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

Jill Wechsler

As public health authorities, patients, and manufacturers applaud the fast development and production of billions of doses of innovative vaccines against COVID-19, the campaign continues to extend global access to the life-saving preventives. The “America first” vaccination and treatment policy of the United States through the initial 18 months of the outbreak generated loud criticism from international health organizations and patient advocates. The emergence of the omicron variant, moreover, has demonstrated clearly the global nature of the pandemic and the critical importance of expanded vaccination in Africa and other regions to control COVID-19 in all regions.

Global vaccine access concerns came to a head in the US in the fall of 2021 when FDA authorized booster doses of vaccines from Pfizer-BioNTech, Moderna, and Johnson & Johnson while most of the world still awaited initial protection. Marion Gruber, the head of the Office of Vaccine Research and Review in the Center for Biologics Evaluation and Research (CBER), and her deputy, resigned in protest. Gruber recently joined IAVI, an international organization that advances the development and distribution of innovative vaccines and therapeutics.

Prospects have brightened for broader access to COVID-19 vaccines as production has soared to more than 11 billion doses in 2021, supporting predictions for doubling that amount by mid-2022. The COVAX vaccine sharing initiative recently announced that in 2021 it shipped more than 1 billion doses to 144 countries and territories—a noteworthy achievement, but still far short of the 2-billion-plus vaccine goal set earlier last year. Manufacturing difficulties in the US, European Union, and India prompted curbs on vaccine exports, while several vaccine candidates from other manufacturers failed to gain regulatory approval from FDA and the European Medicines Agency. These setbacks limited efforts by COVAX, the Gavi Alliance, and the Coalition for Epidemic Preparedness Innovations (CEPI) to obtain and distribute needed preventives.

Vaccine supplies for poorer regions have improved with expanded vaccine production in India and other nations and the development of new vaccine formulations with extended shelf-lives and reduced deep-freeze requirements that facilitate distribution. A report from Medecins Sans Frontieres identifies 120 biopharma manufacturers in third-world countries capable of producing mRNA-based vaccines, findings based on evidence that firms able to make sterile injectables can produce mRNA treatments (1). Established drug makers in Africa, Asia, and South America are collaborating with researchers to develop and test additional COVID-19 vaccines, a process that could be facilitated by licensing agreements to make existing mRNA formulations by Moderna and Pfizer-BioNTech that have been slow to appear.

Meanwhile, BioNTech has unveiled plans to build a modern facility in Rwanda to utilize messenger RNA (mRNA) technology to develop new preventives against malaria, tuberculosis, and other diseases (2). And Moderna says it will fund an mRNA vaccine facility in Africa, possibly at sites in Senegal, Rwanda, or South Africa (3).

Gavi now aims to raise $5 billion from the US and other industrial nations and international organizations to boost vaccine access and bring the pandemic under control (4). Global vaccine supplies may expand, moreover, as several biopharma companies that fell behind on testing and producing COVID-19
vaccines are moving toward regulatory approval. Novavax recently filed data to support FDA Emergency Use Authorization (EUA) of a vaccine that utilizes more conventional recombinant technology and recently gained conditional marketing authorization in the European Union, Indonesia, the Philippines, and Australia (5). Similarly, the German biotech CureVac has linked up with GlaxoSmithKline to test a second-generation mRNA vaccine candidate, with plans to launch Phase I studies in 2022.

A notable new entry is the Corbevax COVID vaccine, which has been licensed by a research team at the Baylor College of Medicine in Houston to Biological E in India for production of a low-cost preventive for lower- and middle-income countries (6). Indian regulators have approved emergency use of the shot, but scale-up and production present notable challenges.

As FDA and vaccine makers examine the need to update COVID-19 vaccines to better attack omicron and other variants, a consensus has emerged on the importance of international collaboration among regulatory authorities to ensure the effectiveness of revised preventives under different mix-and-match treatment scenarios. The World Health Organization and regulatory authorities are examining what evidence is needed to determine that a revised vaccine works well against current and potential variants, with an eye to avoiding widely differing booster options. Such collaboration will be even more important if annual COVID booster shots become the norm.

