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

Jill Wechsler

Amidst political pressures and dissension on multiple fronts, FDA and its panel of vaccine experts weighed the evidence and worked to ensure a science-based decision on whether to authorize additional shots of Pfizer’s COVID-19 vaccine to further protect those that already received the recommended doses. The 

 of FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) concluded with the panel recommending that a third dose of the Pfizer/BioNTech Comirnaty vaccine be authorized only for people over age 65, plus those at high risk of infection related to occupation, such as health care workers and teachers.

A formal recommendation from FDA on the Pfizer booster, likely to be issued today, will be considered this week by the Advisory Committee on Immunization Policy (ACIP) at the Centers for Disease Control & Prevention (CDC). That panel will advise practitioners and health agencies on when and where to administer any additional shots in ongoing efforts to curb the COVID-19 pandemic.

The FDA advisors agreed unanimously on the more limited booster plan after soundly rejecting Pfizer’s original request to authorize its third shot for everyone over age 16, as covered by the biologics license application (BLA) for the vaccine approved by FDA’s Center for Biologics Evaluation and Research (CBER). The panel felt there was insufficient data to support more widespread administration and that boosters could pose added risks for men under age 40, who have experienced rare cases of myocarditis following vaccination. A main point of discussion was whether waning immunity from the initial two-dose vaccine regimen was due to effects of the Delta variant or to limitations of the Pfizer vaccine itself. Pfizer researchers published 

 summarizing its research to support a booster dose, but that failed to convince the advisory panel of the need for widespread third shots.

The debate over the issue was intensified by the recent announcement of pending departures of leading FDA officials who had expressed dismay over earlier statements by President Biden backing booster shots in the United States while FDA was examining the issue. Marion Gruber, long-time Director of CBER’s Office of Vaccine Research & Review (OVRR), and OVRR Deputy Director Phillip Krause announced last month that they would both retire from FDA after many years of service, most recently shepherding through speedy emergency approvals for effective COVID-19 vaccines.

In addition, Gruber and Krause were prominent co-authors of a 

 questioning booster shots while much of the world still awaited initial COVID-19 vaccines. The article by a group of vaccine scientists formed by the World Health Organization (WHO) argues that much uncertainty remains about the timing and value of extra shots, and that boosters for healthy adults should be delayed until at least 40% of the global population is vaccinated.

The debate within the Biden administration and FDA opened the door to widespread criticism and questioning of the booster shot policy. Leading House Republicans charged FDA officials with caving to White House pressure to speed access to booster shots and demanded that FDA Acting Commissioner Janet Woodcock 

 related to the study and implementation of a booster shot option plus communications between the agency and the White House on this issue.

While the politicians look to make points over the policy debate, the VRBPAC panel weighed the scientific evidence presented at the September 17 session. That included current data on COVID-19 prevalence, infection and hospitalization rates from the CDC and from the United Kingdom. Of particular interest was a report on how a recent Pfizer vaccine booster program in Israel reduced infection rates and hospitalizations. Pfizer presented its own analysis on how protection by Comirnaty waned over six months after initial doses and how boosters could provide important added protection. But the advisors found the Israeli and Pfizer data too limited and unconvincing to approve boosters for the entire US population. The narrower recommendation to add shots for the elderly and immune-compromised is seen as a compromise to provide protection where most needed while sponsors gain added information.

A main issue for the international health research community is whether limited supplies of effective preventives should be provided to those already protected by authorized shots, while vaccines remain severely limited in many regions of the world. The advisory panel did not address that question directly, and ample vaccine supplies in the US appeared to offset the issue.

Members of the advisory panel and experts from CDC and FDA did agree that more widespread vaccination of the American public would do more to prevent high COVID-19 infection rates than booster shots for those already benefitting from protection. However, that possibility was further countered by the ranting of vaccine opponents about the safety and value of any COVID-19 preventive, as heard in multiple presentations during the usual one-hour public comment period at the VRBPAC meeting.

The debate will continue, as Moderna has announced it also will seek FDA approval of a third shot to its two-dose vaccine regimen, citing similar waning of antibodies six months after the second shot and no added safety concerns. Perhaps Moderna will consider closely the recent debate and target its booster plan to the higher-risk population, as recommended by the advisory panel for the Pfizer preventive.

