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

Jill Wechsler

FDA is poised to approve an Emergency Use Authorization (EUA) for the much-anticipated vaccine against COVID-19 developed by Pfizer and BioNTech following a strong vote of support today by FDA’s vaccine advisory committee. The unprecedented development of this preventive in less than a year, as well as a similar one from Moderna, which seeks an EUA next week, is an achievement that warrants applause for industry, regulatory authorities, and the biomedical research community. Hopes are high that these and additional vaccines will reduce disease and restore global health and economic recovery in the coming year. However, such success in combatting the pandemic depends on the ability of manufacturers to quickly and efficiently produce and distribute the huge quantities of vaccines demanded by the United States government and public health organizations around the world.

Concerns have been raised by difficulties Pfizer has had manufacturing and scaling up production for its novel RNA vaccine technology. Despite high efficacy rates documented in clinical trials, Pfizer quietly disclosed in a November press release that it would produce only 50 million doses this year, instead of the 100 million initially expected. Now, US officials say they expect 6.4 million doses from Pfizer and another 12.5 million doses from Moderna this year, if that company also gains an EUA. That will provide shots for only 10 million Americans initially, far less than needed to provide treatment for more than 17 million health care workers and nursing home residents in the top priority vaccination group. State health agencies, which are charged with determining where to send vaccines as they roll out, are struggling to adjust programs downward.

Pfizer officials indicated in press reports that manufacturing delays arose earlier this year as some early vaccine batches failed to meet standards and the company experienced difficulties obtaining raw materials and supplies ranging from sterile water and laboratory equipment to lipids, chemical components, and enzymes. While manufacturing and quality control issues were not on the agenda of the FDA vaccine advisory committee, agency staffers said they will continue to engage with Pfizer to ensure product quality over coming months. And to file for a biologics license application (BLA), which FDA expects Pfizer to do in the near future, the agency expects to see additional information on manufacturing facilities beyond what’s submitted in the EUA application.

Looking ahead, Operation Warp Speed (OWS) officials say they expect to receive enough additional vaccine from Pfizer and Moderna to reach the goal of inoculating 100 million Americans by the end of February 2021. Such coverage, though, relies on obtaining additional products from Johnson & Johnson and from Astra Zeneca, which expect to submit final clinical trial data by late January or early February 2021. As these products rely on more common vaccine production technology, they expect to produce large volumes more readily. OWS acknowledges it will need products from these and other firms to supplement its relatively small 100-million dose purchase from Pfizer, which now may be difficult to increase as other governments have ramped up vaccine orders.

At the same time, other countries are experiencing similar reductions in initial vaccine supplies. UK officials expected some 10 million doses from Pfizer this year, but now may get only five million. The European Union has purchased 200 million doses but may receive about 20 million from Pfizer-BioNTech manufacturing sites in Belgium and Germany once the Europeans approve the product. Canada’s initial supply from Pfizer is less than a million doses, far below its 75 million purchase.

The smaller volumes of initial US vaccine supplies leave state health agencies with much fewer doses than expected, complicating the development of local plans for allocation and administration. The medical community still smarts from the debacle earlier this year in procuring and distributing sufficient COVID-19 diagnostic tests and personal protective equipment (PPE) needed by health professionals. No one wants a repeated failure with vaccine distribution.

Despite disappointment with reduced vaccine supplies this year, the delay may provide some breathing room to test and adjust the nation’s planned, but untried, system for distributing millions of doses of innovative vaccines. The required sub-zero cold storage for the Pfizer-BioNTech product promises to be challenging, as seen in a recent run on dry ice supplies in many localities. Both the Pfizer and Moderna vaccines, and possibly some later ones, require two shots, which requires accurate documentation and patient tracking to ensure appropriate and timely vaccine resupply for second doses.

