Jill Wechsler

If the debate has been heated over vaccines for adults and on the need for extra booster shots, FDA and its expert advisors will face even more scrutiny over the safety and value of vaccinating children under age 12. This population generally has had much lower COVID-19 infection rates than adults, but hospitalizations now have increased dramatically with the spread of the Delta variant, plus the return to school and other activities. The rise in pediatric COVID cases has alarmed the medical community, yet widespread vaccine hesitancy among many parents will make it critical to present strong safety results to gain broad protection for children.

The issue has moved to center stage as Pfizer/BioNTech announced plans to seek FDA approval this month of a smaller dose of its Comirnaty vaccine for children ages five-11, as well as similar approval from the European Medicines Agency and other regulatory authorities. As Pfizer did in expanding use of its vaccine to younger adolescents, the company will file an emergency use application (EUA) with FDA, based on results from a Phase II/III study of a two-dose regimen on over 4000 participants aged six months to 11 years.

 The study shows, according to Pfizer, that a lower 10-microgram shot for the five-to-11 age group, one-third the dose for adults and adolescents, provides a sufficiently robust neutralizing antibody response, while also supporting safety and tolerability in these young subjects.

The clinical trial also enrolled similar numbers of younger children ages 6 months to five years and hopes to provide topline readouts for this group by year-end. Children under age five received a lower three microgram dose for each of two injections, and results will be evaluated for two age cohorts, children two-five years of age and those six months to two years old.

This initial Pfizer/BioNTech statement did not present specific study data, but sponsor said it will submit its research results for publication in a scientific peer-reviewed journal, while also preparing its filing for FDA. The announcement specified that clinical trials in multiple regions enrolled 2,268 children ages five-11, with one-third receiving placebo. However, due to the generally lower infection rate among youngsters, there were too few numbers of ill participants to determine higher protection from the vaccine vs. placebo; that conclusion is based on a comparison of higher immune response levels in vaccinated vs. unvaccinated study participants.

The sponsor also notes that the lower dose for children can be linked to fewer side effects. In an early study that administered higher doses to young participants, adverse events were higher, although still comparable to older patients. But those children who received the lower dose experienced fewer incidences of fever, headache and fatigue, while also showing a strong antibody response. Even after increasing the size of the pediatric trial at FDA’s request, Pfizer found no cases of heart inflammation or other serious side effects that have occurred after vaccination with some older individuals, although the sponsors continue to monitor study participants for ongoing effects.

FDA staff will review the Pfizer data closely following its submission and is expected to ask its Vaccine and Related Biological Products Advisory Committee (VRPBAC) to weigh the results and make recommendations. If approved, the Advisory Committee on Immunization Policy (ACIP) at the Centers for Disease Control and Prevention (CDC) then will propose a specific vaccination schedule.

In response to earlier pressure from some quarters for FDA to quickly authorize preventives for younger children, agency leaders explained the need for very careful scientific evaluation to ensure that any vaccines for children are safe, as well as effective. FDA acting commissioner Janet Woodcock and Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), penned a statement in early September emphasizing that FDA “will follow the science” to fully assess the safety of current vaccines. Woodcock and Marks also warned parents not to pressure pediatricians to provide their children with a vaccine approved for adults and adolescents:as far as vaccines go, children are not just young adults.

https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-positive-topline-result

https://content.govdelivery.com/accounts/USFDA/bulletins/2f09162

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If the debate over vaccines for adults and the need for extra booster shots has been heated, FDA will face even more scrutiny over the safety and value of vaccinating children under age 12.

The Next Big COVID Challenge: Vaccines for Children Under 12

Amid 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 preventive to further protect those already receiving recommended doses. The day-long meeting Sept. 17, 2021 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 patients 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 (DCD). 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 BLA for the vaccine recently approved recently 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 a letter in Sept. 15 the 

 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 U.S. 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 anti-COVID vaccines.

