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

Jill Wechsler

After weeks of anticipation, FDA has granted full approval for the Pfizer-BioNTech COVID-19 vaccine, raising hopes that this action will help overcome the vaccine hesitancy that has plagued efforts to broadly immunize the US population. The 

 was no surprise, as staff in the Center for Biologics Evaluation and Research (CBER) have been working overtime to review extensive clinical data contained in thousands of documents as quickly as possible. Consequently, FDA fully assessed the Pfizer biologics license application (BLA) in 40% of the time allotted for this process, producing a decision that hopefully will “give people confidence to get vaccinated,” said CBER Director Peter Marks at a press conference. FDA Acting Commissioner Janet Woodcock termed the approval decision “a pivotal moment” in the fight against the pandemic, noting that the BLA should make the public “confident that this vaccine meets the FDA’s gold standards for safety, effectiveness, and manufacturing quality that we require for an approved product.”

The approved vaccine now carries the brand name Comirnaty, devised for the manufacturers by the Brand Institute to convey a sense of “community” and “immunization.” FDA notes that the manufacturers now may promote the vaccine according to its rules, efforts that hopefully will further encourage vaccination in the United States and elsewhere. Such uptake may be advanced by vaccination mandates from federal, state, and local government agencies. President Biden remarked that the BLA should be a signal to both public and private employers to move forward with vaccine requirements. The Pentagon has announced plans to mandate vaccination for military forces, both active duty and reserve units, while hospitals and nursing homes look to require such protection for all staffers.

that Comirnaty has been administered to more than 1 billion patients around the world. Production is slated to increase from 1.2 billion vaccine doses so far to 3 billion this year and 4 billion doses in 2022, according to the manufacturers. The partners also plan to seek licensure of a third, or booster, dose via a supplemental BLA, and to extend full approval to individuals over 12 years of age. Patients ages 12 to 16 still can obtain the vaccine under the Emergency Use Authorization (EUA) that remains in effect, as can immunocompromised individuals seeking a third booster shot to protect against the delta variant.

The BLA package submitted in May 2021 included longer-term follow-up data from its Phase III clinical trial plus extensive information on manufacturing and facilities. We didn’t “just look at data summaries,” commented Marks. He explained that the task of evaluating the Pfizer-BioNTech BLA involved reviewing hundreds of thousands of pages of reports, including four months of follow-up data on half of the 40,000 clinical trial participants. Staff also visited sites where the clinical trials were conducted to ensure that the information was collected accurately and met all standards. FDA wanted to ensure “that we saw all adverse events,” Marks said, adding that FDA also did a full benefit-risk assessment based on real-world data for the hundreds of millions of patients that have received the vaccine over the past year.

The BLA review process also involved visiting numerous manufacturing facilities to ensure quality production. The manufacturers noted in a press release that there is no change in the formulation for Comirnaty and that providers may continue to use already distributed product obtained under the EUA.

 for Comirnaty also specifies a number of post-approval studies and commitments to further assess product safety and efficacy. These include additional studies on the risks for myocarditis and pericarditis after receiving Comirnaty, a side effect that has been seen and assessed by FDA, notably in younger male patients. The companies also will create a registry to monitor the vaccine’s impact on pregnant women and infants.

FDA’s action represents the agency’s first approval of a vaccine using messenger RNA technology, a move expected to further bolster R&D on therapies and preventives in this area. Further evidence of the vaccine’s safety and efficacy will hopefully encourage broader public vaccination and begin to rein in the now-resurgent COVID pandemic.

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FDA’s full approval of the Pfizer-BioNTech COVID-19 vaccine raises hopes that this action will help overcome vaccine hesitancy.

Pfizer Vaccine Approval Key to Boosting Vaccination Rates

Biopharmaceutical companies will pay more than $3 million to file an application seeking FDA approval of a new drug application (NDA) or biologics license application (BLA) during fiscal year 2022. This record charge to 

agency analysis of additional personnel and resources 

needed to process its growing workload. The annual program fee paid by each manufacturer with marketed prescription drugs holds fairly even at about $370,000. And while the actual increase in the application fee is not that much, passing the $3 million mark has drawn attention and further concern about FDA’s overdependence on revenue from regulated industry.