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FDA advisors agreed unanimously on a more limited booster plan after rejecting Pfizer’s original request to authorize its third shot for everyone over age 16.

Vaccine Booster Battle Reveals Rifts Among Regulators and Sponsors

In a move that revealed just how difficult it is to craft policies designed to curb industry pricing practices, Democrats failed to gain sufficient support this week to advance long-debated legislation to permit Medicare drug price negotiations. Three centrist Democrats opposed the measure in debate on Sept. 15, 2021, sufficient to block the bill from moving out of the key House Energy and Commerce Committee.

The vote put a temporary halt on efforts to approve the Democrats’ lead proposal to permit government negotiations of reimbursement for certain medicines covered by Medicare, a key provision to help pay for the $3.5 trillion budget package on a tight schedule for moving through Congress. Opposition from Reps. Kurt Schrader (D-Or), Scott Peters (D-Ca), and Kathleen Rice (D-NY) has sent party leaders back to the drawing boards in search of drug pricing reform provisions more acceptable to moderates in both the House and Senate. The spending bill may move forward without this provision from the House Ways & Means Committee, which continues to debate related health care spending provisions.

The three centrists offered a more modest drug pricing measure, which they claim would lower consumer out-of-pocket costs, while also maintaining incentives for private investment and innovation. A major change here would limit price negotiations to fewer medicines covered by Medicare Part B—only those drugs that lack competition or patent exclusivity. Such a revision would raise much less revenue and is adamantly opposed by progressive Democrats. They see it as caving in to Big Pharma and severely limiting savings for patients.

These developments on drug pricing legislation reflects the success of industry in raising fears that such measures will block patient access to needed medicines and dry up investment in important R&D on new therapies. Pharmaceutical Research and Manufacturers of America (PhRMA) is spending more than $1 million on TV ads as part of a massive lobbying and communications campaign emphasizing the potential harm to patients seeking cures for deadly diseases. A 

 ran on Sept. 15, 2021 to highlight how Medicare price negotiations threatens “patient’s ability to get the medicines they need” and that one legislative proposal “would cut $1.5 trillion from innovative research companies” over 10 years. In countries with such price controls, claims the letter signed by all of PhRMA’s members, new cancer therapies and breakthroughs are “either delayed or not available at all.”

Smaller biotech firms and financial investors similarly emphasize that drug price negotiations won’t just harm Big Pharma but will dry up investment in vital R&D operations. A 

letter to the White House and to House and Senate leaders on September 8

, which was signed by 400 small biotech company heads and leading investment companies in the field, emphasized that “draconian” price negotiation legislation “would immediately halt private funding of drug discovery and development."

Meanwhile, legislators backing the Medicare price negotiation plan counter-charge that industry is exploiting consumer fears and using its vast resources to block any fair and reasonable cost-cutting efforts. But opposition to the Democrats’ main price cutting proposal already is stronger in the Senate, where many key members have voiced concerns about government interference in private sector investment. The situation sets the stage for intense negotiations and Congressional infighting in the coming weeks.

Democrats failed to gain sufficient support to advance long-debated legislation to permit Medicare drug price negotiations.

Pharma Blocks Democrats’ Drug Pricing Plan

As part of a broad initiative to prepare for and prevent future global disease outbreaks, White House officials recently announced a nearly $3 billion program to ramp up production of vaccines and their components to better serve patients in the United States and globally. 

This program is part of a broader $65 billion, 10-year pandemic preparedness plan 

announced Sept. 3, 2021 that also supports development of new therapeutics and diagnostics, as well as improved infectious disease surveillance, expansion of the national stockpile of critical medical supplies, and building regulatory oversight of these programs [see “American Pandemic Plan: Transforming Our Capabilities”.

The roll-out of the preparedness plan was an opening salvo in the administration’s heightened effort to increase vaccination rates and testing to keep schools open, strengthen the economy, and defeat the virus globally. In a 

, President Biden promised additional steps for providing protections for other countries and promised to release more details of his pandemic preparedness plan in coming weeks.

