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

Jill Wechsler

State laws imposing strict curbs on surgical abortions have put FDA in the center of the debate on access to medicated abortion and morning-after pills and even to widely used contraceptives. A possible change in leadership on Capitol Hill has aggravated fears of political push-back on FDA regulation and approval of such treatments, as well as policies that could block prescriptions to medicines that treat a range of conditions that could affect maternal health and broader disease treatment.

A prime target of reformers is to limit patient access to the abortion pill, mifepristone, which is approved by FDA for use in the first 10 weeks of pregnancy, together with a second readily available pill misoprostol. Although the Justice Department has said it will take action against states that ban use of the medicine, the federal government may have limited authority to oppose such local actions. In addition, some analysts anticipate that abortion opponents will bring multiple legal challenges to FDA’s authority to approve medicated abortion pills, an issue likely to end up before the Supreme Court.

Meanwhile, FDA has raised alarms over the rise in rogue online pharmacies offering often bogus or dangerous “abortion pills.” Such operations have multiplied since the Supreme Court decision in June limiting abortion rights, which has sent demand for abortion medications soaring. Adding fuel to the fire is the move by some legitimate vendors and healthcare providers to give these pills to people before they become pregnant. Online telemedicine provider 

 and some physicians offer “advance provision” of mifepristone so that patients can be prepared to perform an abortion when needed. FDA, however, has objected to the practice, maintaining that a medical professional should be consulted to determine pregnancy status.

At the same time, FDA is under pressure from leading physicians and abortion advocates to remove all restrictions on how mifepristone is prescribed and used to make it more accessible to patients. FDA initially required that patients see a certified doctor to obtain the abortion pill as part of a Risk Evaluation and Mitigation Strategy (REMS) adopted for the treatment

During the pandemic, FDA temporarily permitted doctors to conduct examinations and prescribe mifepristone via telemedicine, a policy that is still in force but open to restoration of the earlier restriction. However, agency officials are wary that a move by FDA to make permanent its telemedicine consult policy is sure to draw protests from abortion opponents and could jeopardize further access to the pills, which have become more vital at a time of spreading curbs on abortions in any form.

Even though all patients are supposed to have no-cost access to birth control pills under the Affordable Care Act (ACA), some health plans and formularies have set co-pays and cost-sharing requirements for many products that threatens to limit availability of needed treatments. A report on 

Barriers to Birth Control issued in October 2022 

by the House Committee on Oversight and Reform cites widespread restrictions on multiple contraceptive products, based on data from leading health insurers and pharmacy benefit managers.

One response from women’s health advocates is for birth control pills to become available without prescription, and several manufacturers have expressed interest in developing such products. However, an anticipated approval has been delayed, as FDA recently postponed an advisory committee meeting scheduled for November to review a

 requested Rx-to-OTC switch for the progestin-only birth control pill Opill

 made by Perrigo subsidiary HRA Pharma. The HRA pill has been available by prescription since its approval in 1973, providing ample safety and efficacy data. FDA said it wanted to review additional information and left open when it would reschedule the committee discussion of what would be the first non-prescription daily birth control pill. Such a switch is sure to ignite disputes between advocates seeking easier and less costly access to birth control, and opponents claiming that a physician must review the health status of any woman seeking to use the pill.

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A possible change in leadership on Capitol Hill has aggravated fears of political push-back on FDA regulation and approval of contraceptives and other medications.

FDA Embroiled in Reproductive Rights Debate

The long, convoluted FDA process to halt marketing of drugs that fail to confirm safety and efficacy in required postapproval confirmatory studies highlights the need to update and revise FDA’s now-controversial accelerated approval policy. This initiative has succeeded in speeding multiple important therapies to patients over the past 30 years. But the recent advisory committee vote to remove Makena from the market due to its failure to demonstrate benefits for patients illustrates how difficult it is for the regulators to ensure that such drugs document safety and effectiveness in a timely manner.

Makena was approved more than 10 years ago as a treatment to lower the risk of preterm birth in patients considered at-risk for miscarriage, but a confirmatory trial failed to support earlier results. Even so, Makena marketer Covis Pharma has opposed removal, asserting that the drug remains vital for certain high-risk patients. However, FDA’s independent expert panel voted 14–1 in favor of FDA’s decision to halt sales of the therapy, setting the stage for the agency to proceed with its lengthy effort to remove from the market an expedited drug that fails to confirm benefit.