Pharmaceutical Firms Across Asia, Africa, and Latin America with Potential to Manufacture mRNA Vaccines,

BioNTech, “BioNTech Plans to Initiate the Construction of an mRNA Vaccine Manufacturing Facility in Africa in mid-2022,” Press Release, Oct. 26, 2021.

Moderna, “Moderna to Build State-Of-The-Art Mrna Facility In Africa to Manufacture Up to 500 Million Doses Per Year,” Press Release, Oct. 7, 2021.

World Leaders Launch Call for Renewed Support for Vaccination

in 2022 as Part of the Global Fight Against COVID-19,”

Novavax, “Novavax Submits Final Data Packages to US FDA as
Prerequisite for Emergency Use Authorization Application Request for COVID-19 Vaccine,” Press Release, Dec. 31, 2021.

P. J. Hotez and M.E. Bottazzi, “A COVID Vaccine for All, ScientificAmerican.com, Dec. 30, 2021.


Volume 46, Number 2
February 2022
Page: 14–15

When referring to this article, please cite it as J. Wechsler, “Global Vaccine Access Challenges FDA and Industry” 

Articles

The global nature of the COVID-19 pandemic emphasizes the critical importance of expanded vaccination.

Global Vaccine Access Challenges FDA and Industry

Senate leaders are developing a broad legislative package to enhance the government’s ability to prevent and respond to future public health emergencies, with an emphasis on securing supply chains, expanding health data collection, and supporting access to vital medical products. A preliminary discussion 

 was released last week by the Senate Health, Education, Labor & Pensions (HELP) Committee to gain input and support from the multiple parties affected by its provisions 

A main focus of the bi-partisan legislation, jointly issued by committee chair Patty Murray (D-Wash) and ranking member Richard Burr (R-NC), is to clarify responsibilities for the multiple federal agencies involved in health care and national preparedness, including FDA. Lead provisions would enhance the authority of the Centers for Disease Control & Prevention (CDC), while also extending Congressional oversight by requiring Senate confirmation of the CDC director. There 

are measures that set new research and operational requirements 

for the National Institutes of Health (NIH) and the Biomedical Advanced Research and Development Authority (BARDA) in the Department of Health and Human Services (HHS). Many of the provisions that apply specifically to FDA are not new but would clarify and extend existing authorities.

While BARDA would collaborate with NIH and CDC in establishing research centers to advance the discovery and early development of priority medical products and countermeasures, FDA would support such efforts with added guidances and policies for expediting countermeasure development and review. These initiatives would aim to modernize and improve clinical research and further harmonize with foreign regulators by advancing the use of digital technologies, decentralized clinical trial methods, real-world data and evidence, and R&D platform technologies. FDA would report on these programs and on the agency’s ability to hire, recruit, and retain needed experts to carry out its many assignments. A noted provision calls for expedited FDA review of new drugs and biologics to treat certain infectious diseases, building on legislation enacted in 2012 that provided an additional five years of market exclusivity to sponsors of new antibiotics and antifungals.

Under the heading of “mitigating shortages,” FDA would ensure the registration and oversight of all foreign establishments that produce drugs or devices marketed in the United States, including product components. There’s a proposal to test unannounced FDA inspections of foreign drug facilities, even though that approach has proven impractical and difficult for the agency to carry out. An advanced manufacturing pilot program further bolsters FDA support for novel drug production systems over the next five years.

To enhance the development and availability of medical devices and diagnostics, FDA would gain more explicit authority to crack down on counterfeit products and to require early notification from device makers of anticipated supply shortages. Additional guidance would accelerate the development of 

 diagnostic tests for health emergency use and clarify FDA’s ability to request records from device manufacturers when needed to conduct remote inspections.

Another initiative to enhance the nation’s ability to quickly detect and respond to emerging pathogens calls on BARDA to fund “warm-base” manufacturing surge capacity able to rapidly develop needed medical countermeasures—facilities that FDA would monitor to ensure they are well-maintained and meet good manufacturing practices (GMP) standards. Several provisions would expand and secure the Strategic National Stockpile (SNS), assess supply chain vulnerabilities, invest in innovative medical countermeasures, and regularly review surge capacity and supply chain flexibility for SNS supplies.