At the same time, new fees for generic drugs, biosimilars, medical devices, animal drugs and outsourcing facilities (drug compounders) will see modest, or no, increases. Most notable is that 

fees for developing and filing applications for new biosimilars

 will drop or hold even. With program reserves higher than expected, the Center for Drug Evaluation and Research (CDER) halved fees for establishing, maintaining, and reactivating biosimilar product development (BPD) programs. Application fees for biosimilars remain at $1.7 million, and annual program fees at slightly more than $300,000.

Similarly, generic drug fees remain fairly flat. Filing an abbreviated new drug application (ANDA) will cost $226,000, while the annual program fee stays at about $1.5 million. 

Fees for each manufacturing facility will range from $42,000 for a domestic API producer to $210,000 for a foreign manufacturer of finished dosage forms

These varying fees for applications, facilities, and annual program oversight for medical products reflect the range in FDA oversight of differing R&D and manufacturing operations. Sponsors usually submit fairly few NDAs a year, and thus pay high rates for those, compared to the program fee. But as generic-drug makers often file multiple ANDAs and maintain many facilities, the individual fees are lower, compared to a relatively higher annual program fee, which varies with company size. And because FDA provides considerable support and advice to biosimilar makers during product development, that fee program begins prior to filing an application; the application fee is less than for an NDA but much more than for an ANDA.

FDA bases its rates for FY 2022 on projections that sponsors will submit 161 NDAs/BLAs to CDER, about 1350 efficacy and labeling supplements, and 2388 manufacturing supplements. The program will fund the cost of holding some 4500 meetings with sponsors and oversee more than 9500 active investigational new drug applications (INDs). Workload increases at both CDER and the Center for Biologics Evaluation and Research (CBER) altogether will require a $27 million increase in Prescription Drug User Fee Act (PDUFA) fees to reach $1.149 billion in FY 2022.

The fees set for fiscal year 2022 (begins Oct. 1, 2021) are noteworthy, as their announcement comes as FDA and industry are finalizing agreements for new five-year user fee programs. These need to be reauthorized by Congress early next year in order to start collecting new fees Oct. 1, 2022. PDUFA application fees are slated to increase to $4 million over the next five-year fee program, which will be specified along with multiple other revisions in new “commitment letters” that FDA has negotiated with industry for its various user fee programs (PDUFA VII, BsUFA III, GDUFA III). The process of enacting legislation to reauthorize the fees every five years provides members of Congress with an opportunity to add a broad range of policy and program requirements that often impose notable changes on FDA operations and priorities.

The user fees set for fiscal year 2022 are noteworthy, as their announcement comes as FDA and industry are finalizing agreements for new five-year user fee programs.

FDA User Fees to Rise and Fall as New Fee Agreements Move Forward

The White House is looking to pay for some of its prime social and health initiatives by reducing outlays for prescription drugs, according to an 

 that supports several leading drug-price control policies strongly backed by Democrats. There’s not much new on the reform list, but the emphasis is designed to gain support for broader spending measures from both party centrists and reformers, as well as some Republicans.

The lead proposal reiterates earlier calls for granting Medicare authority to negotiate drug prices. Here the change would apply only to “a subset of expensive drugs that don’t face any competition on the market,” a more limited list of therapies that lack generic alternatives. And the plan does not aim to compel price negotiations by linking reform to an international reference price or by challenging manufacturer intellectual property.

The administration also calls for penalties on pharma companies that raise prices faster than inflation. And it seeks to establish “a firm cap” on the amount that Medicare beneficiaries must pay out-of-pocket for drugs each year, with some of the reforms offsetting that added cost.

Drug importing and support for generics and biosimilars are on the table, as the plan repeats earlier proposals for federal agencies to work with states and Tribes to “import safe, lower-cost prescription drugs from Canada.” Similar initiatives by the Trump administration and others have backed drug importing plans, but implementation has proven difficult and unrewarding.

