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

Jill Wechsler

FDA is looking for greater consistency and fewer surprises in discussions by and decisions from its cadre of expert, independent advisory committees. These panels are formed to provide scientific and medical expertise to help shape FDA decisions in all regulatory areas, most notably to evaluate, approve, or reject applications for new drugs, biologics, and medical products. To gain a more efficient and transparent advisory system, the Center for Drug Evaluation and Research (CDER) has launched an initiative to gain more efficient and transparent operations of its advisory panels, says CDER director Patrizia Cavazzoni.

The initiative has gained attention in the wake of the recent loud eruption over 

FDA’s approval of Biogen’s Alzheimer’s drug 

June 7, 2021, despite strong opposition from an advisory committee at a meeting in November 2020. Although Cavazzoni’s comments on the role of advisory committees aired a week later (June 14, 2021) at the annual meeting of the Biotechnology Innovation Organization (BIO), the virtual presentation was recorded in late May, before the controversial Aducanumab approval decision. Three members of the Peripheral & Nervous System Drugs advisory committee publicly resigned in protest, criticizing FDA for ignoring the independent, scientific recommendations of the panel.

At the BIO meeting, Cavazzoni said that FDA is taking a “comprehensive look” at its advisory committee program to ensure appropriate expertise on its panels, with an eye to reducing some of the “emotional undertone” that may come from some members and public stakeholders. She called for FDA to partner with industry to examine the structure, purpose, and operations of advisory committees, a topic that BIO also is reviewing to provide input. Cavazzoni noted that it is important to “get back to the fundamental reasons for advisory committees” and for all participants to listen to “thoughtful responses to questions from experts.” Most important is to limit some of the emotional comments from members, including reactions to some public speakers. “We have seen,” she said, “how a committee can be swayed by emotion in the face of very hard facts.”

Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), also commented at the BIO meeting that FDA has tried to follow the science throughout the pandemic and emphasized that approach regularly with the advisory committee process. But it’s “challenging,” he observed, to bring together a group of advisors that doesn’t normally sit together and to have them come to a strong conclusion, despite variables raised by non-scientific issues.

Cavazzoni explained that FDA has to contend with visible constraints in assembling advisory panels due to strong conflict-of-interest (COI) rules that keep many experts out of the committee- member pool. The result, she pointed out, is that some panels lack prominent experts in a field. FDA’s COI waiver process can help deal with this limitation, but Cavazzoni said that it doesn’t fully address the problem.

FDA has long relied on expert advisory committees to address the often controversial and subjective issues raised by the clinical assessment of new medicines, particularly in cases where an application is based on early evidence of potential patient improvement, but not clear long-term results. Among its highly controversial decisions is FDA’s approval in 2016 of eteplirsen to treat Duchenne muscular dystrophy, despite opposition from its advisory committee, but with intense support from patient representatives.

Consumer advocates and other stakeholders have criticized FDA advisory committees for including too many experts with industry ties and for doing too little to identify qualified public and consumer representatives for its panels. Congress enacted legislation in 2007 requiring FDA to conduct more outreach to identify non-industry experts for the committees and to file annual reports on advisory panel vacancies, agency outreach efforts to identify suitable members, and the frequency of COI waivers on these panels. The agency’s

for 2019 on this program found a decrease in the use of waivers, and that of some 333 applications to serve on advisory panels, 40% were qualified and willing to serve. Yet FDA sees a continued need to authorize COI waivers because many individuals who have financial relationships with regulated industry also have expertise that is important to a discussion. Similarly, the agency often finds it difficult to identify alternative experts without any financial interests.

Any revisions in advisory committee practices are likely to acknowledge the efficiencies gained from virtual sessions, as has been the case for most FDA staff meetings and interactions with sponsors and other stakeholders during the pandemic. Remote meetings may continue even as FDA moves to a “new normal,” Cavazzoni said. Marks noted that some sponsors really like to come in to interact with reviewers, but remote meetings free up more time for them, and also for FDA. 

 are easier to schedule and impose less of a time and cost burden on committee members, and Cavazzoni envisions a more “hybrid model” with not all meetings in person, but not all remote.

