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

Jill Wechsler

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.

Articles

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.

Legislation Targets High Cost of Clinical Trials

A notable feature of the Biden administration’s recently proposed 2023 budget for FDA is a package of legislative measures that aim to enhance the agency’s authority and update procedures for regulating medical products. The actual funding increase for FDA is a mere $356 million in budget authority; most of the agency’s added resources come from a wishful $1.6 billion to prepare for future pandemics and from industry-paid user fees, which would increase to $3 billion. The accompanying legislative proposals set the stage for further debate on FDA policies and programs and whether to include some measures in legislation to reauthorize user fees.

It is no surprise that a leading proposal addresses FDA’s accelerated approval process. The agency asks Congress for wider authority to cancel drugs that gained expedited approval for market but have failed to provide confirmatory post-market studies within set time frames. The measure clarifies that FDA can require manufacturers to provide adequate confirmatory studies as a condition of approval in the first place.

Several provisions address FDA procedures for preventing shortages in drugs and medical devices. There’s a request for authority to extend certain drug expiration dates when companies submit data supporting longer shelf-life listings. And FDA wants notification from medical device makers when there is potential for a shortage, plus regular assessment of supply chains and risk management plans to avoid such developments.

Proposed changes in how the 180-day exclusivity period for new generic drugs is calculated and implemented once again aim to enhance competition among generic-drug makers. Here the legislators seek to prevent a first-approved generic drug from using a range of “parking” strategies to extend market exclusivity. The 

from generic-drug makers that it’s unnecessary and likely to limit patent settlements between brand and generic firms that support the current competitive system.

Several leading lawmakers want to enhance FDA’s oversight authority over dietary supplements. Here they propose to require supplements to be listed with the agency and to boost enforcement for unlawfully marketed products.

FDA also proposes measures to retain its flexibility for conducting remote inspections of manufacturing facilities beyond the pandemic. The agency seeks extended authority to compel manufacturers to participate in remote evaluations and to apply this policy to medical devices and bioresearch monitoring programs. Another measure would require importers to pay for the destruction of medical products found to be counterfeit, instead of FDA or other government agencies having to foot the bill. And manufacturers of certain medical devices would have to assess the cybersecurity of their products more regularly and disclose any apparent risks.

The new budget plan also affects the goals and policies within FDA’s centers. The Center for Drug Evaluation and Research (CDER), for example, looks to use some of any added funds to enhance the agency’s battle against opioid abuse and bolster its ability to ensure the safety of marketed products, says CDER Director Patrizia Cavazzoni. Added top priorities are to advance therapies for rare diseases, to modernize CDER technology platforms, and to strengthen the drug supply chain.

All of these initiatives require adequate staffing, Cavazzoni emphasized during a program sponsored by the Alliance for a Stronger FDA on April 4, 2022. This is an ongoing challenge for her, as well as all of FDA. Attrition actually dropped in 2020, as many long-time staffers postponed retirements to help fight the pandemic, she noted. But now vacancies have increased—at a time when CDER needs added expertise to handle its growing workload involving COVID, as well as compounding, drug supply chain security, and advanced manufacturing. One strategy for attracting new scientists to FDA is to allow them to work remotely; not requiring people to move to Washington, D.C. has “extended our reach,” she pointed out.

The last thing CDER needs is any large organizational change, Cavazzoni added, noting that she is looking for “the right people” to fill the “boxes we now have.” And more connectivity through modernized IT systems within CDER, she believes will further a “true, multi-disciplinary approach” to application review.

To better detect early signals of potential disruptions in the pharmaceutical supply chain, Cavazzoni also emphasized the importance of manufacturers providing FDA with data on volume production for each product at each facility. When a firm has, say, three plants that produce a certain product, it’s critical to know where most of the drug comes from in order to fully understand the impact of a potential shut-down and whether that will lead to shortages, she pointed out.

In addition, FDA needs downstream information from distributors to gain an effective end-to-end picture of the supply chain from manufacturers all the way through to purchasers. The agency’s ability to collect such information was enhanced during the pandemic, but Cavazzoni explained that it now needs to be clearly authorized and funded through the budget process.

Legislative proposals set the stage for debate on FDA policies and programs and whether to include some measures in legislation to reauthorize user fees. 