While the White House announcement signals the administration’s continued intent to make prescription drugs more affordable and less burdensome for consumers, this latest plan basically adds new emphasis to policy changes in this area. In response to Biden’s announcement, 

PhRMA president Stephen Ubl blamed high drug costs

 on insurance industry policies and warned that the president’s policies would “undermine access to life-saving medicines”. PhRMA looks to shift the policy debate to measures designed to reduce health care costs overall, as opposed to specific drug pricing proposals, and to build on broader public applause for industry’s success in fast development of anti-COVID vaccines and therapies.

A recent posting by the Biotechnology Innovative Organization (BIO) highlights a range of state initiatives that set payment limits on drug outlays. These include new laws requiring drug price transparency and notices of price increases; programs to link local drug prices to those in Canada; and rule updates to permit pharmacies to dispense interchangeable biosimilars.

At the same time, consumer advocacy groups penned 

a letter to Health & Human Services (HHS) Secretary Xavier Becerra 

seeking to combat high drug prices by limiting patent monopolies of brands seen to stifle generic competition. The group led by Public Citizen emphasizes that HHS already has authority to establish generic-drug competitors to patented drugs, including the exercise of “march-in” rights on drug patents developed with federal funding.

The administration is looking for its drug pricing reform to help build support for a $3.5 trillion social policy bill backed by Democrats and headed for consideration as part of a massive budget reconciliation package moving through Congress. Here, a significant drug pricing package will be proposed to offset some of its considerable costs, particularly those to expand Medicare to younger age groups and to add vision and hearing benefits and long-term care.

Meanwhile, the $1 trillion infrastructure package just approved by the Senate with bipartisan support includes only one drug pricing provision—a proposed delay in implementing the “rebate rule” authorized by the Trump administration—a policy that limits manufacturer rebates on drugs covered by Medicare Part D unless the rebates are passed through to the dispensing pharmacy to benefit consumers. The new rule was calculated to cost the government nearly $200 million over 10 years, so the added delay provides a “savings,” much applauded by PBMs and health insurers that currently benefit from manufacturer rebates.

The President calls for granting Medicare authority to negotiate drug prices and penalties for pharma companies that raise prices faster than inflation. 

Biden Highlights Drug Pricing Reforms to Advance Legislative Agenda

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

The top priority for the Center for Biologics Evaluation and Research (CBER) is to approve BLAs for COVID vaccines to address vaccine hesitancy, said CBER Director Peter Marks. He emphasized that the agency is working to “move this forward” as quickly as possible in remarks at the Drug Information Association (DIA) virtual annual meeting on June 30, 2021. Even if full approval encourages only 5% more individuals to get vaccinated, “that will make a difference,” he observed, adding that “having an approved vaccine may help.”

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

To move forward, Pfizer initiated a rolling submission of a BLA on May 7, 2021, initially filing existing preclinical and clinical information, with manufacturing and facility data to come. On July 16, 2021, FDA formally accepted the company’s BLA for individuals age 16 and older and granted the application priority review (1). Moderna announced on June 1, 2021, that it also had launched a rolling BLA submission, with an eye to gaining priority review and approval by year-end (2). FDA acknowledges that BLAs require more information than the initial EUAs, including data from conformance lots, full characterization reports, additional facility inspections, closer scrutiny of individual safety cases, and more follow-up on adverse events. Marks explained in a letter to The New York Times that CBER staff can’t turn around such evaluations in a few weeks but will require several months to fully assess the complete data (3). Marks emphasized that the review of applications for full approval of COVID-19 vaccines is “one of the highest priorities” at FDA, but that the extensive additional manufacturing and clinical information warrants a “high-quality review” to avoid undermining the public trust in the agency.

Even so, some public health authorities have criticized FDA for moving too slowly in processing the BLAs, while others agree with Marks that any appearance of hasty action or incomplete oversight may only aggravate latent fears.