Articles

FDA's CDER has launched an initiative to gain more efficient and transparent operations of its advisory panels.

FDA Advisory Committees Under Scrutiny

FDA’s surprise decision this week to approve Biogen’s treatment for Alzheimer’s disease has raised serious questions about the validity and value of the agency’s accelerated approval process. The 

Aduhelm (aducanumab) based on data from one clinical trial that shows some effect on reducing amyloid beta plaques in patients with mild cognitive impairment. Unlike most surrogate markers supporting early approval, that effect has not been linked to clinical benefit, challenging its validity for anticipating patient gains.

The broad labeling approved for the new drug, moreover, has generated heated debate among scientists, researchers, patients, and payers as to the long-term impact of the approval decision on the credibility and independence of FDA decisions. Coming in the wake of an assessment of several cancer therapies that gained accelerated approval but failed to document long-term benefit, the decision has raised questions about approving new drugs and biologics based on preliminary evidence of possible benefit that awaits later confirmation. FDA emergency use authorizations (EUAs) for some questionable and harmful anti-COVID-19 treatments already have eroded public confidence in the scientific and medical validity of some agency actions, and many research leaders fear this recent decision will heighten those concerns.

The very high price tag set by Biogen for the treatment also is heightening the debate over pharmaceutical costs, reimbursement, and prescribing. In setting a price of $56,000 a year, way above the cost-effective threshold of $2500 to $8000 calculated by the Institute for Clinical and Economic Review (ICER), Biogen stands to earn some $17 billion a year from the drug, according to Wall Street analysts, particularly with a label that opens prescribing to both early and severely debilitated Alzheimer’s patients. All eyes are on how Medicare and health and drug plans will set coverage parameters and how doctors and medical authorities will identify those individuals most suitable for treatment. 

the drug’s appropriate use and insurance coverage at a meeting on July 15, 2021. Biogen says it has begun to negotiate value-based contracts with major payers such as Cigna and CVS Health to support access to the drug. But just how the parties will link payment to treatment outcomes remains to be seen.

was launched in the 1980s to provide early access to treatment for dying AIDS patients with no available treatment. Since then, it has been used to speed approvals of new therapies, primarily for AIDS and cancer where validated surrogate markers have provided evidence that a drug has potential for curbing disease. Many accelerated approval products have been able to document continued benefit from post-approval studies, building support among industry sponsors and patient advocates for the process. Some consumer groups and health care providers, though, complain of long delays in confirming benefit and have questioned the often high cost of paying for unproven treatments.

of its Oncologic Drugs Advisory Committee to evaluate supplemental indications for several leading cancer therapies where confirmatory trials provided only limited evidence of ongoing clinical benefit. Although FDA revoked the added indication for only one product, it continues to examine these therapies and to struggle with the difficulties in conducting postapproval trials. Biogen is not expected to provide confirmatory data from a postapproval study for years, if not decades, further undermining the accelerated approval paradigm.

It remains to be seen whether the flexibility applied by FDA reviewers to the new Alzheimer’s drug reflects a broader, less rigorous approach to approving treatments for devastating conditions with urgent need of treatment. The significance of FDA’s action is apparent in a personal message from Patrizia Cavazzoni, director of the Center for Drug Evaluation and Research (CDER). She notes that 

CDER reviewers carefully vetted highly complex data

 to reach its conclusion that the surrogate endpoint is “reasonably likely” to predict clinical benefit. Cavazzoni acknowledges “residual uncertainties” about the drug and its potential for reducing clinical decline from Alzheimer’s disease, but critics maintain that this and earlier studies show no link between reducing amyloids in the brain and improved health. In basing its approval on “potential benefit,” as opposed to clear clinical benefit, FDA has angered and confused both its critics and advocates.

Some industry analysts predict that this more flexible approval standard will drive a surge in R&D for additional Alzheimer’s drugs as well as other experimental treatments for rare and lethal diseases. Several leading pharma companies are testing new Alzheimer’s treatments that also aim to reduce amyloid in the brain or to clear other invasive substances. But many scientists fear that approvals based on limited evidence of clinical benefit may generate confusion and uncertainty that only deters investment in R&D.

