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

Jill Wechsler

Congressional leaders, as well as regulated industry, want more information from FDA on its strategy for resuming inspections of manufacturing facilities to better assure the quality, safety, and efficacy of medical products. The suspension of in-person field inspections in March 2020 has resulted in a huge backlog of delayed site visits, as FDA sent investigators only to those operations deemed “mission critical.”

FDA Acting Commissioner Janet Woodcock recently confirmed that the agency is returning to normal procedures for domestic inspections, although foreign inspections will still be limited to mission-critical situations. 

 before the Senate Health, Education, Labor and Pensions (HELP) Committee on July 20, 2021, Woodcock outlined FDA’s plan to “transition to standard operations” for US inspections, which means focusing on higher-risk establishments and scheduling postponed surveillance inspections based on risk.

Meanwhile, Congressional leaders continue to demand more information on how and when FDA will resume standard operating procedures for inspections, reflecting concerns that postponed oversight may delay the approval of new drugs and biologics. 

 to Woodcock dated July 22, 2021, Republicans and Democrats on the House Energy and Commerce Committee requested details on the status of foreign inspections; whether delayed inspections are hindering the approval of applications for new drugs, generics, and biosimilars; FDA’s ability to utilize inspection reports from trusted inspectorates; and how FDA’s data modernization initiative will improve its inspection program. The legislators also want to know how much of the $38.3 million provided to FDA to help address the pandemic is being used to support the resumption of domestic and foreign inspections, and the impact of FDA’s decision to preannounce all inspections for the foreseeable future.

FDA normally conducts nearly 1000 foreign and domestic inspections a year for medical products, but has made less than 100 critical site visits in the United States in the last two years, and only a handful overseas. In its “

Resiliency Roadmap for FDA Inspectional Oversight

” issued May 5, 2021, FDA acknowledged that it had postponed most inspections in 2020 due to the pandemic, focusing primarily on manufacturing operations producing drugs needed to prevent critical shortages and to support the approval of novel drugs or treatments for COVID-19. For 2021 the agency has some 15,000 domestic surveillance inspections on its to-do list, most of those involving food and other products, but a third related to drugs.

To better manage this considerable volume of inspection work, FDA aims to enhance the Office of Regional Affairs (ORA) field inspection program through the agency’s data modernization initiative to provide cross-program interoperability, Woodcock reported to the Senate panel. This includes new technology supporting regulatory assessments to improve the receipt, review, and analysis of industry data and records, including a review of inspectional approaches using next-generation assessment technologies.

Furthermore, FDA has established a new agency-wide Inspectional Affairs Council to better coordinate inspection approaches and assessments across product centers. This panel aims to “optimize the inspection process,” explained Judith McMeekin, associate commissioner for regulatory affairs, in a presentation July 14, 2021 to the Alliance for a Stronger FDA (1). McMeekin, who manages ORA’s 5000 inspectors and other staffers, noted that the Council will provide a forum for the leadership of FDA centers to jointly assess strategies and policy issues across operations to ensure optimal use of resources.

McMeekin reported that ORA has conducted about 30 mission critical foreign inspections during the pandemic, which has involved a tremendous effort to mitigate risks to investigators. ORA also worked to facilitate the emergency approval of vital vaccines to combat the pandemic by devising methods to inspect key vaccine clinical research sites, collaborating with the Center for Biologics Evaluation and Research (CBER) to plan the visits. In just four weeks, a team of more than 50 ORA investigators inspected 26 clinical research facilities to ensure the accuracy and reliability of data to be considered by FDA’s vaccine advisory committee. Here, FDA sent in two inspectors, instead of one, to assess data in the shortest amount of time, supplying them with portable projectors able to review documents from a distance.

McMeekin also highlighted ORA’s need for additional funding, particularly to enhance its operations related to drugs and medical products. Only 10% of its budget is supported by user fees, she explained, and most of its appropriated funds are allotted to food safety and oversight. To expand its drug inspection activities, lab capacity, and scrutiny of more imported packages containing drugs, ORA is looking to tap more medical product user fee funds, while also increasing appropriated support to bolster its staff dealing with medical devices and biologics, as well as its cadre of foreign inspectors.