The public release of this broad legislative proposal in January 2022 sets the stage for including some provisions in the delayed 2022 budget bill that faces a February18 deadline for enactment. The White House also is working with Congress to gain agreement on a pared-down version of the Build Back Better Act, which could advance certain measures for examining the nation’s pandemic response to date and strategies for enhancing preparedness for the future. Such a package could also authorize billion-dollar investments in R&D and production of cutting-edge technology to bolster US production of semiconductors and other high-tech equipment, where supply chain disruptions have stymied domestic manufacturing in vital industries. Provisions more specific to FDA may be included in legislation to reauthorize FDA user fee programs that Congress is slated to consider later this year.

The draft PREVENT Pandemic Act aims to secure supply chains, expand health data collection, and support access to vital medical products

Pandemic Preparedness Legislation Bolsters FDA Oversight

Delays in sponsors providing postapproval evidence of effectiveness for therapies benefitting from streamlined FDA regulatory pathways, along with high launch prices on many of these quasi-experimental medicines, are generating pressure for further review and reform of the agency’s accelerated approval (AA) process. FDA reports that only about half of AA products have completed research to confirm benefits, including many leading oncology treatments carrying “dangling” indications. The agency’s approval of Biogen’s Aduhelm Alzheimer’s treatment last year based on questionable surrogate endpoint data, moreover, has heightened calls among legislators and researchers for tightening study timeframes and clarifying program requirements.

Deliberations by FDA’s Oncologic Drugs Advisory Committee (ODAC) accelerated the debate with its April 2021 meeting to assess the lack of confirmatory evidence for added uses of several leading cancer therapies. Since then, members of Congress, officials at FDA and other federal health agencies, sponsors, and research organizations have weighed in on both the benefits in facilitating early patient access to effective treatments, along with the need to reform the process and timeframes for fully evaluating early evidence of effectiveness. Since then, several biopharma companies have withdrawn certain uses for therapies unable to provide that confirmatory data. Most recently, 

 pulled two indications for the cancer drug Zydelig, acknowledging difficulties in providing evidence to support those uses since approval in 2014.

Now AA revision tops FDA policy reform lists. While sponsors often experience difficulties enrolling patients in clinical trials once a therapy is available on the market, weak FDA penalties for delay, as well as incentives for a firm to provide an approved therapy for as long as possible, contribute to perennial delays in submitting follow-on results. The need for better systems to generate reliable information on medical product safety and effectiveness was cited as a top priority by Robert Califf at his Senate confirmation hearing in December 2021, and he is expected to tap his expertise on providing timely and valid clinical research data in addressing these issues. The discussion is slated to involve appropriate use of real-world data (RWD) to support postapproval studies, as well as requirements for sponsors to design and launch confirmatory trials at the time of application approval, an approach that has become a regular discussion point in FDA-sponsor preapproval meetings.

Also up for debate are proposals to penalize sponsors for excessive delay in launching and conducting these studies and for the Centers for Medicare and Medicaid Services (CMS) to limit Medicare reimbursement of a drug until the manufacturer confirms early indications. While such requirements raise concerns about discouraging investment in innovative R&D, additional public-private collaborations could expand the infrastructure and lower the cost of conducting post-approval studies. And wider acceptance of RWD in confirmatory studies would be particularly helpful for small biotech companies that lack resources to prepare for or conduct post-approval studies before gaining initial market approval. These and other issues were discussed by Califf and others at a 

 organized by the UCSF-Stanford Center of Excellence in Regulatory Science and Innovation (CERSI) .

The current debate builds on considerable discussion of the AA program in recent years. Richard Pazdur, director of FDA’s Oncology Center of Excellence (OCE), has provided strong support for breakthrough and other accelerated development and review programs for cancer drugs, along with proposals for improvement: 

seeks better compliance with post-marketing requirements for oncology therapies benefitting from accelerated programs. A 

 from the Institute for Clinical and Economic Review (ICER) in April 2021 presents proposals for revising and strengthening the AA process. And a broader reform proposal prepared in 2020 by the 

set the stage for identifying ways to maintain early access by addressing AA concerns.