One outcome, though, is that FDA analysts and pundits no longer will assume that agency reviewers will follow the recommendations of its advisory committees, as usually is the case. The advisory committee that assessed the Biogen drug last November voted almost unanimously against approval based on the limited evidence of effectiveness, but FDA reached its own conclusion.

FDA’s approval of Biogen’s treatment for Alzheimer’s disease has raised questions about the agency’s accelerated approval process. 

New Alzheimer’s Drug Heightens Debate Over FDA Accelerated Approval Process

In laying out its formal budget proposal for fiscal year 2022, the Biden administration supports a notable increase in funding for public health and research as a lead priority for the coming year. While Congress will reject or modify many of the specifics, the federal government’s remarkable success in combatting the COVID-19 pandemic continues to generate bipartisan support for advancing biomedical research and public health and safety.

FDA’s oversight and guidance in speeding the development of critical COVID-19 vaccines, diagnostics, and therapies is rewarded with additional funding to continue and strengthen those capabilities. The 

requests $6.5 billion for the agency, up 8%, with $3.6 billion in public appropriations and $2.9 billion in user fees paid by industry. The added $344 million, according to the 

, is allocated primarily to three main areas: critical public health infrastructure, including data modernization and expanded laboratories, facilities, and staff; core safety programs for food and medical products and global supply chains; and ensuring public health by increasing secure inspections, promoting health equity, and addressing the opioid crisis.

Among the specifics, FDA seeks $19 million to enable its field inspection program to carry out site visits delayed by the pandemic and to avoid a reduced frequency in both domestic and foreign inspections going forward. To help end the opioid crisis, FDA would gain $38 million to support research for developing overdose reversal treatments and new non-opioid pain medications and to devise systems to better track and manage opioid use.

For several years now, FDA has emphasized the need to modernize its data and communications systems for medical products and food, and the new budget may finally advance its Enterprise Technology and Data modernization efforts. An additional $45 million would support wider use of artificial intelligence and advanced IT systems to enable data sharing across product centers and ease communications among agency offices, streamline core business processes, and better track medical product manufacturing to better anticipate shortages.

The budget plan also cites the need for legislation to make permanent certain temporary policies that will expire with the end of the current public health emergency. This includes authority to require medical device manufacturers to notify FDA of product shortages, to request records and other information from medical device makers and clinical research sites in advance or “in lieu of” a physical facility inspection, and to require data and studies from drug manufacturers to extend product expiration dates as a way to prevent product shortages.

The Biden spending plan further outlines initiatives to enhance public health more broadly, including programs to address gun violence and the opioid epidemic and to continue investment in biomedical research to prepare for future pandemics. Reforms that allow Medicare to negotiate prices with drug manufacturers and impose rebates on companies that raise prices faster than inflation would save more than $500 billion over 10 years, the analysts calculate, but without offering many specifics for implementing such contentious changes.

While the National Institutes of Health (NIH) would see a hefty 22% rise in funding for a $50.5 billion 2022 budget, $6.5 billion of that increase would fund the new Advanced Research Projects Agency for Health (ARPA-H) within NIH, a hot-button proposal that has raised many questions. Designed as a parallel to the Defense Department’s Defense Advanced Research Projects Agency (DARPA), stakeholders already are debating if ARPA-H should reside within NIH or be independent, how it could advance “transformational” research issues for multiple diseases, and how its projects would involve private sector R&D and technology transfer. A 

review of the ARPA-H initiative from the Congressional Research Service 

summarizes these issues and options for going forward.

The administration also seeks an $8.5 billion budget for the Centers for Disease Control and Prevention (CDC), a notable $1.5 billion increase (up 21%) in funding for this usually neglected agency. And the Biomedical Advanced Research and Development Authority would gain $227 million for a $823 million spending plan to build the national stockpile and help prepare for future pandemics.

Congressional debate on FDA’s budget will begin June 10 at a hearing before the Senate Appropriations subcommittee that deals with the agency. Acting Commissioner Janet Woodcock will make the case for the administration’s spending plan and FDA program priorities, and again before the relevant House appropriations subcommittee. But the main decisions on budget support for the agency will turn on broader revenue and spending issues for federal programs as the nation continues to promote economic growth and public health recovery.