In going forward with scheduling of site visits in the US, FDA is utilizing a rating system to assess the number of COVID-19 cases in the local area and risks to personnel, in consultation with state and local authorities. For now, the agency is pre-announcing domestic inspections to ensure a facility is available and safe for FDA staffers to visit, but FDA officials recognize that it will take some time to restart its foreign drug inspection program due to the more extensive planning required to arrange for safe travel and site visits.

Associate Commissioner for Regulatory Affairs (ACRA) Judy McMeekin (July 14, 1:30-2:30 PM ET)

Articles

FDA officials discuss resuming normal facility inspection operations, both domestic and foreign.

FDA Under Pressure to Restore “Normal” Drug Inspections

A broad White House proposal to advance competition in major US industries features several measures intended to make medicines more affordable for patients. The 

 also instructs the Department of Health and Human Services (HHS) to aide consumers by reducing the cost of hearing aids, limiting certain hospital mergers, and clarifying insurance options offering affordable coverage.

With 72 wide-ranging proposals, the initiative challenges multiple areas where curbs on free competition may harm consumers and workers. There are measures designed to help workers negotiate with employers, limit airline fees, curb data collection and surveillance by tech companies, and support open online marketplaces.

To spur competition in the health care arena, HHS is 

within 45 days to map out ways to combat high drug prices and “price gouging” and enhance domestic pharmaceutical supply chains. One item on the list is to revive a rule that requires health marketplaces to offer at least one health plan with a standard benefit to make it easier for consumers to compare coverage options. The Federal Trade Commission (FTC) and Department of Justice (DoJ) also will review merger guidelines to prevent patient harm from certain hospital mergers and assess the need for controversial rules requiring hospitals to disclose the prices they negotiate with health insurance firms.

The FTC also will investigate and take action against “pay for delay” and other agreements between pharma manufacturers found to discourage competition. And regulators will reduce the cost of hearing aids for consumers by permitting over-the-counter sales of these products to inject competition into the market. This puts pressure on FDA to issue proposed rules for over-the-counter (OTC) hearing aids without delay.

The White House also revives support for importing less expensive drugs from Canada, directing FDA to work with states and tribes to establish procedures to obtain lower-cost medicines without imposing risks to public health. Such drug importing proposals have been on the table for more than a decade but have been opposed by Canadian officials and difficult for state and federal agencies to implement. A Trump administration drug importation program prompted two states to develop and seek FDA certification of such importation plans, a process that has been challenged by brand pharma companies. FDA is weighing a citizen petition opposing authorization of state import programs but recently informed industry lawyers that it needs more time to review these “complex issues.”

A related area of focus involves facilitating the development, testing, and approval of generic drugs and biosimilars. The Biden initiative calls on FDA to fully implement agency plans issued in 2017 and 2018 to advance competition in prescription drug markets by clarifying the approval framework for these products, including standards for interchangeability and for biologics licensing. The executive order further advises FDA to implement recent legislation designed to prevent brand manufacturers from limiting access to drug samples needed to test new generic products.

Additionally, HHS should provide effective educational materials and communications to improve the understanding of biosimilars and interchangeable products among healthcare providers, patients, and caregivers. Similarly, FDA and FTC are instructed to identify and address deceptive, false, and misleading statements designed to undermine consumer confidence in the safety and effectiveness of generics and biosimilars. And FDA should collaborate with the Patent and Trademark Office to prevent patent extensions designed to delay competition from generics and biosimilars. The Centers for Medicare and Medicaid Services (CMS), moreover, should prepare for coverage of interchangeable biological products and support new payment models to increase utilization of these products.

Despite offering multiple strategies for tackling high drug prices, the Biden proposal largely leaves it to Congress to move forward on the more contentious proposals, such as granting Medicare authority to negotiate pharma reimbursement. House Democrats are looking to include such measures in the reconciliation bill to approve the federal budget for 2022, now moving through the legislative process.