Although there is agreement among US federal health officials that initial vaccines should go to “essential” healthcare workers and to nursing homes, state health agencies have the task of identifying local distribution priorities and ensuring safe transport of vaccines from distribution hubs to local hospitals and health facilities. States also have authority to decide which groups are next in line following vaccination of those top priority populations. Some want vaccines early for police and fire fighters. There’s also a clamor to first treat highly vulnerable individuals, based on age and health status; groups at higher risk due to ethnicity and living conditions; or essential and frontline workers considered more vulnerable due to the nature of their jobs, such as teachers, truck drivers, food workers, and maintenance and cleaning crews. Most Americans won’t be eligible for vaccination until next spring, or later.

Just as important as getting the right number of doses to appropriate patients is for health systems to establish information systems able to track these actions and longer-term outcomes. It’s critical to obtain timely information on adverse events, response differences among patient groups, duration of immunity, and other impacts. Manufacturers are expected to monitor patients for two years to learn more about duration of immunity and side effects, while also relying on health system medical record systems to capture broader data on vaccine responses and coronavirus infection numbers.

Articles

Success in combatting the pandemic depends on the ability of manufacturers to quickly and efficiently produce and distribute the huge quantities of vaccines demanded by the United States government and public health organizations around the world. 

Vaccine Scale-up and Production Key to Combatting Pandemic

The imperative to prevent, treat, and cure the deadly COVID-19 virus has generated new research and manufacturing strategies, bolstered by unprecedented support from the federal government, private investors, and timely regulatory guidance and advice. Aware of intense pressure and great opportunity, industry moved quickly to identify compounds with potential to treat ill patients and to mitigate the virus’ lethal effects. The federal government poured billions into drug and vaccine development and production through its Operation Warp Speed (OWS) task force. At the same time, FDA struggled to meet often divergent and unclear requests and mandates from the White House and the Department of Health and Human Services (HHS), developments that have undermined public confidence in the agency’s independence.

FDA’s first crisis involved confusion over the development and approval of diagnostic tests for the COVID-19 pathogen, a situation that resulted in notable delays in public access to products able to reliably identify infected individuals. While FDA was not solely responsible for the situation, knowledgeable observers believe that more proactive leadership from the agency could have accelerated advances in this critical area.

The agency’s new commissioner, Stephen Hahn became further entangled in administration efforts to promote certain unproven COVID-19 therapies and to demand that FDA issue Emergency Use Authorizations (EUAs) for potentially harmful treatments. Hahn’s initial support for such authorization alienated agency staffers and medical authorities alike and raised concerns about the agency’s ability to fully test and vet promising vaccines and other critical therapies.

These issues came to a head in October as vaccine experts within FDA and from leading medical institutions emphasized the importance of obtaining sufficient safety and efficacy data on any vaccine prior to approving it for administration to millions of individuals. This approach was considered critical to offset growing public “vaccine hesitancy” arising from fears that companies and regulators were taking shortcuts to speed the development of COVID-19 vaccines for political purposes. Vaccine manufacturers supported the call for adequate test data to obtain results that could generate public support in the coming months.

The accelerated development of several COVID-19 vaccines highlighted the critical role of FDA’s Center for Biologics Evaluation and Research (CBER). In May 2020, CBER Director Peter Marks opted to remain at FDA instead of shifting over to the administration’s OWS task force, as did Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), who moved temporarily to lead OWS therapy development efforts. Under Marks’ leadership, CBER issued critical guidance in June clarifying the requirements for developing and testing new vaccines to protect against COVID-19 infection, with an emphasis on the need for large, randomized, placebo-based clinical trials to provide adequate safety and efficacy data, as well as upfront manufacturing information (1). Further guidance in October specified similar approaches for gaining FDA EUA for a new vaccine (2).

Many of these clinical development programs benefited from OWS funding, as did early production of large quantities of test vaccines—a marked change from the usual practice of delaying investment in scale-up and production until clinical testing showed results. The aim was to provide sufficient quantities of any preventive as soon as testing demonstrated an immune response. FDA guidance emphasized the need for early chemistry, manufacturing, and controls (CMC) data, while providing leeway in batch stability records (1). Vaccine sponsors signed up contract manufacturers and other firms to be prepared for fast scale-up when authorized. OWS also supported added production of glass vials and injectors critical for vaccinating hundreds of millions of individuals.