The debate over accelerated approval ignited in 2021 with FDA’s approval of Biogen’s Aduhelm to treat Alzheimer’s Disease. That decision generated a range of reform proposals to ensure that sponsors conduct required confirmatory studies and release results. FDA’s Oncologic Drugs Advisory Committee (ODAC) also highlighted the issue at meetings in April 2021 and September 2022 challenging “dangling approvals” for cancer therapies, which prompted some manufacturers to withdraw certain indications and others to renew confirmatory study efforts.

A September 2022 report from the Health and Human Services’ (HHS) Office of Inspector General (OIG) found that more than one-third of early approvals failed to meet timeframes for completing confirmatory studies, and that FDA’s difficulties in compelling withdrawals permit some therapies to stay on the market for years without verifying predicted clinical benefit, at considerable cost to insurers and Medicare and Medicaid. The 

approximately $700 million on Makena in recent years and said it was “crucial” to give FDA the tools to effectively administer the accelerated approval program.

Congressional leaders responded to FDA concerns by proposing legislation that requires sponsors to have confirmatory trials underway before gaining an early approval. Additional reforms aimed to facilitate FDA withdrawal of an approval if further study results fail to confirm efficacy within a certain period of time. These and other proposals initially were included in legislation to reauthorize FDA user fees but were dropped to meet tight deadlines for Congress to approve the funding measure. Efforts continue on Capitol Hill to include accelerated approval revisions in proposed legislation, but a tight Congressional calendar dims prospects for enacting regulatory reform measures.

Stricter oversight of the accelerated approval program appears likely, though, as drug costs and benefits remain in the spotlight. Medicare’s decision to limit coverage of Aduhelm has prompted health plans and insurers to scrutinize more closely the costs and utilization of therapies with conditional approval status. Although anxious to retain the accelerated approval program, the cancer community and numerous patient disease groups recognize that FDA should be able to remove those products where sponsors are unable or unwilling to confirm initial efficacy. The 

 at FDA’s Oncology Center of Excellence (OCE) aims to pressure sponsors to provide postapproval data in a timely manner and to withdraw products from the market when postapproval studies fail to confirm benefit or are not completed with due diligence.

Despite the lack of alternative treatment to Makena for women at risk of miscarriage, FDA is under pressure to halt marketing of the drug to maintain confidence in the accelerated approval program, which was established 30 years ago and is credited with facilitating access to more than 300 treatments for cancer and serious conditions. More recently, FDA has taken action to revoke approvals of some 35 drugs, most for specific indications. Leaving Makena on the market, even for limited use, is opposed as likely to encourage other sponsors to delay confirmatory studies and flout agency rules to maintain profitable sales.

In a recent speech to the National Organization for Rare Disorders (NORD), FDA Commissioner Robert Califf acknowledged the wide benefits of FDA’s accelerated approval program in generating therapies to treat serious rare diseases. He also urged fast action to reduce uncertainty about the true risks and benefits of those therapies approved based on biomarkers and limited clinical trials. More collaboration is needed, Califf said, to establish a “

system of evidence generation that provides the confirmation of benefits and risks over years

An advisory committee’s vote to remove Makena from the market illustrates how difficult it is for regulators to ensure that such drugs document safety and effectiveness in a timely manner.

Pressure Mounts for FDA to Reform Accelerated Approval Program

FDA’s Center for Biologics Evaluation and Research (CBER) is updating how it manages a growing volume of cellular and gene therapy development programs, seeking added resources and revisions in its oversight of these cutting-edge therapies. Most visible in the elevation of CBER’s Office of Tissues and Advanced Therapies (OTAT) into a new “super” Office of Therapeutic Products (OTP). The change aims to improve functional alignment, increase review capabilities, and add expertise on new cell and gene therapies by establishing multiple branches and divisions in the expanded regulatory unit, as announced in the 

Stated goals are to help CBER address the “substantial growth in innovative, novel products” that present new “scientific, medical and regulatory challenges that require changes to its structure,” including strategies to advance the Regenerative Medicine Advanced Therapy (RMAT) program. The added resources are needed to oversee more than 2000 development programs involving cellular and gene therapies, many involving innovative testing and manufacturing processes. This soaring workload has over-taxed CBER staffers, resulting in serious difficulties in retaining and hiring capable scientists.

The structural changes at CBER reflect agreed-on plans to hire new staffers with funding from recently reauthorized user fee programs. The PDUFA VII commitment letter calls for an additional 132 new hires for CBER in this coming year and another 48 employees the following year, most to support cell and gene therapy reviews at OTP. The reorganization plan calls for OTP to have seven offices—for therapeutic products, clinical evaluation, review management, pharmacology/toxicology, and two for CMC—for gene therapy and for cellular therapy and human tissues. There will be 14 divisions and 32 branches within those offices, providing attractive supervisory opportunities for both new and experienced staffers.