Meanwhile, the Biden administration looks to start the more targeted program to bolster vaccine production in the US by tapping an already approved $2.7 billion in funding authorized last March. This effort was announced by White House coronavirus response coordinator Jeffrey Zients at a press briefing on Sept. 2, 2021, called to provide an update on US efforts to ramp up production of COVID-19 vaccines for patients in the US and in other countries. 

that the US has shipped more than 130 million doses to 90 countries, more than all other vaccine doses than all other countries in the world combined. However, even that greater volume of vaccines provided to the global community remains a fraction of the billions of doses that health officials say are needed.

Zients emphasized the importance of increasing vaccine manufacturing capacity at home and in other countries around the world by investing across the whole supply chain, from producing lipids to bioreactor bags to vials and syringes. He noted that the Biden administration has tapped funds already available to accelerate production “of critical vaccine manufacturing equipment, inputs and supplies” and to expand “fill/finish lines at factories” to get vaccine doses into vials faster and at a larger scale. The added $3 billion, he noted, will enable vaccine manufacturers to “add new production lines and facilities.” And this will create “thousands of good-paying American jobs” and “strengthen our long-term capabilities to respond to future threats.”

The White House unveiled its broader $65 billion pandemic preparedness plan the next day, as mentioned above, which lays out long-term strategies for expanding vaccine and drug manufacturing and for building a biomedical research pipeline as key components for quickly responding to future disease outbreaks. Described as similar to the Apollo mission to the moon, both public health and national security experts called for a “mission control” office to coordinate efforts by multiple government agencies to track and identify emerging disease threats and map strategies for combatting them. Administration officials proposed launching the program with an initial $15 billion budget as the debate over Biden spending proposals has stalled on Capitol Hill.

For the total program, more than half of the $65 million request would fund efforts to design and test new vaccines within 100 days after a pandemic threat appears and to speed production and distribution by eliminating the need for cold storage and replacing sterile injection with skin patches and nasal sprays. Rapid production of neutralizing antibodies would advance new antiviral therapeutics, and genome sequencing of patients with symptoms, wastewater sampling, and formation of early-warning data networks would enable earlier detection of viral outbreaks. The plan would expand the national stockpile to ensure access to next-generation personal protective equipment and testing equipment and build resilient supply chains for medical products, including active pharmaceutical ingredients.

The program also would support the efficient regulatory approval of new platform technologies and the establishment of “large, agile, and flexible clinical trials networks that can be rapidly ramped up for urgent needs.” Further information is presented in a “scientific appendix” to this 27-page plan, although many health experts maintain that a much more detailed program is necessary.

The White House announced a nearly $3 billion program to ramp up production of vaccines and their components.

Biden Bolsters Vaccine Production in Pandemic Preparedness Plan

Legislative proposals for curbing outlays on prescription drugs have moved to center stage, as Congress looks hard for ways to pay for costly initiatives to repair the nation’s infrastructure, offset global warming, and expand health care programs. These developments have focused attention on a 

recent report from the bipartisan Congressional Budget Office 

(CBO) analyzing how drug pricing policies could reduce the number of new therapies coming to market. Industry has long warned of such an outcome and has ramped up efforts to preserve US market support for global biopharma R&D.

The CBO report explains why companies investing in new drug development may drop long and costly research in some medicines if Congress approves legislation that permits Medicare to limit reimbursement for certain leading drugs. The main bill in question, the Elijah E. Cummings Lower Drug Costs Now Act (HR 3), would give the Department of Health and Human Services (HHS) authority to negotiate drug prices on a certain number of high-use medicines in Medicare drug plans based on an international index of prices at several other countries. Manufacturers that fail to agree to the set prices for Part D coverage would face stiff penalties. While such a policy is estimated to save the government some $900 billion, CBO calculates that it would reduce the number of new drugs coming to market by two new therapies in the first decade, adding up to possibly 60 fewer drugs over 30 years.

The analysts explain that potential changes in company profits and in drug development costs are main factors influencing how many new drug candidates enter clinical trials at different stages. A 15–25% drop in expected returns on higher-cost drugs could reduce new drug approvals by 0.5% a year, an amount that would accumulate over time. Thus, the simulation model calculates that the proposed curb on future market prices will lead biopharma companies to abandon the development of drug candidates with less certain returns on investment, particularly in Phase I and Phase II clinical development. Those less profitable therapies, as for rare conditions or infectious diseases, may be first on the chopping block, as opposed to new medicines that address clear needs for large patient cohorts.