In addition, Gruber and Krause were prominent co-authors of a leading article published in The Lancet questioning booster shots while much of the world still awaited initial COVID 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 commissioner Janet Woodcock provide them with all documents related to the study and implementation of a booster shot option plus communications between the agency and the White House on thisissue.

While the politicians look to make points over the policy debate, the VRBAC panel weighed the scientific evidence presented at the Sept. 17 session. That included current data on COVID-19 prevalence, infection and hospitalization rates from the Centers for Disease Control and Prevention (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 from 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 U.S. 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 still is whether still limited supplies of effective preventives should be provided to those already protected by authorized shots, while vaccines remain severely limited in many in regions of the world. The advisory panel did not address that question directly, and ample vaccine supplies in the U.S. 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 infection rates than booster shots for those already benefiting from protection. However, that possibility was further countered by the ranting of vaccine opponents about the safety and value of any COVID preventive, as heard in multiple presentations during the usual one-hour public comment period at the VRBAC 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.

https://www.fda.gov/advisory-committees/advisory-committee-calendar/vaccines-and-related-biological-products-advisory-committee-september-17-2021-meeting-announcement#event-information

https://www.nejm.org/doi/full/10.1056/NEJMc2113468?query=TOC&cid=NEJM+eToc%2C+September+16%2C+2021+DM295772_NEJM_Non_Subscriber&bid=617019028

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02046-8/fulltext

https://www.republicanwhip.gov/wp-content/uploads/2021/09/Letter-to-FDA-on-Political-Interference.pdf

FDA’s Vaccines and Related Biological Products Advisory Committee announces its recommendations for the authorization of a third dose of the Pfizer/BioNTech Comirnaty vaccine.

Vaccine Booster Battle Reveals Rifts Among Regulators, 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, 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. PhRMA (Pharmaceutical Research and Manufacturers of America) is spending more than $1 million on TV ads as part of a massive lobbying and communications campaign emphasizing thepotential harm to patients seeking cures for deadly diseases. A PhRMA full-page ad in the Washington Post ran on Sept. 15 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 Sept. 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.

https://catalyst.phrma.org/americas-biopharmaceutical-companies-to-congress-government-negotiation-is-the-wrong-approach

https://nopatientleftbehind.docsend.com/view/a6bxibzxysaeggm3?mkt_tok=NDkwLUVIWi05OTkAAAF_bv9xwWlCfMU6-GDrBC04DroGiq0E6LkCXRRXVM5gpeUxbbDlenS_eRSMkmpN7GABcT_aORMtrBCmuadp_SMHsP8iMIufGdRevi5t-hcrKZc4

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

Pharma Blocks Democrats’ Drug Pricing Plan

In an important step for modernizing drug formulation and biopharmaceutical development, FDA is launching a program to test the safety and suitability of novel inactive ingredients for use in new drugs and biologics. This final initiative, first proposed two years ago, supports a two-year pilot program to test up to four new excipients likely improve the effectiveness and safety of important new drugs.

 The aim is to encourage sponsors of clinical trials to formulate innovative therapies with those new excipients that FDA finds acceptable for use under this program.

FDA spelled out the pilot program in a Federal Register notice published Sept. 8, 2021.

 The agency explains that the initiative is open to novel excipients that have not been used previously in food or in FDA-approved products and how excipient manufacturers looking to participate should submit information by Dec. 7, 2021 on the novel inactive ingredient and its potential for enhancing public health. The program aims to evaluate four selected novel excipients likely to advance drug development, such as by increasing solubility for an oral formulation taken chronically. Those ingredients authorized under this program then may be used in the formulation for an experimental drug slated for clinical trials, provided that the sponsor demonstrates that it is safe for use in that specific treatment. After FDA approves a new drug or biologic utilizing the new excipient, that ingredient then would be added to FDA’s Inactive Ingredient Database, making it available for use by other manufacturers, including those producing generic drugs.