Additional information on FDA’s accelerated approval process is available at 

https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/accelerated-approval

. And there’s a useful summary of the agency’s four similar, but different, programs to facilitate patient access to new medicines at 

https://www.fda.gov/patients/learn-about-drug-and-device-approvals/fast-track-breakthrough-therapy-accelerated-approval-priority-review

Delays in sponsors providing postapproval evidence of effectiveness for therapies benefitting from streamlined FDA regulatory pathways are generating pressure for further review and reform of the agency’s accelerated approval  process. 

Concerns Mount over Limited Evidence for Accelerated Approvals

In a highly unusual decision for a therapy approved by FDA, the Centers for Medicare and Medicaid Services (CMS) 

 of Biogen’s new and controversial Alzheimer’s treatment Aduhelm (aducanumab). The CMS National Coverage Determination (NCD) did this by 

applying its Coverage with Evidence Development (CED) requirement to the drug

, utilizing a process that has been directed primarily in recent years to a limited number of approved medical products, mainly medical devices and diagnostics. If the proposal is finalized, only patients able to enroll in postapproval trials would have access to the drug.

The aim of the NCD process is to gather further evidence to demonstrate the drug’s potential for improving the health of patients suffering mild cognitive impairment due to Alzheimer’s disease. The CMS policy will authorize access to the drug only to those individuals able to enroll in a clinical trial, most taking place at academic research institutes that CMS will identify and list on its website. Under the accelerated approval granted Aduhelm by FDA’s Center for Drug Evaluation and Research (CDER) in June 2021, Biogen is required to conduct at least one Phase IV trial to demonstrate that the drug’s ability to reduce amyloid in the brain has a broader benefit for patients’ cognitive ability, and that the drug’s serious side effects are limited. Biogen objected loudly to the CMS proposal, noting that it may take years to design and launch postapproval studies, and that such trials will enroll only a limited number of patients. CMS also indicates that its CED requirement will apply to additional monoclonal antibodies targeting amyloid beta in Alzheimer’s disease.

Aduhelm came to market last year amidst heightened controversy over its approval despite limited evidence of efficacy. The debate turned to outrage when Biogen set the price for the new treatment at $56,000 a year. At that level, Medicare spending on the drug was projected to far exceed any other drug if even just a small portion of some 6 million US Alzheimer’s patients sought treatment. In December 2021, after a year of dismal uptake of the drug, Biogen cut its launch price in half to $28,200 a year in an effort to boost prescribing—and avoid a negative NCD from CMS. However, even that reduced cost continued to promise hefty outlays for Medicare. Many leading health centers and physicians said they still would not prescribe the drug due to its limited evidence of efficacy, known side effects and continued too-high cost. The Institute for Clinical and Economic Review (ICER) calculated that Aduhelm would be cost-effective if priced at $3000 to $8000 a year.

In making national coverage decisions, CMS is supposed to evaluate whether a medical product or process is “reasonable and necessary” and not bring cost into the equation. But the fact that a very high number of Medicare patients are potential users of the new drug made that difficult.Before Biogen cut its price, CMS had announced a whopping 15% boost in premiums for the Medicare Part B program, which administers injectables such as Aduhelm. CMS had explained that about half of the premium increase was designed to protect the program against high spending on the new Alzheimer’s therapy. Following Biogen’s cost reduction, Health & Human Services (HHS) secretary Xavier Becerra 

said CMS would reassess the scope of the premium hike

, although the uncertain financial health of the Medicare Trust Fund may deter any significant readjustment in rates.

CMS emphasizes that its CED decision arises from extensive review over the past six months of all relevant published evidence and feedback from stakeholders. The agency opted for the CED process to gain further evidence on whether this new therapy provides any improvement or relief from the effects of Alzheimer’s disease. CMS will accept further public comments on this proposal for 30 days and announce a final coverage decision by April 11, 2022. Alzheimer’s disease groups have called loudly for Medicare coverage of Aduhelm as the only available treatment for the widespread debilitating condition.