The larger issue for policy makers is whether such a decline in new drug development would have a serious impact on patients and health outcomes, something that here CBO does not address. Market approval of more widely used new treatments for heart disease or common cancers may actually lead to lower prices in the market, which could have wider public benefits. Or, price limits for innovative therapies with potential for large sales and profits could have a serious effect on investment in newer, smaller biotech companies. BioCentury Editor Steve Usdin 

fails to recognize the broader impact of price controls on the ability of new, highly innovative firms to gain financial support, as such developments would reduce interest among venture capital investors in the biotech market and in portfolios of investigational programs.

Other commentaries recognize the complexities of drug pricing proposals, as seen a 

recent report on the impact of enacting HR 3 by Paul Ginsburg and Steven Lieberman

, issued by the Brookings/USC Schaeffer Initiative for Health Policy. It outlines a broad range of impacts from legislation authorizing government controls on what manufacturers can charge for their drugs, noting that effects would vary, depending on the process used to set prices, what penalties fall on those firms that don’t comply, what types of drugs are affected, the prevalence of competitor products, whether payers could negotiate lower prices, if pricing curbs apply only to Medicare or to all US patients, and how such a program would go about setting the price.

Manufacturers, meanwhile, continue to raise concerns about the potential harm on the prescription drug market from such proposed pricing policies. The Biotechnology Innovation Organization (BIO) predicts that halting development of even only a few new therapies could have serious consequences for people living with rare diseases and for patients needing new antibiotics or antivirals to treat future life-threatening illnesses. BIO and its members also are examining the impact of price controls in states with active biopharmaceutical R&D operations, as seen in a recent “Good Day BIO” posting. The 

Pharmaceutical Research & Manufacturers of America

 (PhRMA) and its members have ramped up lobbying on these issues, emphasizing that a cap on out-of-pocket drug costs for Medicare patients is preferable for reducing consumer health care costs than price controls.

Another response to concerns about reduced new drug development is to offset any drop in industry R&D with increased government support for the National Institutes of Health—perhaps using some of the savings from proposed legislation for this purpose. And while the public generally supports drug price controls, especially if linked to reduced outlays on specific medicines, that 

enthusiasm wanes notably when seen to reduce R&D for new treatments

A report from the bipartisan Congressional Budget Office analyzes how drug pricing policies could reduce the number of new therapies coming to market.

Will Price Controls Limit Drug Development? The Debate Heats Up 

The holy grail for expanding access to less costly biotech therapies in the United States has been FDA approval of interchangeable biosimilars that do not require a physician to prescribe the alternative treatment. The development and utilization of biosimilars has been slow and disappointing since Congress enacted the Biologics Price Competition and Innovation Act (BPCIA) in 2010 authorizing follow-on products in this area. FDA has approved only 30 biosimilars since then, with just 20 on the market through 2020. But on July 28, 2021, FDA authorized the first interchangeable biosimilar for the US market, raising hopes for more affordable biotech treatments to come (1). It was no surprise that the first interchangeable is for an insulin therapy, predicted to reduce costs for some of the nation’s 34 million diabetics and setting the stage for what analysts expect to be a surge in the development of interchangeable products.

Despite FDA assurances that biosimilars are as safe and effective as innovator therapies, prescribers have been slow to switch patients to these alternatives, especially where brand manufacturers warn of adverse reactions to products undergoing an abbreviated testing process. Extensive patent protections and complex legal issues have enabled innovators to delay new competition, as has the need for a physician to prescribe the follow-on product.

Now all eyes are watching closely to see how well an interchangeable product competes with a well-established brand. FDA approved Semglee—made by Viatris and Biocon Biologics (formerly Mylan)—as interchangeable with Sanofi’s Lantus, a long-acting insulin analog. FDA Acting Commissioner Janet Woodcock praised the action as “momentous,” emphasizing the agency’s support for a competitive marketplace for biological products and for increasing patient access to “safe, effective, and high-quality medications at potentially lower cost” (1).