While shifting many staffers to operations involved in COVID-19 product development and review, FDA also worked overtime to maintain support and approval of new therapies for the usual broad spectrum of serious medical conditions. Innovative biomedical R&D faced added challenges from delays in many new and ongoing clinical trials due to pandemic complications. Moreover, FDA had to cancel regulatory inspections, particularly those involving foreign firms. Instead, the agency looked to evaluate the quality status of an operation producing a new drug or vaccine through greater reliance on compliance history, production records, analysis of actual products, and inspection reports from other trusted regulatory authorities.

Supply chain security for drugs and medical products emerged as a critical issue, as the global pandemic raised fears about reliable access to medicines and their components produced overseas. Shortages in certain vital therapies for treating hospitalized patients, including antibiotics and sedatives, prompted FDA to bolster efforts to detect pending shortages in advance and to support alternative production activities, including broader drug compounding and the administration’s “buy American” campaign to expand production of drugs and medical products in the United States. These developments highlighted the importance of manufacturers’ ability to establish modern, more reliable pharmaceutical manufacturing operations able to maintain high quality, reliable production with well-documented internal oversight.

The pandemic slowed but did not derail a range of FDA initiatives designed to improve the regulatory process. CDER finalized the overhaul of its Office of New Drugs, with an expanded number of offices and divisions implementing a new team-based “integrated review” approach for assessing new drug applications.

In addition to focusing on vaccine development, CBER’s Office of Tissues and Advanced Therapies (OTAT) continued to experience a surge in proposals for developing new cellular and gene therapies and regenerative medicines. Hundreds of investigational new drug applications flooded OTAT, many raising challenging and unique medical and technical issues, including concerns about ensuring product quality, purity, and strength. In expediting development programs, FDA focused on clarifying strategies for product characterization, process validation, scale-up, and ensuring stability.

FDA has approved more than 40 innovative medicines this past year and worked hard to meet user fee time frames for prescription drugs, generics, and biosimilars. Those numbers may drop in the coming months, as sponsors face continued difficulties in launching new clinical trials and in documenting quality manufacturing operations. With the coronavirus again surging across the nation and the world as this historic year draws to a close, the only certainty is that both obstacles and opportunities will continue to challenge biopharmaceutical companies, regulatory authorities, and the research community in the months ahead.

Development and Licensure of Vaccines to Prevent COVID-19, Guidance for Industry

 Emergency Use Authorization for Vaccines to Prevent COVID-19 Guidance for Industry 

Washington editor, jillwechsler7@gmail.com.


Vol. 44, No. 12
December 2020
Pages: 14–15

When referring to this article, please cite it as J. Wechsler, "Pandemic Brings Major Changes to FDA and Drug Development in 2020," 

Manufacturers and regulators accelerate R&D and production of new vaccines and therapies. 

Pandemic Brings Major Changes to FDA and Drug Development in 2020

In unveiling a set of drug price control measures last week, the president displayed his bitterness that vaccine makers failed to announce their success in achieving high efficacy rates for new preventives before the Nov. 3 election. Instead of focusing on his administration’s remarkable achievement in financing and supporting record-breaking development of critical vaccines to combat COVID-19, President Trump lashed out at Pfizer for conspiring to delay the good news on its vaccine as part of a conspiracy to block his re-election.

The administration took on Big Pharma in issuing a new final interim rule Nov. 20, 2020 to establish a 

that caps Medicare Part B drug reimbursement for 50 selected medicines at the lowest price paid by any developed country. The policy applies to Medicare Part B drugs, which are administered in doctors’ offices and hospitals and include many costly biotech therapies that require intravenous administration. Although the proposal predicts notable savings for taxpayers, analysts say it is more likely to cut reimbursement for doctors and hospitals. That drew 

 from the American Hospital Association, as well as the Pharmaceutical Research and Manufacturers of America (PhRMA). The most visible savings would go to Medicare, as the rule technically implements a process for testing a new payment method for a federal healthcare program.