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

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

Manufacturers also are looking for more common guidance and requirements from regulators around the world, and less “global disharmony” in policies and standards. Marks and others acknowledged that regulators could do more to come together and avoid claims that their vaccine is better than others. An initial area for collaboration may involve determining the need for COVID vaccine boosters or new preventives for variants. There also is interest in agreeing on what tests or measures would support boosters and or the need for annual COVID-19 vaccines.

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

1. BioNTech, “U.S. FDA Grants Priority Review for the Biologics License Application for Pfizer-BioNTech COVID-19 Vaccine,” Press Release, July 16, 2021.
2. Moderna, “Moderna Announces Initiation of Rolling Submission of Biologics License Application (BLA) with U.S. FDA for the Moderna COVID-19 Vaccine,” Press Release, June 1, 2021.
3. Peter Marks, “The F.D.A. on the Vaccine Reviews: ‘We Want to Assure the Public’,” 


Vol. 45, No. 8
August 2021
Pages: 14–15

When referring to this article, please cite it as J. Wechsler, "FDA Prioritizes Vaccine Review and Process Improvements," 

Full approval of COVID-19 vaccines may increase public confidence, but better coordination in development and review is needed.

FDA Prioritizes Vaccine Review and Process Improvements

In response to continued criticism of FDA’s initiative to make promising new therapies available to seriously ill patients based on early clinical results, the agency’s leading cancer expert lashed out at the alarmists and urged continued support for this early access process. A comprehensive review of FDA’s accelerated approval program reveals that it has brought many important treatments to patients years before the completion of confirmatory studies, and that relatively few products have been removed from the market post approval, asserted Richard Pazdur, director of FDA’s Oncology Center of Excellence (OCE). The current attack on accelerated approvals misses “the broader gains of the program,” he stated in 

a discussion sponsored by Friends of Cancer Research (FOCR)

Instead of attacking the program, Pazdur said they need to address “what’s going right” with it. “We need to look at the big picture of what this initiative has provided for us.” He

 cited 165 accelerated approvals over the last 10 years,

 with only about 10 therapies removed from the market [complete list of accelerated approvals available. “If you just look at the problems, you miss the broad gains” of the process, he commented, which is apparent in early patient access to multiple new drugs for deadly cancers, many addressing serious unmet medical needs.

Ned Sharpless, director of the National Cancer Institute (NCI) and former FDA acting commissioner, agreed that the accelerated approval program “has been transformative” in bringing new cancer therapies to patients that previously were blocked by regulatory hurdles. He attributed reductions in cancer deaths to expedited reviews, particularly of new treatments for lung cancer.

Pazdur further explained that a failed postapproval trial for an innovative product “does not necessarily mean a failed drug.” More likely is that the study suffered from poor trial design, selection of the wrong patient population, or inappropriate study endpoints. Some drugs fail in confirmatory studies, he added, which also often is due to how the trial is designed. He noted that many critics of the program consider overall survival the only valid endpoint but cited alternatives such as tumor reduction or delay in disease progression as appropriate.

While an initial approval of a new cancer drug may not be based on optimal results, the aim, Pazdur explained, is to get the drugs out to see how to use them in new combinations and for different procedures. The risk of ignoring the program’s benefits, he added, is the creation of a more orthodox regulatory approach that ignores the needs of patients.

These experts participating in the FOCR program were responding to a growing attack on FDA’s accelerated approval program, which has heated up since FDA utilized the process to authorize marketing of Biogen’s Alzheimer’s treatment, Aduhelm. The drug was rejected for approval by an FDA advisory committee in November 2020, and the agency’s decision to grant conditional approval in June 2021 

prompted many experts on that committee to challenge the agency’s action

“Sure, we can improve the program,” Pazdur said. He noted difficulties in removing a drug from market when it doesn’t meet primary endpoints but added that such issues can be best addressed in early discussions with sponsors on the goals of accelerated studies and plans for conducting confirmatory trials.