FDA also emphasized its rigorous testing and analytical process for documenting that a biosimilar has “no clinically meaningful differences” with its reference product and that there are no additional risks for a patient switching to an interchangeable treatment. The key to expeditiously developing less-costly biosimilars is the ability of manufacturers to conduct analytical studies to confirm the structural and functional similarity of a proposed biosimilar to a reference product. Biosimilar manufacturers do not need to conduct many expensive and lengthy clinical trials to establish similarity, FDA explains, but may rely more on extensive structural and functional comparisons (2). To document interchangeability, however, the manufacturer has to conduct switching studies to demonstrate that there are no added safety risks or decreased efficacy for an individual moving between the reference product and biosimilar (3).

At the same time, FDA and other regulatory authorities recognize that large-molecule biologics are not identical copies of a reference drug and usually contain a mix of many slight variations of a protein. Manufacturers thus need to submit data showing similar variations compared to the brand. Additional animal toxicology and clinical pharmacology studies support the structural and functional assessments, and manufacturers look to control for the pattern and degree of variations between different batches to ensure that safety and effectiveness does not change.

Despite years of disappointment, recent progress has fueled predictions for significant growth in biosimilars, even before FDA’s action on Semglee. A report from IQVIA issued in October 2020 predicted an accelerated increase in biosimilar approvals and sales that will yield $100 billion in savings over five years. As biotech therapies account for a larger portion of the prescription drug market, the analysts expect an increase in biosimilar development programs and greater uptake of these competitive products by prescribers and patients (4).

Similarly, a new analysis by Amgen on the current state of the US biosimilar marketplace predicts significant growth as more biosimilars launch at deep discounts and capture larger market share (5). In addition to financial savings, the analysts believe that payers and providers will support biosimilar uptake, as confidence grows in manufacturers’ ability to produce high-quality products and ensure reliable supply.

FDA also is assisting firms in navigating innovator patents and exclusivity periods with an update and expansion of its Purple Book of approved biological products. Budget legislation approved by Congress in December 2020 instructed FDA to include important patent and technical information on reference products to facilitate the development and approval process for biosimilars (6).

The legislators also are eyeing measures to deter innovator promotional messages that disparage follow-on competitors, spurred by FDA criticism of an Amgen promotional communication for undermining consumer confidence in biosimilars to its Neulasta (pegfilgrastim) injection. In July 2021, FDA’s Office of Prescription Drug Promotion (OPDP) sent Amgen an Untitled Letter criticizing the company for making a false claim of greater adverse events with the injection system used by biosimilars compared to the Amgen product (7). OPDP advised Amgen and other firms to “carefully evaluate the information presented in promotional materials for reference products or biosimilar products” to ensure correct product identification and avoid consumer confusion. 

Additional action on Capitol Hill may advance biosimilar use, such as legislation approved earlier this year by the Senate that increases public access to information on biosimilar and interchangeable products to help address patient concerns. Even more important for biosimilar makers is to enact measures that enhance Medicare reimbursement for follow-on products by revising the payment formula for biosimilars under Part B and requiring favorable formulary placement by Part D drug plans.

1. FDA, “FDA Approves First Interchangeable Biosimilar Insulin Product for Treatment of Diabetes,” Press Release, July 28, 2021.
2. FDA, 

, Fact Sheet, accessed Aug. 12, 2021.
3. FDA, 

, Fact Sheet, accessed Aug. 12, 2021.
4. IQVIA, Biosimilars in the United States 2020–2021, Competition, Savings and Sustainability, Institute Report, Sept. 29, 2020.
5. Amgen Biosimilars, 2021 Biosimilar Trends Report, Current State of the Marketplace, Amgen (2021).
6. FDA, “FDA In Brief: FDA Enhances Purple Book to Support Transparency in Biosimilars,” Press Release, Feb. 24, 2020.
7. FDA, 

Letter to David Shechter, PhD, Senior Manager, Regulatory Affairs, Amgen


Vol. 45, No. 9
September 2021
Pages: 14-15

When referring to this article, please cite it as J. Wechsler, “Biosimilars Move to Center Stage,” 

Will FDA’s approval of Semglee create a surge in the development of interchangeable biosimilars?

Biosimilars Move to Center Stage

Amidst a very busy time for the agency, FDA formally unveiled its plan for revising and renewing its fee program for drugs and biologics, with an eye to gaining Congressional approval early next year. The program 

, is set to collect more than $1 billion in annual fees to support additional staffers and multiple initiatives in the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). The aim is to build on the current fee program [link to 8/20 posting your pub on new user fees for 2022] so that Congress will reauthorize the Prescription Drug User Fee Act (PDUFA VII) in time for it to be operational by Oct. 1, 2022.