The White House also announced that it plans to eliminate drug company rebates to pharmacy benefit managers (PBMs) and insurance companies for Medicare Part D drugs. The idea is to shift those savings to consumers, although a review of an earlier version of this change found that it would raise premiums paid by seniors for Medicare drug coverage and that any savings would go to the government, and not to consumers. A rule to implement this change is under review by the Office of Management & Budget. While manufacturers have applauded curbs on rebates, PBMs and payers are furious and 

third proposal revises federal anti-kickback rules

 on business relationships between doctors and other parties, including biopharma. The changes aim to support a shift toward value-based reimbursement for medical services and products, including drugs. The proposal may clarify policies for when drug company fees to health professionals are appropriate, such as for consulting or participating in speaker programs, or for offering discount cards to cover patient co-pays for certain medicines.

It’s unusual for any administration to release significant new policies so close to the end of a presidential term. The MFN pricing rule was published with just the required 60 days needed to finalize it before Inauguration Day on Jan. 20, 2021. Although Democrats generally support drug pricing limits, it’s not clear how the Biden administration and Congress will respond to the last-minute Trump proposals. In any case, PhRMA says it will consider “all options to stop this unlawful onslaught on medical progress,” and is expected to file suit against the MFN policy.

The Trump administration unveiled a new drug price control policy, drawing opposition from pharma manufacturers and pharmacy benefit managers.

Trump’s Revenge on Pharma

President-elect Joe Biden hit the ground running this week with initiatives to combat the widening coronavirus pandemic. The first public 

from the Biden-Harris transition team was to name members of a COVID-19 advisory board charged with initiating policies and actions to combat the fast-rising infection rate in the United States

The 13-member panel includes well-known scientists, physicians, and public health experts. Former FDA Commissioner David Kessler is one of three co-chairs, in addition to former Surgeon General Vivek Murthy and Yale University public health professor Marcella Nunez-Smith. The task force also includes former Director of the Biomedical Advanced Research and Development Agency (BARDA) Rick Bright, former FDA official and national security advisor Luciana Borio, health policy advisors Ezekiel Emanuel and Atul Gawande, and infectious disease experts Eric Goosby and Michael Osterholm. The group has the task of advising the incoming Biden administration on initial public actions and communications related to the pandemic. It will consult with state and local officials on public health and economic steps to get the virus under control, along with ways to provide relief to families and to reopen schools and businesses safely.

In addition, the incoming Biden administration has formed a special coronavirus transition team to lay the groundwork for responding to the pandemic before and immediately after the official inauguration of the new president in January. This much larger task force includes transition officials from several federal agencies involved in dealing with COVID-19. This team of more than 50 federal officials is headed by a central coordinating group to oversee activities related to domestic programs, national security and foreign policy issues, and technical and legal policies. One aim is to set priorities for gathering information from the Departments of Health and Human Services (HHS), Homeland Security, and State, among others, once the Biden transition team gains access to federal agency data and resources—normal and expected actions still being delayed by the Trump White House.

Initially, the Biden transition team has indicated it plans to work with and maintain operations of the current administration’s Operation Warp Speed (OWS), which has overseen and funded the production of promising COVID-19 vaccines and is in the midst of planning the logistics for a complex vaccine distribution process as data emerges on safe and effective preventives. Biden advisors have discussed revising the OWS name to reduce any public perception that it is emphasizing speed over safety, as part of efforts to rebuild confidence and acceptance of vaccines and therapies that gain FDA approval in the coming weeks.

is expected to build on campaign documents that highlighted the importance of slowing community spread of the virus through greatly increased COVID-19 testing, expanding the nation’s cadre of public health workers, ensuring access to health insurance, and providing states with funds and resources to distribute vaccines and therapies effectively and equitably. To combat continuing charges from the Trump White House that politics has motivated recent vaccine clinical trial efficacy announcements, Biden emphasizes the need to “put scientists in charge of all decisions on safety and efficacy,” to publicly release clinical data on any FDA-approved vaccines, and to have FDA career staff report publicly on questions related to product approvals.