FDA Seeks Expanded Authorities, Along with More Funds

Despite the pandemic, FDA has worked to maintain appropriate oversight of biopharmaceutical production activities, while also advancing strategies to encourage industry adoption of advanced manufacturing systems. The larger goals of enhanced quality production are to prevent drug shortages and ensure adequate supplies of needed medical products, as outlined in a number of studies and initiatives. Several policies and programs encourage purchasers of drug ingredients and of finished products to consider a firm’s ability to consistently produce high-quality products, an approach that fits broader federal “buy American” programs seeking to avoid supply chain problems that arise from import delays and difficulties.

Along these lines, a report from the National Academies of Sciences, Engineering and Medicine (NASEM) on strategies for preventing drug shortages and ensuring supply chain resiliency encourages healthcare systems to purchase from suppliers demonstrating superior quality and reliability. To this end, the report recommends that FDA publicly disclose the location of all manufacturing facilities that supply ingredients and components of drugs and medical products (1). Such information would include the FDA Establishment Identifier (FEI) and location of finished dosage forms, active ingredients, and excipients for drugs sold in the United States.

The annual report from the Office of Product Quality (OPQ) in the Center for Drug Evaluation and Research (CDER) similarly discusses efforts to assess manufacturing facilities and avoid drug shortages during a time of reduced onsite inspections (2). OPQ describes its greater reliance on alternative oversight tools, including the analytics reported under CDER’s Knowledge-Aided Assessment and Structured Application (KASA) drug review program and its Emerging Technology Program (ETP)—initiatives that support company adoption ofadvanced manufacturing systems and quality-evaluation methods to better ensure timely production.

And a broader February 2022 report on efforts to strengthen the US medical supply chain from the Department of Health and Human Services (HHS) highlights efforts to increase US production of raw materials and fill/finish capacity for vaccine production, as well as increased vial manufacturing, as part of HHS efforts to ensure access to vaccines, therapeutics, and diagnostic tests during the pandemic (3).

Concerns about ensuring the quality of pharmaceutical ingredients and products made overseas also is reflected in Congressional efforts to strengthen FDA’s foreign inspection program. The recently approved $6 billion FDA budget for the 2022 fiscal year calls for the agency to conduct real-time, unannounced plant inspections in foreign countries and instructs FDA to spend $5 million of its added funding on hiring additional foreign-based investigators for this purpose (4). Because of logistical difficulties in conducting surprise inspections overseas, FDA officials plan an analysis that compares the impact of announced vs. unannounced foreign site visits to better understand the value of such efforts.

Meanwhile, FDA continues to devise a program for manufacturers to collect and report a slate of measures designed to indicate quality production. The agency recently outlined a revised approach for this initiative, which builds on earlier efforts to devise a system for companies to measure and track data on manufacturing process performance and pharmaceutical quality systems effectiveness.

The new plan calls for manufacturers to report data on the proportion of manufacturing lots accepted within a certain time period, effectiveness of corrective action and prevention action (CAPA) activities, proportion of laboratory tests completed on schedule, and shipments of products delivered correctly and on time, as outlined in a Federal Register notice published March 9, 2022 (5).

This proposal aims to address strong industry opposition to FDA efforts in 2015 and 2016 to establish such a quality measurement program. The underlying rationale is that by collecting data on manufacturing operations and product quality, companies can help FDA—and themselves—identify risk factors likely to lead to shut-downs and shortages. Industry strongly objected to FDA’s initial data submission plan, prompting the agency to start over and collaborate with academics and industry in conducting pilot programs to assess the impact on companies voluntarily providing quality management maturity (QMM) data.

At the same time, the pandemic focused broader government and public attention on how drug manufacturing and quality operations affect national security and public health.

FDA’s new performance metrics system aims to offer more flexibility for manufacturers to report data on key quality indicators. The agency asks manufacturers to weigh in by June 7, 2022 on the plan, particularly whether each establishment should report these data, how contract manufacturers should be measured, the process for revising metric reporting in the future, and the importance of trying to measure the “quality culture” of a company.

Building Resilience into the Nation’s Medical Product Supply Chains,

 The National Academies Press, Washington, DC, 2022.

Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, 2021 Annual Report, Assuring quality medicines are available to the American public

and Industrial Base One-Year Report, February 2022

US House of Representatives, Bills-117RCP35 JES Division A, 

Division A–Agriculture, Rural Development, Food and Drug Administration, and Related Appropriations Act, 2022, Congressional Directives


Volume 46, Number 4
April 2022
Pages: 14–15

When referring to this article, please cite it as. J. Wechsler, “FDA Maps Strategies to Advance Pharmaceutical Quality,” 

Quality metrics and more domestic production aim to avoid supply disruptions and drug shortages.

FDA Maps Strategies to Advance Pharmaceutical Quality

Consumer advocates continue to press for initiatives to lower drug prices by revising or reducing patent protections, as seen in the recent campaign to implement “march-in rights” for drugs developed with federal government support. At the same time, governments around the world are advancing a proposed agreement on a waiver to intellectual property (IP) protections for COVID-19 vaccines. Disagreement on these and related issues has put IP claims at the center of debates over biopharma R&D policy and funding, particularly as Congressional leaders fail to set limits on US prices for new therapies for COVID-19, cancer, and other serious conditions.

These issues recently gained attention as reformers renewed calls for the National Institutes of Health (NIH) to seize patent rights to drugs it helps develop, a popular strategy for activists seeking broader access to valuable medicines that has long been rejected by government officials as well as manufacturers and academic researchers. Now the battle has gained headlines as a 

group of nonprofit organizations petitioned

 Health and Human Services (HHS) Secretary Xavier Becerra to seize patent rights to six important therapies for cancer, COVID-19, HIV, hepatitis C, insulin, and asthma that the critics claim are too costly for patients to realize benefits. A main target is patents on Pfizer’s prostate cancer drug, Xtandi, which 

have identified as particularly expensive.

The Biotechnology Innovation Organization (BIO) responded by emphasizing how “strong, predictable” patent protections have been critical for the fast development of new COVID-19 vaccines and therapeutics and that dismantling the current IP system will weaken the response to the next pandemic. Similar arguments were voiced by a coalition of nearly 100 academics, R&D organizations, and IP experts, who called on Becerra to reject any seizure of patent rights.

 They emphasized that the exercise of “march-in” rights undermines deals

 between commercial companies and universities that develop important new cures with support from federal research funds

In addition to challenging biopharma patent protections at home, international public health and consumer organizations have pressed the World Trade Organization (WTO) to revise IP policy governing COVID-19 vaccines and therapies to facilitate broader production and access around the world. Now after two years of discussion, key members of the Council for Trade Related Aspects of Intellectual Property Rights (TRIPS) announced an agreement in mid-March on a possible IP waiver for these vaccines. This initial proposal was backed by the United States, European Union, India, and South Africa and 

The compromise, however, generated objections on all sides. Public health groups said the proposal does not go far enough in applying only to vaccines, and not to diagnostics and much-needed antivirals and other therapeutics. They seek “bolder steps” to extend reforms beyond patents to include trade secrets and to address broader WTO efforts to gain compulsory licenses.

In turn, biotech and pharma companies predicted that such an agreement would dry up investment in biomedical R&D, particularly in smaller companies that have been the source of much R&D related to combatting the pandemic. 

 as a first step towards dismantling patent rights. Similarly, the 

International Council for Biotechnology Associations 

(ICBA) said that the IP waiver agreement would have a “chilling impact” on investment in smaller companies, where IP is particularly important for encouraging research leading to new breakthroughs.

The strong objections from all sides, observed some patent experts, may signal that the agreement probably struck a reasonable balance between the opposing parties. The WTO hailed the plan as an important “breakthrough,” while acknowledging that it would take many more months of work to gain agreement from all 164 WTO members. That timeframe supports the more telling criticism that such a patent waiver comes too late in the COVID-19 pandemic to have much impact, as manufacturers already have produced hundreds of millions of vaccine doses and taken steps to broaden global distribution. However, this type of agreement could set a precedent for future global health emergencies, and it could be extended to therapies and diagnostics in six months.

Consumer advocates continue to press for initiatives to lower drug prices by revising or reducing patent protections.

