2019 as part of its drug price control campaign. FDA implemented the policy by outlining a pathway for states to import certain drugs from Canada, as one option under the broader plan. The requirements are authorized by section 804 of the Food, Drug & Cosmetic Act, and specifics for establishing Section 804 Important Plans (SIPs) were spelled out in an

Several states expressed enthusiasm for establishing such import programs, but implementation has been slow. Opponents such as the Pharmaceutical Research and Manufacturers of America (PhRMA) filed lawsuits challenging the program, claiming that FDA would be unable to ensure the safety and efficacy of such imported medicines. However, the Biden administration has signaled support for the initiative and recently instructed FDA to work with states and Indian Tribes in establishing SIPs as its own drug pricing proposals have stalled. In March 2022, 

 from Florida, Colorado, Vermont, Maine, and New Mexico to provide assistance of preparing SIP proposals and navigating the import program. And FDA guidance published May 25, 2022 furthers this process by outlining key requirements of the SIP program in a Q&A format designed to help “small entities” understand the process.

The guidance reflects the challenges for states and other parties less familiar with FDA rules and requirements in establishing and operating SIPs. Issued jointly by the Center for Drug Evaluation and Research (CDER) and the Office of Regulatory Affairs (ORA), the advisory explains how the Canadian government must license a “Foreign Seller” to ship products to the US. There are procedures for SIPs to submit import requests to FDA and requirements for testing imported products to ensure quality and stability. SIPs also have to submit adverse event reports, implement recalls where needed, and document cost savings to American consumers.

All these specifics continue to raise skepticism that SIPs will ever operate effectively and achieve promised benefits. In addition, the Canadian government stated early on that it opposed the program and is unlikely to provide the required vetting of sellers at its end. Such drug import programs have disappeared in the past due to similar hurdles and requirements, and it remains to be seen if even those committed states have a different experience in the drug import area.

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FDA once again is taking steps to facilitate the import of less costly prescription drugs.

FDA Moves Forward with State Drug Import Plans

A new framework for extrapolating clinical trial data from adult studies seeks to facilitate the testing and approval of therapies for children more quickly and at less cost. The process for achieving such gains is presented in a draft guideline recently released by the International Council for Harmonisation (ICH) that maps out common methods and strategies for identifying how development programs for adult drugs can inform pediatric indications. By establishing common regulatory requirements among regions, the initiative aims to speed the approval of and access to new drugs for young patients around the world, while limiting the number of children needed for testing in clinical trials.

proposed pediatric extrapolation guideline

to gain broader review and assessment by regulatory authorities and drug development sponsors around the world . This harmonization process began in 2017 and now appears on track to adopt a final guideline in 2024. An ICH assembly in Korea in November 2022 is slated to discuss this and several other proposed standards moving through the review process, such as quality risk management and analytical validation requirements, and newer projects on structured product quality, stability testing, and model informed drug development. In recent years, ICH has adopted guidelines on estimands and sensitivity analysis in clinical trials and on reproductive toxicology testing to support clinical studies; a newer initiative aims to update the E8 guideline on the conduct and reporting of clinical trials by incorporating quality-by-design principles into clinical research.

ICH also is moving forward with an initial roadmap for developing guidance on model-informed drug development (MIDD), considered a key approach for achieving a more efficient and more predictive clinical research process, with potential for reducing unnecessary patient exposure. The 

MIDD discussion group released a plan on March 31, 2022 

that lays out general principles, anticipated gains, time frames and options. The aim is to develop a general principles guideline in the next three-to-four years and a completed standard in 10 years. That would set the stage for revisions in several basic guidelines, such as on dose response information, population pharmacokinetic-pharmacodynamic studies, and disease progression modeling.

The ICH initiative on pediatric extrapolation was outlined at a 

organized by FDA and Health Canada to update stakeholders on that and several other ICH projects. Lynne Yao, director of FDA’s Division of Pediatric and Maternal Health in the Center for Drug Evaluation and Research (CDER), described ICH efforts since 1994 to establish common global regulatory standards designed to provide children with access to medicines appropriately evaluated in adults and to support the inclusion of pediatric patients in product development programs where appropriate and feasible.

These initiatives for advancing pediatric clinical investigations have expanded since publication in 2000 of the initial ICH E11 guideline on pediatric clinical investigations. An addendum, E11 (R1), appeared in 2017 and recognized the need for more detailed standards on pediatric extrapolation. In response, an expert working group was formed to develop a reflection paper on the need and scope of an ICH E11A guideline on pediatric extrapolation. Initial steps involved aligning terminology and developing a systematic approach for considering study design, statistical methodologies, and modeling and simulation strategies in this area, Yao explained.

Now a draft ICH E11A guideline provides a framework for utilizing pediatric extrapolation methods to meet regulatory standards for approval. It outlines a systematic approach for pediatric extrapolation studies that involves a full assessment and synthesis of existing data; quantitative predictions on the degree of similarity; development of a framework for potential reduction of required evidence; and later revision of uncertainties and assumptions. Pediatric extrapolation plans would consider patient response to treatment and identify gaps in knowledge involving dose selection, types of efficacy studies, and the need for a safety plan. The goal is to achieve more alignment among regulatory authorities on terminology and what study designs, statistical methodologies, and modeling and simulation strategies will advance pediatric extrapolation in drug development.

ICH standards for pediatric extrapolation, moreover, may help address broader concerns about the scope and extent of data extrapolation to support added indications for new drugs in patients not studied in original pivotal trials. While authorities generally agree that such extrapolation is valid and important for extending disease treatment to added patient populations, some experts question whether sponsors over-rely on limited clinical data to support added indications. This issue was highlighted in the recent debate over the extrapolation of limited clinical evidence in approving the Alzheimer’s treatment Aduhelm for patients with mild cognitive impairment. While experts agree that FDA and sponsors should have flexibility to expand an indication of an approved drug based on extrapolation of initial clinical data, pressure has increased for requiring postapproval studies to support such actions and to provide clear evidence of appropriate use.

A new initiative aims to speed the approval of and access to new drugs for young patients around the world, while limiting the number of children needed for testing in clinical trials.

New Guidelines Aim to Advance Pediatric Drug Development

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.

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.