In the Senate, where broad agreement is needed

 to advance such pricing proposals, the Senate Judiciary Subcommittee on Competition Policy, Antitrust, and Consumer Rights opened the 

discussion of these issues at a hearing this week on “cracking down on anticompetitive conduct in prescription drug markets.” Subcommittee Chair Amy Klobuchar (D-Minn) supported legislation to further limit pay-for-delay and other tactics that keep generics off the market. While representatives of brand manufacturers maintained that existing antitrust policies promote innovation while ensuring appropriate competition, reformers argued that current policies and judicial decisions permit a range of anticompetitive conduct to limit generic marketing such as “product hopping,” blocking patents, and abuse of citizen petitions. 

White House proposal includes measure to make drugs more affordable.

Drug Prices Targeted in Biden Competition Initiative

Facing continued criticism of FDA approval for Biogen’s Alzheimer’s disease treatment, Aduhelm, acting commissioner Janet Woodcock took the unusual step of calling on the Office of the Inspector General (OIG) of the Department of Health and Human Services (HHS) to examine the review process for that drug. In a letter to acting inspector general Christi Grimm last week that was posted on Twitter July 9, 2021, 

Woodcock requested an “independent review and assessment of interactions 

between representatives of Biogen and FDA during the process that led to the approval of Aduhelm.” 

This surprising move reflects Woodcock’s aim to protect FDA’s reputation for maintaining the gold standard for objective and science-based assessment of all new medical products. The action also seeks to distance Woodcock from the Aduhelm approval decision, as she struggles to gain support for leading FDA permanently.

FDA granted accelerated approval for Aduhelm on June 7, 2021

 based on slim evidence that it may provide benefit for some Alzheimer’s patients, gains to be confirmed in post-approval studies. However, the approval decision ignited an eruption of criticism, largely due to a very broad label supporting prescribing for both early and late Alzheimer’s conditions. Biogen’s $56,000 price tag on the drug, moreover, generated outrage that it would bankrupt Medicare, which provides care for most patients likely to use the drug.

Among the loudest critics were members of FDA’s Peripheral and Central Nervous System advisory committee, which had soundly rejected approval of the drug at a meeting in November 2020 due to the sponsor’s failure to provide convincing evidence of the drug effectiveness. Three members of that panel resigned in protest and called for the removal of top officials at the Center for Drug Evaluation and Research (CDER) and relevant new drug review offices.

As members of Congress demanded an investigation into the agency’s review process, FDA sought to stem the attack by releasing documents indicating a thorough analysis of clinical data for the drug. 

CDER officials used the press to further explain their actions

However, the criticism escalated further with the revelation by the STAT website of 

efforts by high-level FDA staffers to find a pathway for approving the Biogen drug 

despite the advisory committee rejection, largely to meet patient demands for any promising treatment. That internal discussion led the agency to decide that the possibility of some potential benefit supported accelerated (but not final) approval of the drug.

FDA supported a move by Biogen to revise the label for Aduhelm

 to limit prescribing to patients with milder forms of Alzheimer’s disease. Such action is highly unusual so soon after product approval and was seen as a way to reduce potential spending on the drug and thus deflect criticism. However, the revision is not expected to limit prescribing noticeably, although it may provide insurers with some flexibility to negotiate reimbursement.

Meanwhile, the House Energy & Commerce Committee and others plan to hold hearings on the issue and Woodcock’s role in the decision. Sen. Joe Manchin (D-WV) called on President Biden to fire Woodcock for permitting the Aduhelm approval, while Democrats are looking to add drug pricing provisions to current budget legislation. It remains to be seen if Woodcock’s request for an OIG investigation will calm the opposition and prevent heads from rolling at FDA.

FDA’s review and approval of Aduhelm triggers controversy and a call for review from within the Agency.

Woodcock Seeks Outside Investigation to Restore FDA Credibility

As federal officials struggle to boost US vaccination rates to combat the coronavirus pandemic, manufacturers and regulators are responding with efforts to file and evaluate biologics license applications (BLAs) for COVID-19 vaccines to further assure the public of product effectiveness and safety. The rise of COVID variants has made public health officials anxious to expand immunity more widely and quickly in areas with low vaccination rates, and experts hope that full approval of existing and new vaccines will increase public confidence in their value.