Meanwhile, speculation continues over who the President-elect will name to lead HHS and other health agencies—senior roles that usually are lower priorities for new administrations but now are considered critical for the nation to combat the pandemic and restore economic health. Through his campaign, Biden consulted with a wide circle of former Obama administration public health leaders, generating much speculation about who now will play leading roles. Normally, new administrations announce main Cabinet officials first before filling out the numerous agency office directors. But in the current climate, new leaders for FDA and the Centers for Disease Controls and Prevention may come sooner.

The first public announcement from the Biden-Harris transition team was to name members of a COVID-19 advisory board charged with initiating policies and actions to combat the fast-rising infection rate in the United States 

Tackling COVID Top Priority for New Administration 

As part of the administration’s campaign to reduce the United States’ reliance on an increasingly global pharmaceutical supply chain and to minimize potential shortages for critical drugs, FDA has

 published a list of those drugs and medical products c

onsidered critical for addressing public health emergencies. The list will provide a basis for bolstering biopharmaceutical production at home of essential medicines and medical products and for addressing supply chain vulnerabilities

The White House launched this process with an 

ssued August 6, 2020 instructing FDA to develop the essential medicines list in 30 days

]. The resulting list includes 233 drug and biological products and APIs for treatments able to protect against emerging infectious diseases plus chemical, biological, radiological, and nuclear threats. An 

 covers 96 important medical devices such as diagnostic testing kits, personal protective equipment, monitoring devices, ventilators, and items for vaccine delivery

. The listed products are identified as those most needed for treating patients in acute care medical facilities and for responding to future pandemics and biomedical threats.

To bolster purchases of US-made drugs, the program also calls for federal agencies that fund healthcare programs to favor domestic sources in purchasing essential medicines. FDA is coordinating government-wide efforts to acquire listed products, identify supply chain vulnerabilities for these products, and to support advanced manufacturing and innovative technologies likely to bolster the competitiveness of US-based manufacturing compared to foreign countries. The August executive order also calls for FDA to accelerate the approved of US-made essential medicines and to refuse entry into the US of products from foreign plants that have blocked FDA inspections. Moreover, the administration looks to streamline environmental and other regulations likely to curb domestic biopharma production.

 from manufacturers and other stakeholders on the criteria it used to develop the essential medicines list, on additional medicines and products to include on the list, and on how often the list should be reevaluated. It’s general criteria for listing essential medicines includes both acute-care treatments and those needed for longer-term health management, with a preference for dosage forms most commonly needed in acute care facilities [see 

 ]. Where multiple drugs might be available, FDA looks for treatments for the widest population, for multiple conditions, and those with unique safety profiles.

Concerns that ongoing vulnerabilities in the US medical supply chain may compromise public access to essential medicines continues to draw attention on Capitol Hill, generating calls for legislative action after the elections. Members of Congress from both parties support a range of initiatives to reduce US dependence on foreign manufacturers, including a $500 million pilot program to support domestic production of medical products. At a recent program on ensuring a “responsive Rx supply chain,” Rep. Elissa Slotkin (D-Mich) discussed a package of bills supporting Buy American requirements for medical supplies and pharmaceuticals. Similarly, Rep. Buddy Carter (R-Ga) cited how the COVID-19 crisis has 

the nation’s dependence on outsourced goods and the need for legislation to support US production of APIs, drugs, and excipients

The legislators cited over-dependence on China for protective equipment and other medical supplies and fears that manufacturers in foreign countries will look to supply their own market before supporting exports to the US. Rep. Carter wants to build state medical product stockpiles to reduce dependency on national stockpiles and to provide sufficient support to attractive private biopharma companies back to the US.