It will be interesting to see how the CMS proposal affects other biopharma companies that are testing their own Alzheimer’s therapies. Eli Lilly is conducting clinical trials that directly compare its donanemab to Aduhelm, while Eisai and Roche are moving forward with additional treatments. These and other sponsors now will have to calculate the impact of bringing new drugs to market that would be subject to CED requirements.

Meanwhile, the scientific and medical community continues to criticize the Aduhelm approval. The European Medicines Agency (EMA) recently recommended against approving the drug, and objections have been raised in Canada to a pending review. CMS has navigated its process to greatly limit Aduhelm prescribing and its outlays for the drug, but the debate is far from over.

The Centers for Medicare and Medicaid Services took action to limit prescribing and use of Biogen’s new and controversial Alzheimer’s treatment Aduhelm (aducanumab).

Medicare Limits Aduhelm Coverage to Patients in Clinical Trials

Despite major challenges and demands created by the coronavirus pandemic, FDA maintained a steady pace in 2021 in approving important new therapies for market, including new vaccines and treatments for COVID-19. Last year saw the Center for Drug Evaluation and Research (CDER) approve 50 new molecular entities (NMEs), many benefitting from priority and accelerated review timelines. In addition, the Center for Biologics Evaluation and Research (CBER) approved several vaccines and cellular products to further expand the new medicines list.

The CDER total is slightly less than the 53 novel drugs brought to market in 2020 and the 2018 record total of 59 innovative therapies. As in recent years, 

a majority of the new products received orphan drug status, and 15 had indications to treat cancer

. More than half moved forward through expedited procedures, 14 benefitting from accelerated approvals and 32 granted priority reviews. Continued requests for faster vetting requires additional involvement of CDER experts to provide R&D advice and to meet tighter deadlines, which agency officials say cannot be sustained without additional review staff and resources.

CBER approved 10 biologics license applications

 (BLAs), notably one granting full approval for Pfizer-BioNTech’s Comirnaty vaccine. Some analysts include only about half of these in combined lists of FDA’s new NMEs, notably new vaccines for Hepatitis B and for tick-borne encephalitis and therapies for myeloma and lymphoma.

Probably the most discussed new drug is Biogen’s Aduhelm for Alzheimer’s disease, which CDER okayed for market despite limited evidence of its efficacy and a thumbs-down on approval from its advisory committee. FDA reviewers, however, decided its benefits outweighed risks, as no other treatment is approved for this very serious condition.

Other notable new therapies from CDER include treatments for myasthenia gravis, lupus, Pompe disease, severe asthma, sickle cell disease, to prevent dwarfism in children, and to manage very high cholesterol. Lung cancer, endometrial cancer, and leukemia gained added treatment options, as did transplant patients.

The lists, moreover, do not include those innovative COVID-19 therapies and vaccines granted Emergency Use Authorizations (EUAs). In December 2021, FDA authorized two notable oral medications to treat early COVID-19 infections—Pfizer’s Paxlovid and Molnupiravir from Merck and Ridgeback Biotherapeutics—providing a more accessible alternative to antivirals that require infusion in a clinic or doctors’ office.

Analysts note that several additional new products failed to gain approval in 2021 due to FDA’s inability to conduct necessary inspections of certain manufacturing sites. That situation is unlikely to change any time soon as the agency has once again pulled back on inspectional activities due to the spread of the omicron variant to COVID-19.

In July 2021, FDA revived efforts to ramp up inspections of domestic production facilities, an effort that made a notable dent in the agency’s sizeable inspection backlog for medical products. The hope was to visit most of the 3000 sites in need of oversight in 2022 and also to test a new program to enhance foreign inspection operations.

These goals were put on hold with the agency’s 

 on Jan. 4, 2022 that it would continue only mission-critical inspections through Jan. 19, 2022, and postpone most other inspectional activities, including foreign site visits. Also delayed is the planning effort set to begin in February for revising foreign inspection assignments in an effort to address challenges in staffing overseas offices and rebuilding the cadre of US-based inspectors willing to travel to foreign drug production sites.