The top priority for the Center for Biologics Evaluation and Research (CBER) is to approve BLAs for COVID vaccines to address vaccine hesitancy, said CBER Director Peter Marks. He emphasized that the agency is working to “move this forward” as quickly as possible in remarks last week at the Drug Information Association (DIA) virtual annual meeting. Even if full approval encourages only 5% more individuals to get vaccinated, “that will make a difference,” he observed, adding that “having an approved vaccine may help.”

FDA won plaudits this past year for devising a clear and pragmatic process for awarding Emergency Use Authorization (EUA) for COVID-19 vaccines able to meet high standards for product safety and efficacy. Although the three vaccines with EUAs have experienced few adverse events and have provided clear protection against infection for much of the population, strong vaccine hesitancy is limiting efforts to expand these gains. With variants and a possible second wave of COVID-19 infections still possible later this year, FDA officials recognize that full BLA approval may help counter concerns about the “experimental” nature and limited testing of the available preventives.

To move forward, Pfizer initiated a rolling submission of a BLA on May 7, 2021, initially filing existing preclinical and clinical information, with manufacturing and facility data to come. Moderna announced on June 1, 2021, that it also had launched a rolling BLA submission, with an eye to gaining priority review and approval by year-end. FDA acknowledges that BLAs require more information than the initial EUAs, including data from conformance lots, full characterization reports, additional facility inspections, closer scrutiny of individual safety cases, and more follow-up on adverse events. Marks explained that CBER staff can’t turn around such evaluations in a few weeks but will require several months to fully assess the complete data. And he emphasized at the DIA meeting that the BLA review process must be careful to not cut any corners. Even so, some public health authorities have criticized FDA for moving too slowly in processing the BLAs, while others agree with Marks that any appearance of hasty action or incomplete oversight may only aggravate latent fears.

In planning for more efficient and effective vaccine development for the next epidemic or pandemic, FDA and manufacturers agree that master protocols would be helpful, as would the early designation of a single central laboratory to handle testing and assays across different platforms. A valid concern is that each of the approved vaccines from Moderna, Pfizer-BioNTech and Johnson & Johnson was tested and developed using different endpoints and assays and without head-to-head comparisons. Marks acknowledged that early on there was consideration of establishing a master protocol to test three or four initial vaccine candidates with one control group, but that timing issues prevented that approach. Waiting for all manufacturers to be ready for clinical studies would have delayed product approvals for three or four months, he explained, which most likely would have increased COVID deaths.

Marks also cited the need for better strategies to quickly scale up vaccine production, acknowledging that manufacturing drug substance and drug product is “a huge issue.” That doesn’t mean building more plants to have them sitting there until needed, Marks said. For vaccine manufacturing, one needs productive facilities that can shift from “slow simmer” to “low boil” very quickly. Here advanced manufacturing methods may be important, with disposable and modular systems that can be easily transported to support production on a global basis. And although vaccine manufacturing requires considerable expertise, semi-automated processes would be more scalable and require a smaller, but still highly skilled, cadre of workers.

Manufacturers also are looking for more common guidance and requirements from regulators around the world, and less “global disharmony” in policies and standards. Marks and others acknowledged that regulators could do more to come together and avoid claims that their vaccine is better than others. An initial area for collaboration may involve determining the need for COVID vaccine boosters or new preventives for variants. There also is interest in agreeing on what tests or measures would support boosters and or the need for annual COVID vaccines.

Conversely, Marks noted, different authorities working at cross purposes and promoting diverse claims will only spur vaccine hesitancy and may delay efforts to bring the pandemic to an end.

The rise of COVID variants has made public health officials anxious to expand immunity more widely and quickly in areas with low vaccination rates, and experts hope that full approval of existing and new vaccines will increase public confidence in their value.  

Full Approval of COVID Vaccines Key to Addressing Hesitancy

An updated version of legislation to modernize clinical research policies and FDA expedited approval pathways is circulating on Capitol Hill in anticipation of gaining approval in the coming year. The latest “Cures 2.0” draft released by Reps. Diana DeGette (D-Col) and Fred Upton (R-Mich) also supports the creation of the Biden administration’s proposed Advanced Research Projects Agency for Health (ARPA-H) to accelerate research on cures for devastating diseases such as cancer, diabetes, Alzheimer’s and more.