The Biden administration supports a notable increase in funding for public health and research as a lead priority for the coming year. 

Biden Budget “Wish List” Maps FDA and Health Care Priorities

The importance of a flexible, efficient infrastructure able to produce critical, high-quality drugs and medical products quickly and reliably has been heightened this past year by the soaring demand for medicines to combat COVID-19. Recent events have expanded interest in advanced drug manufacturing and continuous production methods able to provide needed therapies and prevent shortages that could compromise public health. Heavy reliance on foreign suppliers for necessary medical equipment and APIs similarly has increased concerns about supply interruptions as nations limit exports to protect the health of domestic populations. The result is a resounding call for more flexible production systems and regulatory policies able to respond quickly to supply disruptions and heightened demand for new preventives and treatments.


FDA officials have long pressed bio/pharma manufacturers to step up investment in advanced manufacturing technologies, as seen in multiple statements and proposals from Janet Woodcock during her many years as director of FDA’s Center for Drug Evaluation and Research (CDER). Former FDA Commissioner Scott Gottlieb urged added funding in 2018 to support continuous drug manufacturing and 3D printing to ensure steady output of finished drugs. And Former Commissioner Stephen Hahn highlighted in August 2020 how advanced drug manufacturing techniques could help address manufacturing and supply chain problems generated by the pandemic (1). There has been some progress, as seen in CDER’s report on drug product quality for 2020, which notes that FDA approved the first application utilizing a continuous biomanufacturing process in 2020 and semi-continuous processes for two other products (2).


The Biden administration has acknowledged the importance of reliable advanced drug and vaccine production to ensure access to treatments for COVID-19. A White House executive order early this year sought sufficient supplies of vials and needles, as well as APIs, to support expanded vaccine supply and distribution. And the administration included pharmaceutical and biotech products on a list of key industries important for enhancing supply chain resiliency (3).


A related goal by federal officials has been to expand drug manufacturing in the United States to reduce reliance on foreign sources and global supply chains. An early executive order from the Biden White House supported “Buy American” policies by calling on federal agencies to contract for American-made products before purchasing imported goods. The government also has funded retrofitting of US biopharma facilities to boost domestic production of COVID-19 vaccines. While some experts consider added tax incentives and financial support key for encouraging more domestic biopharma production, other analysts note the value of geographic diversity in supply to reduce the risk of disruptions in any one place from hurricanes and other natural disasters.

Many of these issues are examined in a report for CDER from the National Academies of Sciences, Engineering and Medicine (NASEM) on strategies to modernize pharmaceutical manufacturing to ensure reliable access to high-quality drugs, particularly in response to disruptions caused by the pandemic (4). While the report identifies several important manufacturing innovations on the horizon, the expert panel recognizes that adopting new methods and systems is costly, especially for companies with already approved facilities.
A notable finding of the report is that drug regulatory policies pose a barrier to innovation, in that manufacturers looking to adopt continuous or other advanced manufacturing methods first must gain FDA review of any new technology, a process that can delay approval of a new drug application. And implementing new technology for a marketed drug involves submitting a post-approval changes application, an equally perilous and time-consuming oversight process. Varying regulatory expectations and policies among international health authorities, moreover, further complicate prospects for implementing new technologies for both new and established medicines.

The NASEM experts note that CDER has taken steps to foster manufacturing innovation with its Emerging Technology Program and Emerging Technology Team (ETT) to assist firms in evaluating and documenting new production approaches. But to provide more support and expertise to advance modern manufacturing, the panel advises FDA to clarify further what data are required in regulatory filings to demonstrate the identity, safety, purity, and potency of a drug produced with innovative technology. More consistency in evaluating residual risk to product quality from modern manufacturing methods, and greater harmonization in regulatory requirements across regions, is crucial for effective risk-benefit evaluation of new manufacturing methods.