These changes come in the wake of FDA approval of two new gene therapies that have drawn wide attention for both their therapeutic potential and for million-dollar price tags. Bluebird bio’s Zynteglo was approved by FDA in August for patients with beta thalassemia, an inherited blood disorder causing serious anemia. That was followed a few weeks later with approval of Bluebird’s Skysona to treat a rare neurological disorder afflicting young boys. Zynteglo carries a $2.8 million price tag, Skysona’s list price is $4 million, but both therapies are expected to target fewer than 1500 patients, limiting the overall cost impact for the US healthcare system. A greater spending effect would come from FDA approval of a new treatment for sickle cell disease from Vertex Pharmaceuticals and CRISPR Therapeutics, which plan to begin a rolling review by FDA in the coming months. The important potential benefits of these treatments, along with concerns about their impact on healthcare spending and access, speaks to the need for a highly capable and sufficiently resourced FDA oversight program.

These developments also highlight the importance of sound testing and production methods for therapies made from living organisms, which are inherently variable and difficult to control and measure to assure product safety, identify, quality, purity, and strength. The surge in applications from a broad range of firms, moreover, has made it difficult for CBER staffers to schedule formal meetings with each sponsor seeking advice on how best to perform manufacturing and testing processes. And publishing new guidance on these changing and emerging issues also takes time and resources.

In response, FDA looks to engage a broad range of sponsors on topics related to product development through a series of virtual town hall meetings. The first was 

 and addressed how manufacturers should describe and inform FDA about chemistry, manufacturing, and controls (CMC) in applications for gene therapies. Wilson Bryan, OTAT (now OTP) director, opened the session by describing plans for establishing OTP as a super office to increase review capabilities and enhance expertise on gene and cellular therapies and set the stage for OTP branch chiefs to field a broad range of queries, ranging from basic CMC policies for various stages of development, to the scope of potency assays and impact of delivery devices on dose potency and quality [a recording of the town hall meeting is available at the FDA events link]. 

Main topics were comparability testing, assays for product characterization, and process controls. OTP staffers emphasized the importance of determining process requirements early in development to avoid late changes and analytical method variability that could raise uncertainties likely to delay clinical trials. Products with complex mechanisms of action, they advised, stand to benefit from early product characterization and potency assay development. And developers of gene therapies should use multiple production lots during a clinical study to ensure product consistency and quality, even for treatments for very small patient populations.

Manufacturers raised questions about differing CMC issues between early Phase I and late-stage clinical trials and voiced concerns about product characterization related to autologous cell-based gene therapies. A main theme from FDA was the importance of sponsors establishing a well-controlled manufacturing process and qualified analytical testing well before administering any new gene product. While CBER plans to issue guidance on manufacturing changes and comparability for cellular and gene therapy products, the information provided at this session provides unofficial guidance for implementing changes in product manufacturing and the scope of comparability assessments and development studies expected to support such changes.

CBER maps modernization plan to handle surge in research and applications. 

FDA Expands Oversight of Cell and Gene Therapies

Regulatory authorities and biopharma companies are engaged in a range of collaborations to harmonize research methods, approval standards, and quality production methods key to expanding global drug production. While some initiatives predated the COVID-19 pandemic, the ongoing health emergency has elevated the importance of collaboration to speed biomedical research efforts and to ensure broad access to quality medicines and vaccines.

An important message from COVID-19 is the critical need for global regulatory convergence, commented Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), at the PDA–FDA Joint Regulatory Conference held on Sept. 12, 2022. He warned, though, that the move toward greater information sharing seen in recent years is “slipping away” as the pandemic recedes, speaking to the importance of joint efforts to provide pharmacovigilance information and review findings.

Such initiatives are not new for FDA, which has worked for decades to provide technical assistance to regulatory authorities in low- and middle-income countries to advance regulatory convergence and improve drug production methods. The Promoting Quality of Medicines Plus (PQM+) program implemented by the US Pharmacopeia with support from the US Agency for International Development (USAID) aims to build in-country regulatory capacity to ensure broad production of high-quality treatments for neglected tropical diseases, tuberculosis, and other infections. A FDA online seminar explained these issues for global regulators from lower-income regions, with agency experts describing the agency’s submission and regulatory processes and collaborative efforts to advance drug quality testing (1).