The proposal builds on the initial 21st Century Cures legislation, which was developed on a bipartisan basis by DeGette and Upton in 2015, and aims to further improve how new critical treatments are tested and delivered to patients. The Cures 2.0 measure has been under discussion for several years and currently is in the form of a 

that is open to revision and addition by fellow lawmakers. A final measure could be included in upcoming federal budget legislation or in the bill needed in 2022 to reauthorize FDA user fee programs.

Provisions in the current draft address interest in advancing diversity in clinical trials, expanding digital health, further utilizing real-world evidence (RWE) in clinical trials and postapproval studies, and enhancing FDA oversight of cell and gene therapies. There are grants to support novel clinical trial designs and other drug development innovations, but many provisions merely instruct FDA to issue reports or participate on advisory panels, without making significant policy changes. And under the “something-for-everyone” approach, the legislation would provide $25 billion to support research at independent institutions, universities, and public laboratories to “continue their work on thousands of federally-backed projects.”

A section that may gain more attention aims to facilitate the completion of post-approval studies for new drugs granted accelerated approval. The approach here is to authorize broader use of clinical evidence, patient registries, and other sources of RWE to satisfy post-marketing commitments, a policy already in effect for regenerative medicine advanced therapy (RMAT) products. But the ongoing controversy over FDA’s recent accelerated approval of Biogen’s Alzheimer’s drug has raised concern about the timing and scope of evidence to confirm the benefits of this very expensive drug with uncertain health gains, and this provision is likely to be expanded to consider broader accelerated approval issues.

The draft bill also addresses the need for manufacturing information to advance expedited development and review of breakthrough drugs, particularly cell and gene therapies. The legislators call for FDA to publish new guidance on standards and data on chemistry, manufacturing, and controls (CMC) to support such applications. The sense is that FDA already has provided much guidance on what clinical safety and efficacy testing is required for innovative products, but a remaining barrier to expedited approvals may arise from uncertainty over what CMC information is needed during development and for initial approval, and what can be provided postapproval. Draft guidance is due in six months and should consider the benefits of requiring more manufacturing information early compared to risks of delaying patient access to a needed treatment.

More controversial is a proposal supporting the establishment of additional FDA Centers of Excellence. The success of the agency’s Oncology Center of Excellence (OCE) to shepherd promising, though risky, cancer treatments through product development, testing, and approval has spurred interest among a range of patient disease groups to gain similar priority treatment for new therapies for rare diseases and neurological conditions, among others. However, FDA officials are not enthusiastic about siphoning off resources for additional centers, and OCE director Richard Pazdur recently emphasized the need for a clear scientific basis plus added resources to actually advance R&D through such entities. 

The broader Cures bill also looks to advance public health by expanding diagnostic testing, vaccine development, and preparedness for future pandemics. A more immediate need is to identify individuals with “long COVID” to ensure care of these patients and to further medical research on diagnostics and therapeutics in this area. The measure supports establishing a national testing and response strategy for future disease outbreaks, with programs to help rare disease patients deal with public health emergencies and to educate all Americans on the importance of vaccines and immunization programs.

 also includes the proposed PASTUER (Pioneering Antimicrobial Subscriptions to End Upsurging Resistance) Act, which supports R&D for new antibiotics with specifics to prevent antimicrobial resistance (AMR). The measure would authorize a “subscription model” for government payment for new antibiotics to ensure return on investment to drug developers despite limiting drug use to the most seriously ill patients to avoid AMR.

Added Cures 2.0 measures fall under the heading of support for patients and caregivers. The bill backs education and training for caregivers and provides support for patients navigating health information systems. FDA will improve diversity in clinical trials, while the Government Accountability Office (GAO) studies barriers to clinical trial participation. And drug manufacturers will be required to collect and report on patient experience in clinical trials, while Medicare expands coverage of costs for individuals participating in certain clinical studies. Another GAO study would recommend ways for Medicare to cover innovative health technologies. Medicare also will examine programs to extend telehealth services and to provide coverage for breakthrough medical devices and for precision medicine.