1. S. Hahn, “Investing in Advanced Manufacturing to Support Public Health Preparedness,” 

 Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, 2020 Annual Report

, page 6 (CDER, February 2021).
3. The White House, “FACT SHEET: Securing America’s Critical Supply Chains,” Press Release, Feb. 24, 2021.
4. NASEM, 

Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations

 (National Academies Press, Washington, DC, 2021). 

Washington editor, jillwechsler7@gmail.com.

When referring to this article, please cite it as J. Wechsler, "Pandemic Highlights Need for Advanced Pharma Manufacturing," 

Expanded interest in advanced drug manufacturing and continuous production methods calls for more flexible production systems and regulatory policies.

Pandemic Highlights Need for Advanced Pharma Manufacturing

In the face of a growing clamor for greater worldwide access to COVID-19 vaccines, biopharma companies are promising to expand distribution of free and low-cost preventives to curb the pandemic globally. Efforts to promote “vaccine equity” and “dose sharing” also aim to limit challenges to international patent protections, as manufacturers maintain that calls to waive intellectual property (IP) rights for pandemic vaccines will stymie innovation and the development of new preventives against COVID variants and future disease outbreaks.

The issue has heated up as the Biden administration announced support for a waiver to IP protection for COVID-19 vaccines under the World Trade Organization (WTO), a move that surprised manufacturers as well as other industrial nations. European leaders at the recent G20 meeting in Rome instead backed voluntary and compulsory IP licensing agreements, technology transfers, and patent pooling arrangements to help low- and middle-income countries access and produce vaccines. The European Commission (EC) said it would seek to open global supply chains, expand vaccine production capacity, and end export bans on vital supplies, 

 EC president Ursula von der Leyen, as part of a program to promote voluntary licensing and knowledge transfer in the context of the TRIPS trade agreement. Along with setting these goals, manufacturers pledged to provide more than 1 billion vaccine doses from BioNTech/Pfizer, Johnson & Johnson, and Moderna at no- and low-profit rates to lower income countries.

Similarly, the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) announced programs to advance global vaccine equity based on projections that manufacturers will produce some 11 billion doses this year. The 

 supports greater dose sharing with other countries, more collaboration to increase vaccine output, eliminating trade barriers that block access to needed materials, and partnering with governments to assist low-income countries distribute available vaccine doses.

In addition to promoting expanded access to vaccines made in the US and Europe, policy makers look to advance biopharma production on a global basis. IFPMA eyes collaborations to increase access to needed supplies of raw materials and to maximize COVID-19 vaccine output without compromising safety and quality.

An initial step is to link vaccine output to available fill and finish operations, an initiative advanced by the COVAX Supply Chain and Manufacturing Task Force, recently formed by leading international health organizations to address current gaps in manufacturing inputs and to ultimately expand production of vaccines and therapies to combat future disease outbreaks. The task force includes IFPMA, the Biotechnology Innovation Organization (BIO), the Coalition for Epidemic Preparedness Innovations (CEPI), the World Health Organization (WHO), the GAVI vaccine alliance, the Bill & Melinda Gates Foundation, and other public health entities. Immediate goals involve coordinating supply chains to identify shortages in raw materials needed for vaccine production and facilitating voluntary technology transfers between manufacturing partners.

Looking to the future, the task force will work to expand vaccine manufacturing capacity in multiple regions by upgrading existing facilities, stimulating public-private investments in vaccine manufacturing innovations, and developing sustainable regional supply chains. The US recently provided $2 billion to support COVAX and additional funding in the near future. At the same time, the Biden administration’s promise of some 80 million vaccine doses for developing nations appeared highly inadequate.

By the time the WTO addresses biopharma IP issues more formally at its year-end ministerial meeting, manufacturers expect that expanded production and distribution of COVID-19 vaccines will be filling global vaccine needs more visibly. Industry has gained strong support for patent protections from Republicans on Capitol Hill, and the notable success of firms in developing and producing effective COVID vaccines in less than a year has heightened support for IP protections and their potential for further stimulating biopharma innovation. And the fact that the Chinese government expressed enthusiasm for patent waivers only heightens concerns about the impact of such a critical change.

In the face of a growing clamor for greater worldwide access to COVID-19 vaccines, biopharma companies are promising to expand distribution of free and low-cost preventives to curb the pandemic globally. 