The specifics for PDUFA VII, which will run from Fiscal Year (FY) 2023 through 2027, are spelled out in the new 

negotiated this past year by FDA and industry leaders. This lengthy description of proposals and policies will be further discussed at a virtual 

provide stakeholders with an opportunity 

to learn more about program changes and to weigh in on proposed enhancements, in comments due Oct. 28, 2021.

Along with specifying the fees industry will pay for FY 2023 through 2027 and relevant changes to timeframes for CDER and CBER to review and approve applications for new drugs and biologics, the 71-page PDUFA VII letter describes many new and expanded initiatives for enhancing oversight of certain therapies and for improving regulatory practices. There are additional pilot programs, timeframes for issuing new guidances, and an expanded range of FDA-sponsor meetings to smooth the path to approval for new therapies. A specific change extends the fee program to allergenic extract products under a one-year phase-in process at CBER. Oversight of combination products would be enhanced by policies governing human factor validation study protocols. The plan also outlines improvements in the process for assessing Risk Evaluation and Mitigation Strategies (REMS) and enhancements for hiring and retaining staffers in CDER and CBER.

To support the development of new treatments for rare diseases, FDA proposes a Split Real Time Application Review (STAR) pilot program to streamline the review process for new rare disease endpoints by allowing sponsors to split an efficacy supplement into two components. CDER and CBER also would provide faster staff input on certain novel issues raised during development through two new types of meetings with sponsors.

PDUFA VII also aims to enhance CBER oversight of cell and gene therapies (CGT) by expanding staff and resources for its Office of Tissues & Advanced Therapies (OTAT). One goal is to increase opportunities for manufacturers to gain added FDA feedback on these complex products. CBER also would issue guidance on clinical trial design for CGTs, on capturing post-approval safety and efficacy data, and on information needed in post-approval studies for Regenerative Medicine Advanced Therapies (RMATs).

Another strategy for avoiding delays in the development and approval of innovative products aims to enhance the review of drug manufacturing quality and to advance innovative manufacturing technologies. The user fee program would expedite the development of chemistry, manufacturing, and controls (CMC) data for products likely to provide notable patient benefit, with a focus on science and risk-based approaches through a CMC Development & Readiness Pilot to accelerate assessment of manufacturing data for relevant complex products. Related to this, FDA will hold a public workshop to discuss best practices, barriers, and overall strategies for advancing innovative manufacturing.

FDA also aims to limit development delays related to manufacturing operations by reviewing and updating tools for inspecting biopharma facilities. Building on the increased use of alternative oversight approaches adopted during the pandemic, FDA will issue new guidance on the use of additional facility assessment tools, including plant records and reports from other regulatory authorities.

An important PDUFA initiative will support broader use of real-world evidence (RWE), particularly to meet post-approval study requirements. One new pilot will provide early advice on the acceptability of such data in added labeling claims and indications for approved products. Another is to advance the use of RWE by seeking agreement on what data, study designs, and regulatory approaches can generate RWE that will support regulatory decisions. FDA and sponsors will work to address post-marketing required studies (PMRs) earlier in the pre-market setting and to establish processes for manufacturers to be released from PMR requirements deemed no longer necessary.

Related to this is added user fee support for incorporating more RWE into FDA’s Sentinel System to enhance post-market monitoring. Similarly, FDA seeks to advance its use of digital health technologies (DHTs) in drug development and review, building on broader agency plans for leveraging cloud technologies and related approaches through its Technology & Data Modernization Action Plan. CBER, in particular, will move to replace its older IT system as part of FDA’s IT modernization initiative.

Pharmaceutical and biotech manufacturers strongly support and are willing to pay considerable sums to fund the numerous demonstration projects, policy updates and added meetings designed to further speed new medicines to patients. The PDUFA “goal dates” for FDA to approve a pending new drug application or biologics license application are carefully watched by all concerned players for indications that a new therapy is moving forward as expected or may run into delays.

FDA formally unveiled its plan for revising and renewing its fee program for drugs and biologics.