At the same time, FDA has increased scrutiny of immunotherapies and other drugs awarded accelerated approval based on preliminary data, but that fail to document initial results in confirmatory studies. In April 2021, FDA’s Oncology Drugs Advisory Committee spent three days examining the merits of six indications for three leading immunotherapies where postapproval studies had failed to support initial authorization. The panel voted to reject two approvals, prompting

 Bristol Myers Squibb to withdraw the use of Opdivo 

Merck has said it will pull the gastric cancer indication 

The agency’s leading cancer expert lashed out at the alarmists and urged continued support for the early access process.

FDA’s Pazdur Challenges Attack on Accelerated Approval Program 

Despite the pressures and added regulatory challenges imposed by the COVID-19 pandemic, and the uproar over its surprise approval of Biogen’s new Alzheimer’s therapy Aduhelm, FDA is on track this year to authorize a notable number of new molecular entities (NMEs) and important biotech therapies. In the first half of 2021, the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) gave the nod to 29 novel therapies, slightly ahead of last year’s pace that saw the approval of a near-record 53 new drugs.

added up to 27 NMEs and biologics as of June 30, 2021, with several more additions in July. And 

 a new pneumococcal vaccine and new treatments for multiple myeloma and for lymphoma.

Almost half of the new drugs are treatments for cancer and related conditions, many benefitting from priority review and accelerated approval programs. That includes Jazz Pharmaceuticals’ new blood cancer therapy, a treatment for non-small cell lung cancer from Amgen, and Bristol Myers Squibb’s new CART-T therapy for multiple myeloma plus a cell therapy for large B-cell lymphoma.

Important non-cancer approvals also include the first new treatment for vaginal yeast infections in two decades and the first therapy for chronic weight management authorized since 2014, arising from approval of an added indication for Novo Nordisk’s type 2 diabetes injectable Wegovy (semaglutide) for obese or overweight adults. FDA also okayed new therapies for Duchenne muscular dystrophy, lupus nephritis, chronic heart failure, and notably, an extended release injectable to manage HIV, replacing daily pills with monthly injections.

There were advances in the over-the-counter drug world, too. In June, FDA approved the first nonprescription nasal antihistamine to expand treatment options for patients age six and older; younger children still must obtain Bayer Healthcare’s Astepro (0.15% azelastine hydrochloride nasal spray) on a prescription basis.

Important news on the approvals front continued in July, as 

FDA authorized its first interchangeable biosimilar

—Mylan’s Semglee once-daily insulin therapy, biosimilar to Sanofi’s Lantus.

FDA also approved an important treatment for high-risk, early-stage, triple-negative breast cancer, giving the nod to Merck’s Keytruda (pembrolizumab) to be used in combination with chemotherapy for this serious condition.

On the downside, FDA halted use of a treatment approved in February for relapsed or refractory multiple melanoma, Pepaxto, from the Swedish firm Oncopeptides, based on evidence from ongoing clinical studies of higher death rates among patients treated with the new drug versus an earlier therapy. Pepaxto gained accelerated approval, but now 

FDA has alerted patients and health professionals 

to the potential risk and has suspended enrollment in postapproval studies pending further examination of the safety signal.

CDER officials attribute their ability to maintain a fairly normal advise-and-consent process for innovative drugs during the past 18 months on the hard work of its dedicated staff, as well as efficiencies gained from the recent reorganization of its Office of New Drugs (OND). CDER Director Patrizia Cavazzoni noted increases in staff hiring and retention at the May 2021 annual meeting of the Food and Drug Law Institute (FDLI), attributing this surprising development to new remote work flexibilities due to COVID-19 restrictions. She also cited the success of large platform trials and clinical networks, as well as increased sponsor use of decentralized trials. The structural overhaul of OND has resulted in smaller, more flexible review offices with clearer areas of expertise and greater alignment of interrelated disease areas, 

Cavazzoni explained in recent testimony to the House Energy & Commerce Health subcommittee

, which held a hearing to explore the lack of new therapies for neurogenerative diseases.

In the first half of 2021, the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research approved 29 novel therapies.