Vaccine Makers Ramp Up Production, Donations to Protect IP

FDA recently published a final guidance for making post-approval manufacturing changes to drugs and biologics, the culmination of a long-running effort to facilitate improvements in medical product quality through the product life cycle. The Q12 standard crafted by members of the International Council for Harmonisation (ICH) aims to help manufacturers manage changes in chemistry, manufacturing, and controls (CMC) of marketed drugs and biologics, including generics and biosimilars and certain combination products, to encourage continual improvement in biopharmaceutical production.

The main premise of the Q12 standard is that increased product and process knowledge can enhance understanding of which postapproval changes have potential to affect product quality and carry risks for patients. Such changes would require regulatory approval prior to implementation. But manufacturers can reduce such oversight by managing CMC changes through a Pharmaceutical Quality System (PQS) that can identify and manage those Established Conditions (ECs) of a product that are essential to assuring quality and safe use.

Through such efforts, FDA officials and other regulatory authorities hope to provide “a more predictable and efficient approach to management of postapproval changes,” 

 Michael Kopcha, director of the Office of Pharmaceutical Quality in the Center for Drug Evaluation and Research (CDER) in announcing the final standard. Without regulatory harmonization on an international basis, manufacturers often find it too difficult and costly to make changes to approved products, even if the new method offers important product improvements and production efficiencies.

This international effort to gain agreement on policies for overseeing postapproval manufacturing changes builds on a long series of ICH quality manufacturing standards. Ashley Boam, director of CDER’s Office of Policy for Pharmaceutical Quality, 

 the history and main goals of Q12 at the FDA and Health Canada Regional ICH Consultation held on May 14, 2021 to update and discuss with stakeholders this and other leading ICH initiatives.

 maps out a process for manufacturers to identify those higher risk postapproval changes, as opposed to those that offer little risk of reducing product quality or safety. The guidance emphasizes the importance of manufacturers identifying key ECs to determine how they should be monitored and assessed. Changes that affect those ECs that are essential for safe product use, for delivery of the labeled dose, or that impact the drug’s critical quality attributes (CQAs) should be reported to regulatory authorities in preapproval or changes-being-effected filings. Conversely, those changes that do not alter product safety do not have to be approved prior to implementation and often require only notification of an authority in a later filing.

Manufacturers may be able to shift more changes to the notification category by devising a control strategy upfront for accomplishing later innovations. Q12 discusses the value of preparing post-approval change management protocols (PACMPs) and a product lifecycle management document early on to facilitate future improvements.

To further assist manufacturers in utilizing and benefiting from the Q12 process, FDA issued a 

 with Annexes that present illustrative examples of how drug and biotech manufacturers can identify ECs for manufacturing processes and for analytical procedures.

The value and impact of ICH Q12 will depend on its adoption and use by regulatory authorities around the world. Wide acceptance of a modernized change management process is key for manufacturers to be able to implement improvements to authorized products more quickly and efficiently, in order to encourage investment in modern manufacturing systems in multiple markets.

To this end, FDA and other regulatory authorities are devising and offering training for pharmaceutical reviewers and inspectors that helps them understand and utilize the Q12 process. An ICH Implementation Working Group is developing global training materials for regulatory authorities and working with PIC/S on training for inspectorates, Boam noted. Topics of the training modules include established conditions for various products, drug-device combination products, and change management protocols.

And manufacturers have gained additional advice on utilizing Q12 through another FDA guidance that maps out the new process. The 

 spells out the process for determining whether a planned change requires regulatory approval, with the aim of assisting manufacturers in anticipating data requirements and filing procedures in regions where the product has been approved for market.

The larger goal of this harmonized postapproval changes policy is to encourage manufacturers to adopt innovations in product quality and production. More effective management of changes ideally will help avoid supply disruptions and shortages arising from drug quality issues, increase efficient use of resources, and facilitate innovation in pharmaceutical manufacturing.

FDA recently published a final guidance for making post-approval manufacturing changes to drugs and biologics, the culmination of a long-running effort to facilitate improvements in medical product quality through the product life cycle. 