Pharmaceutical manufacturers in Europe and other industrial nations similarly are working to ensure equitable access to vaccines and treatments in future pandemics, as seen in a framework devised by the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) to improve responses to future health emergencies. A declaration issued in July 2022 calls for the assessment and identification of successes in pathogen surveillance and vaccine development and distribution during the pandemic. The organization calls on biopharmaceutical companies to help regulators strengthen pandemic preparedness and response capabilities to accelerate the delivery of vaccines, treatments, and diagnostics in their regions (2).

Similarly, the International Coalition of Medicines Regulatory Authorities (ICMRA) aims to harmonize standards for collecting real-world evidence, for assessing manufacturing information, and for conducting inspections to support quality assessments. One program encourages collaborative assessment of chemistry, manufacturing, and control (CMC) data to facilitate post-approval changes and inspections in different regions (3).

FDA also supports global clinical testing and review efforts, such as Project Orbis at its Oncology Center of Excellence (OCE), which was launched in 2019 to advance cancer drug development and regulation. Under the program, sponsors submit applications for high-impact oncology products simultaneously to participating regulators in Australia, Canada, Singapore, Switzerland, Brazil, the United Kingdom, and the United States to facilitate collaboration and agreement on reviews for new cancer drugs and supplements for added indications. While OCE coordinates the program, each regulatory authority makes independent regulatory decisions.

The International Council for Harmonisation (ICH) continues to seek agreement from regulatory authorities and industry on new and revised standards for clinical testing and quality manufacturing of drugs and biologics. Current efforts aim to advance common strategies for validation and selection of analytical procedures in drug testing, for assessment and control of impurities in drugs, and for validating bioanalytical assays. A new initiative is developing guidelines for including pregnant and breastfeeding women in clinical trials, while another project is mapping harmonized approaches for regulating generic drug development (4). These and other ICH initiatives will be further discussed at its annual assembly Nov. 15–16, 2002 in Korea.

One obstacle to global biomedical regulatory harmonization, however, arises from an effort in the European Union to revise and strengthen its data privacy framework, despite the potential for blocking regulatory access to necessary clinical trial information and adverse event reports. The EU’s General Data Protection Regulations (GDPR) adopted in 2018 aim to limit the release of individual information related to a range of personal activities, including health care. Unfortunately, these policies have created difficulties for FDA bioresearch monitoring program (BIMO) inspections and for sponsors submitting information on study subjects in new drug applications and other documents.

A report from FDA’s Europe Office posted Aug. 9, 2022 describes how the GDPR prevents FDA BIMO investigators from reviewing and copying clinical health data involving EU citizens participating in multi-national clinical trails and in reviewing certain demographic and other information normally included in applications sent to the agency (5). While the EU data framework aims to protect private information on a range of activities, the resulting limits on FDA’s ability to assess EU health information pose difficulties in advancing a global clinical research framework and common regulatory policies.

Global Access to Medicines, Including Anti-TB Medicines

IFPMA, “Pharma Proposes to Work With G7 and G20 on a Joint Solution for Better Access to Vaccines and Treatments Around the World for Future Pandemics,” News Release, July 19, 2022.

ICMRA, “International Pilot Programmes to Streamline Regulatory Assessments and Inspections–Call For Industry Applications,” Press Release, June 2022.

ICH, “ICH Assembly Meeting, Athens, Greece, May 2022 A Successful Hybrid Meeting,” Press Release, June 1, 2022.

H. Messick, “How a European Data Law Is Impacting FDA,” 


Volume 46, Number 10
October 2022
Pages: 14-15

When referring to this article, please cite it as J. Wechsler, “Advancing Global Collaboration for Drug Testing, Regulation, and Manufacturing,” 

FDA backs joint reviews, common research policies, and modern production methods around the world.

Advancing Global Collaboration for Drug Testing, Regulation, and Manufacturing

Ten years ago, FDA launched an initiative to expand the role of patients in informing regulators and sponsors on most harmful effects of a disease and primary goals of treatment that can lead to desirable medical approaches. To further advance and refine the process, FDA is highlighting how the Patient-Focused Drug Development (PFDD) program has encouraged active involvement of many patient groups in bringing their perspectives into the process of developing, testing, and approving new medicines.

The primary goal of PFDD is to “better incorporate the patient’s voice in drug development and evaluation,” says Theresa Mullin, associate director for strategic initiatives in the Center for Drug Evaluation and Research (CDER), who has led this effort since its establishment. The initial program featured FDA-led meetings but was expanded to include a wider range of sessions organized by patient groups themselves, Mullin explained in a webinar sponsored by the 

The PFDD initiative was established by legislation reauthorizing the 

 (PDUFA) in 2012. It called for FDA to organize 20 meetings each year to discuss patient experiences, which symptoms have the most significant impact on daily life, and how well current therapies treat those symptoms. The program grew to 24 meetings in the first year as more groups recognized the benefits of hearing patient perspectives on disease severity and on potential effects of treatment. Then in 2016, PFDD further expanded to include discussions organized by patient groups. There have been 55 of these externally led meetings, which follow the format of the agency-organized meetings in being open to the public and producing detailed reports to post on the FDA website.