Patent Rights Battles Escalate as Debate over Drug Costs and Access Drags On

Congressional leaders are proposing significant changes in FDA’s accelerated approval (AA) pathway for expedited development of important new therapies to address critical health conditions. The AA program has long faced criticism due to sponsor delays in conducting required postapproval studies to confirm clinical benefit. Moreover, FDA’s surprise decision in 2021 to approve Biogen’s controversial Alzheimer’s treatment Aduhelm under the accelerated process has focused attention on the risks, benefits, and possible reforms to the program.

These issues have moved to center stage as Congress begins consideration of a host of proposals for revising and improving policies related to drug development and regulation for possible inclusion in broader legislation to reauthorize FDA user fees. The legislative process began with a hearing March 17, 2022 before the House Energy & Commerce (E&C) Health subcommittee. The panel reviewed more than 20 reform proposals that seek to expand diversity in clinical trials, to encourage domestic drug manufacturing, and to support development of generic drugs, biosimilars, antibiotics, and orphan drugs. And the Cures 2.0 Act furthers ongoing initiatives in data collection and clinical trial design to accelerate the discovery and development of new treatments.

A main focus was on measures to reform the AA process by requiring sponsors to conduct and complete confirmatory studies and to make it easier for FDA to remove those drugs from market that fail to meet postapproval commitments. E&C chairman Frank Pallone (D-NJ) led the debate by sponsoring a bill that requires postapproval studies to be underway at time of approval, not just designed and agreed-on by FDA, and for sponsors to provide frequent updates on the status of these studies. The bill also expedites procedures for withdrawing FDA approval for drugs that don’t meet agreed study timelines and, most notable, establishes a five-year timeframe for automatic expiration of an early approval for drugs that fail to confirm efficacy through post-approval studies.

Yet, the Pallone bill raises questions about whether a requirement to begin confirmatory studies prior to approval will discourage or delay accelerated approvals, particularly for small firms with limited resources to support ongoing clinical research programs without a marketed product. And patient advocates fear that such requirements would delay access to needed therapies. However, there’s broad support for policies to make it easier for FDA to remove products from the market when confirmatory studies don’t support initial indications.

As the AA debate has moved to center stage, FDA officials and reviewers continue to examine the value of the program and where reform is needed. At a forum held March 11, 2022 by the 

for the FDA, staffers at the Center for Drug Evaluation and Research (CDER) reviewed the 30-year history of the initiative, its benefits and challenges. CDER Principal Deputy Director Jacqueline Corrigan-Curay reported that there have been more than 300 accelerated approvals through the end of 2021 for conditions with no approved therapy and where a sponsor can identify a surrogate or intermediate endpoint that permits shorter, smaller clinical trials able to predict likely clinical benefit. While the program was launched in the 1990s to provide faster access to protease inhibitors to treat HIV/AIDS, the explosion in cancer research and identification of surrogate endpoints likely to predict benefit from oncology therapies has greatly increased AAs for cancer treatments—from 18 in 1992–2002 to 112 for the 2013–2022 period. Oncology AAs may be based on tumor shrinkage and studied through single-arm trials that provide earlier measurement of effect, explained Guatam Mehta, medical officer in CDER’s Division of Oncology 2.

Kevin Fain, senior policy advisor in CDER’s Office of New Drug Policy, noted that AA trials must provide substantial evidence that benefits outweigh risks, but that the program allows some “uncertainty as to the relation of surrogate to clinical benefit.” Confirmatory trials are important for addressing that uncertainty and should be underway at time of approval. Corrigan-Curay acknowledged that once a new drug is on the market, sponsors find it difficult to identify patients willing to enter confirmatory studies.

Although most sponsors confirm benefits of AA drugs in about three years, the rise in “dangling” accelerated approvals—indications where confirmatory trials were not completed or did not verify benefit—prompted FDA to address the issue of at a meeting of its Oncologic Drugs Advisory Committee in April 2021. The session led to the removal of indications for several anti-PD(L)1 antibodies and focused attention on FDA’s challenges in seeking such actions. In response, FDA’s Oncology Center of Excellence has launched the Project Confirm initiative to identify sponsors that need to verify or withdraw certain indications for cancer therapies. These agency efforts and likely legislative changes aim to address public concerns about accelerated approvals and restore confidence in the program.

Congress is considering revising and improving policies related to drug development and regulation for possible inclusion in broader legislation to reauthorize FDA user fees.