Some of these initiatives could be addressed by ARPA-H, which would be located at the National Institutes of Health (NIH) with the charge of speeding “transformational innovation in health research.” Specific projects would create new technological and disease models, support high-risk exploration, offer financial incentives for certain critical solutions, and complement NIH and private sector research initiatives.

An updated version of legislation to modernize clinical research policies and FDA expedited approval pathways is circulating on Capitol Hill.

New “Cures” Bill Aims to Advance R&D and Drug Development

Following a three-month review of vulnerabilities in the US supply chain for products important to national security, the Biden administration rolled out a broad initiative to promote domestic production of critical materials, including medicines and their ingredients. The initiative calls for the Department of Health and Human Services (HHS) to establish a public-private consortium for advanced pharmaceutical production to strengthen domestic competitiveness and supply chain resilience in this area (1).

A detailed report by the White House presents strategies for preventing supply chain disruptions in several key industrial sectors. The broader aim is to ensure ready access for US manufacturers to semiconductor chips, rare earth elements, and large capacity batteries for electric vehicles, as well as pharmaceutical ingredients (2). Such gains will bolster America’s economic and national security and address transitory supply chain challenges. Continued US dependence on key pharmaceutical products and APIs from overseas has been driven by pressures to lower costs, the report acknowledges, a situation that leaves the medical supply chain vulnerable and warrants new approaches to support domestic production.

FDA Acting Commissioner Janet Woodcock applauded the announcement, noting that the COVID-19 pandemic revealed“just how vulnerable the supply chain is” and that it is “essential for the national and health security and economic prosperity of the United States” (3). The White House report recommends actions long backed by Woodcock and other FDA officials, including a boost in local pharmaceutical production, R&D to advance innovative manufacturing technologies, robust quality management maturity to support reliable drug manufacturing, and leveraging data to improve supply chain resilience.

To start, the HHS consortium will select 50–100 critical drugs from the “essential medicines” list established by FDA, as part of an earlier federal initiative (4, 5). The aim is to advance the development of novel platform technologies for domestic production of APIs, particularly those for widely used generic drugs. The initiative will be able to tap $60 million provided by the American Rescue Plan to spearhead investments in advanced manufacturing technologies, such as systems with on-demand manufacturing capabilities, to increase production of key pharmaceuticals and ingredients.

FDA anticipates playing a prominent role in advancing these and other supply chain resiliency initiatives and is working with other HHS agencies to develop a further plan for designing and building the long-term capability for US-based manufacture of supplies to combat future pandemics and biological threats (6). And to increase transparency of product sources throughout the pharmaceutical supply chain, HHS will seek legislative authority in two areas: the ability to track API sourcing and production by facility, and a requirement that all pharmaceuticals sold in the United States identify the sources of APIs and finished dosage forms on labeling.

The supply chain security report acknowledges that the shift of drug manufacturing overseas, particularly for generic drug APIs, has reduced US costs by trillions of dollars in the past decade, but has left the American health care system vulnerable to shortages of essential medicines. Change is needed, as the COVID-19 pandemic has highlighted the critical importance of a resilient US healthcare manufacturing sector and of the nation’s ability to rapidly develop and strengthen production of vital vaccines and medical products.

“FACT SHEET: Biden-Harris Administration Announces Supply Chain Disruptions Task Force to Address Short-Term Supply Chain Discontinuities,

Building Resilient Supply Chains Revitalizing American Manufacturing, and Fostering Broad-Based Growth, 100-Day Reviews under Executive Order 14017

Biden Administration Recommends Policy Changes to Secure U.S. Pharmaceutical Supply Chain

,” Press Release, June 8, 2021.
4. FDA, “

Executive Order 13944 List of Essential Medicines, Medical Countermeasures, and Critical Input

s,” www.FDA.gov, Jan. 1, 2021.
5. FDA, “

Drug and Biologic Essential Medicines, Medical Countermeasures, and Critical Inputs for the List Described in Section 3(c) of the Executive Order 13944,

Executive Order 14017 on America’s Supply Chains

When referring to this article, please cite it as J. Wechsler, “White House Promotes US Drug Manufacturing to Secure Access to Vital Medicines” 

HHS is tasked with establishing a public-private consortium for advanced domestic pharmaceutical production. 