Every one of these meetings “was very powerful,” Mullin commented, noting that physicians at FDA said that they had never heard these perspectives and that reviewers found that patient comments helpful in assessing the risks and benefits of a new therapy. And even though patients did not advocate for any particular therapies, they discussed the impact of available treatments and where new therapy could have an impact, a process that supported the development of new treatments for sickle cell disease complications.

To further improve the PFDD process, FDA has issued a series of guidance documents to advance the reliability of PFDD tools and methods. Two final guidances address how to 

collect comprehensive and representative input

how to assess which aspects of disease burden and treatment

outlines processes for selecting, developing, or modifying clinical outcome assessments. Still to come is a fourth guidance on incorporating clinical outcome assessments into endpoints to support regulatory decision making. These advisories aim to encourage manufacturers and researchers to utilize high-quality methods for collecting patient experience information that will be useful in regulatory decisions and to move away from multiple differing efforts for developing clinical assessment measures and tools that repeat the PFDD process with every manufacturer.

In looking to the future, Mullin envisions some kind of “national catalog” of standard core clinical outcomes and assessments based on patient perspectives. This would provide reliable measures of clinical outcomes for disease areas that are meaningful to patients and could gain support from FDA’s Standard Core Clinical Outcome Assessments Grant Program. The overarching aim is to ensure that clinical trial protocols are reasonable and accessible for patients and that clinical outcome assessment measures compare things that people care about.

FDA is highlighting how the Patient-Focused Drug Development program has encouraged active involvement of many patient groups in bringing their perspectives into the process of developing, testing, and approving new medicines.

FDA Expands Patient Input on Drug Development 

As the deadline nears for enacting legislation to renew user fees to fund significant FDA operations, legislative leaders are looking to approve a bare-bones measure as part of a short-term government funding bill. Congress must enact a continuing resolution (CR) by Oct. 1, 2022, to prevent a federal government shutdown, and the legislators now have agreed to include a five-year fee reauthorization in that measure. Such a CR for fiscal year 2023 is expected to run through Dec. 16, 2022, after the upcoming mid-term elections.

A key point of debate is whether to include in the CR package provisions to continue and revise a number of FDA programs also slated to expire next week. These and a number of broader reforms were included in the user fee reauthorization bill that was approved by the House months ago and has been pending in the Senate for weeks. It would make significant changes in FDA programs and operations, including policies for how FDA regulates diagnostics, dietary supplements, and cosmetics.

Also off the table is the proposed Cures 2.0 legislation, which was pulled from the main user fee package due to Republican opposition. That measure supports and revises a range of programs to advance biomedical research, but now its fate is uncertain.

Without reauthorization of new fees for drugs (Prescription Drug User Fee Amendments [PDUFA]), generic drugs (Generic Drug User Fee Amendments [GDUFA]), biosimilars (Biosimilar User Fee Amendments [BsUFA]), and medical devices (Medical Device User Fee Amendments [MDUFA]) before the current fee programs expire next week, FDA will lose its authority to collect fees from manufacturers, along with requirements for meeting certain timeframes and for utilizing agreed-on policies for assessing and approving new drugs and medical products.

FDA also would have to lay off thousands of staffers who are supported by fee revenues of potential layoffs, a prospect that has eroded agency morale and undermined efforts to recruit and hire needed employees. The agency has struggled for months to maintain and expand its professional workforce in a very competitive market for skilled biopharma experts, and the agency’s funding uncertainty has worsened the situation.

Medical product user fees generate approximately $2 billion in agency revenues, about 40% of FDA’s non-tobacco budget. While Congressional leaders on both sides of the aisle support the agency’s programs as important for ensuring the health and safety of Americans, the broader political debate over government funding has erected added hurdles for timely reauthorization of new user fee programs. And some consumer advocates have broadened their criticism of expanded user fee funding of FDA by regulated industry as leading toward bias and undermining agency decision-making. FDA Commissioner Robert Califf has said that the agency has sufficient carryover funds to maintain operations for about five weeks into the new fiscal year that begins Oct. 1, 2022, but FDA still will have to notify more than 3000 staffers of “impending employment actions” without user fee reauthorization by Congress.

Legislative leaders are looking to approve a bare-bones measure to fund FDA operations as part of a short-term government funding bill. 