Meanwhile, FDA will continue to utilize remote tools to maintain oversight of foods, drugs, medical products, and tobacco at home and abroad.

 from CDER provides more complete information on new drug approvals for 2021, including certain existing therapies that gained important new uses and advances in biosimilars. 

FDA maintained a steady pace in 2021 in approving important new therapies for market, including new vaccines and treatments for COVID-19.

FDA Keeps New Drugs Coming

FDA authorized emergency use of Pfizer’s oral antiviral drug, Paxlovid, on Dec. 22, 2021, skipping the advisory committee review to make the drug available as quickly as possible. This decision was followed on December 23 with FDA providing similar authorization for Merck’s Molnupiravir, with 

certain restrictions due to questions raised about its safety and efficacy during an examination by FDA’s expert panel

. These actions by FDA offer patients a take-at-home pill that can keep them out of the hospital at a time when the United States is being devastated by the spreading Omicron variant.

Pfizer’s Paxlovid (nirmatrelvir/ritonavir) 

 (EUA) from FDA for patients over age 12 experiencing mild-to-moderate COVID-19 infection as a way to prevent progression to more severe illness or hospitalization. The treatment is specified for use at early stage of infection and involves taking a packet of three pills twice daily for five days, adding up to 30 pills overall.

Being able to treat COVID-19 with a drug taken orally at home is “a major step forward in the fight against this global pandemic,” said Patrizia Cavazzoni, director of FDA’s Center for Drug Evaluation and Research (CDER). And the approval, she added, comes “at a crucial time in the pandemic as new variants emerge.” At the same time, FDA continued to emphasize the importance of vaccination in protecting individuals from COVID-19 infection.

Despite concerns that the antiviral drug molnupiravir developed by Merck and Ridgeback Biotherapeutics may be less effective and riskier than the Pfizer treatment, FDA granted an EUA for the product to provide an additional option for treating patients (over 18 only) with early symptoms and in need of treatment quickly to prevent hospitalization or more serious disease. Cavazzoni stated that molnupiravir use should be limited to situations where other authorized treatments “are inaccessible or are not clinically appropriate.”

Merck’s drug ran into trouble at the Nov. 30, 2021, meeting of FDA’s Antimicrobial Drugs Advisory Committee, where concerns were raised about possible birth defects if used by pregnant women and potential damage to patients’ DNA. The drug suffered from data released just before the meeting that showed only a 30% decrease in hospitalizations, compared to 50% in preliminary results, a drop that the sponsors had difficulty explaining. Consequently, the panel recommended approving the drug by only a very slim margin.

However, scientists involved with the drug’s development and testing made the case for molnupiravir being a useful weapon in combatting COVID-19. An article in the 

 on Dec. 16, 2021 emphasizes that molnupiravir is an effective treatment that can reduce the risk of hospitalization or death in patients infected with COVID-19. The authors provide details on the clinical trials and analysis, including safety issues. A companion editorial summarizes these issues, noting that the drug has been 

licensed in the United Kingdom and may be particularly valuable in other markets

Merck’s drug may be particularly helpful in the lesser developed countries where access to new therapies is limited. Merck has said it plans to make its patents available to the World Health Organization patent pool and to generic-drug manufacturers so that it can be produced for developing countries at low cost. Similarly, Pfizer stated that it will provide the new drug through a tiered pricing program, where high-income countries will pay more than lower income countries. And the company has signed a voluntary license agreement with the Medicines Patent Pool to expand access to its oral antiviral treatment to 95 low- and middle-income countries.

The main factor clouding the immediate impact of these new drugs is limited supplies. Pfizer said that it planned to provide 10 million treatment courses “between 2021 and 2022,” as per a $5.3 billion advance purchase agreement with the US government. The company also aims to 

produce 120 million courses of treatment in 2022

 through expansion of its own manufacturing and agreements with contract manufacturers. But analysts count fewer than 200,000 courses of the pills now available, raising questions about how quickly the firm will be able to meet what is expected to be widespread demand.

FDA authorized emergency use of Pfizer’s oral antiviral drug to make the drug available as quickly as possible. 