As part of the administration’s campaign to reduce the United States’ reliance on an increasingly global pharmaceutical supply chain and to minimize potential shortages for critical drugs, FDA has published a list of those drugs and medical products considered critical for addressing public health emergencies. 

FDA Identifies “Essential Medicines” for US 

The much-anticipated meeting of FDA’s vaccine advisory committee this week is slated to address a number of critical issues related to testing and approval of vaccines to prevent COVID-19 infection. Although the Vaccines and Related Biological Products Advisory Committee (VRBPAC) will not review an application for any particular product, this panel of virologists and scientists 

will discuss policies and data requirements

 for determining that a pandemic vaccine can be considered safe and effective, particularly when based on more limited, early clinical trial data

Shaping the discussion is the current halt in two major vaccine trials due to unspecified safety issues. US investigators continue to seek more information on patient illness in the AstraZeneca vaccine study announced in early September, although enrollment has restarted for AZ trials in the United Kingdom and other countries. Johnson & Johnson more recently paused its massive COVID-19 vaccine trial due to an “unexplained illness” in a patient. The safety committee for the study has stated by examining whether the ill individual received the vaccine or was in the placebo arm. The sponsors emphasize that these research halts demonstrate their excessive caution and importance of calling on outside monitoring boards to fully investigate such cases.

FDA standards for documenting vaccine safety is an important topic for VRBPAC review, particularly as it relates to granting Emergency Use Authorization (EUA) to an experimental vaccine, an approach that agency officials consider likely and appropriate given the high costs of the pandemic in terms of public health risks and economic hardship. The Center for Biologics Evaluation and Research (CBER) specified in its recent 

 that it expects an EUA application to provide two months or more of safety data for at least half of the participants in a trial following completion of the full vaccination regimen

 . As most serious side effects appear within six weeks of individual vaccination, this timeframe is designed to provide a sufficient period for detecting events such as vaccine-induced enhanced respiratory disease and to distinguish such conditions from coronavirus disease.

A particularly challenging issue for the advisors is the how granting EUA status to an initial product could interfere with further assessment of the vaccine’s safety and with ongoing trials for other preventives. FDA says that the sponsor of an authorized vaccine should continue blinded follow-up assessments for months following an initial distribution, but there some authorities believe that an EUA sponsor should shift all participants in the placebo arm to receive treatment. While that might appear a more ethical decision, it could block efforts to gain further information on vaccine efficacy and side effects, including rare adverse events and fuller comparisons among patient groups with differences in age, sex, comorbidities, and ethnic characteristics. And because of limited information about how long immunity will last from initial vaccines, both manufacturers and regulators look for additional guidance on determining what data need to be collected further to indicate when boosters or additional vaccination would be advisable.

Most analysts expect that some vaccines likely to gain approval in subsequent months may be more effective or provide stronger protection than the early products. However, continued development of alternative vaccines may be hindered by difficulties in enrolling new subjects in randomized trials when a vaccine is on the market. Scientists and vaccine developers emphasize that it’s vital for research to continue on multiple preventives, as certain products may affect certain populations differently, and varying formulations may be more suitable for distribution in certain regions.

These issues raise important ethical considerations for the research community and health authorities. While randomized, placebo-controlled clinical trials are necessary to understand the true effects of a medical product on larger populations, individual participants may gain limited benefit and added risk. And in the face of a lethal pandemic, the risks are even more stark. An alternative research approach may be to use a newly authorized vaccine as a control in testing subsequent preventives, a form of noninferiority trial. Such studies may take much longer and cost more to produce results but could reduce the need for large placebo control arms that deny treatment for thousands.

The much-anticipated meeting of FDA’s vaccine advisory committee this week is slated to address a number of critical issues related to testing and approval of vaccines to prevent COVID-19 infection. 