Manufacturers of drugs and biologics, as well as excipient developers, have long sought a process for FDA to evaluate new inactive ingredients prior to use in a new drug or biologic to support the development of innovative formulations without fear of delay or complications in FDA review and approval of the new product. Biopharma companies support this effort to avoid difficulties in formulating innovative drugs with available, established excipients, for example, in looking to stabilize proteins in new formulations. Excipient makers similarly acknowledge that they would be more willing to invest in production and characterization of novel excipients if it’s possible to gain FDA review of the product’s benefits outside of clinical testing for a new molecular entity. The initiative, as well as ongoing efforts to set international standards for excipient use, have potential to enhance drug formulation and support modern manufacturing and quality control efforts.

https://www.fda.gov/drugs/development-approval-process-drugs/novel-excipient-review-pilot-program?utm_medium=email&utm_source=govdelivery

https://www.federalregister.gov/documents/2021/09/08/2021-19335/center-for-drug-evaluation-and-research-office-of-new-drugs-novel-excipient-review-pilot-program

FDA is launching a program to test the safety and suitability of novel inactive ingredients for use in new drugs and biologics.

FDA Moves to Advance Innovative Excipients

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 U.S. and globally. This program is part of a broader $65 billion, 10-year pandemic preparedness plan announced Sept. 3 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.

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 national speech Sept. 9, 2021, 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 U.S. by tapping an already approved $2.7 billion in funding authorized last March. This effort was announced by White House coronovirus response coordinator Jeffrey Zients at a press briefing on Sept. 2, 2021, called to provide an update on U.S. efforts to ramp up production of anti-COVID-19 vaccines for patients in the U.S. and in other countries. Zients announced that the U.S. 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.

https://www.whitehouse.gov/wp-content/uploads/2021/09/American-Pandemic-Preparedness-Transforming-Our-Capabilities-Final-For-Web.pdf

https://www.whitehouse.gov/briefing-room/speeches-remarks/2021/09/09/remarks-by-president-biden-on-fighting-the-covid-19-pandemic-3/

https://www.whitehouse.gov/briefing-room/press-briefings/2021/09/02/press-briefing-by-white-house-covid-19-response-team-and-public-health-officials-54/

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 U.S. and globally.

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 

 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 U.S. 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 to 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 

 that the CBO analysis 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, 

, 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 U.S. 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 

. 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 a 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, according to the 

Kaiser Family Foundation Health tracking poll.

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. 

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 announced August 23, 2021, 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 

, so that Congress will reauthorize the Prescription Drug User Fee Act (PDUFA VII) in time for it to be operational by October 1, 2022.

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

 negotiated this past year by FDA and industry leaders. This lengthy description of 

 will be further discussed at a virtual FDA public meeting at the end of September. The aim is to provide stakeholders with an opportunity to learn more about 

 and to weigh in on proposed enhancements, in comments due October 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 REMS (Risk Evaluation and Mitigation Strategies) 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 NDA or BLA are carefully watched by all concerned players for indications that a new therapy is moving forward as expected or may run into delays.

FDA has revealed its plan for revising and renewing its fee program for drugs and biologics.

FDA, Industry Map New R&D Initiatives under Next User Fee Program

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

 announced Aug. 23, 2021 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 BLA (biologics license application) 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 U.S. 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.

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 three billion this year and four 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 age 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.

The first COVID-19 vaccine, Comirnaty, has received FDA approval. How will vaccination rates be effected? 

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 (NDA) or biologic (BLA) during fiscal year 2022. This record charge to evaluate new drugs and biologics reflects 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, 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 9,500 active INDs. Workload increases at both CDER and CBER altogether will require a $27 million increase in 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.

https://www.fda.gov/industry/fda-user-fee-programs/prescription-drug-user-fee-amendments

https://www.federalregister.gov/documents/2021/08/16/2021-17505/prescription-drug-user-fee-rates-for-fiscal-year-2022

https://www.fda.gov/industry/fda-user-fee-programs/biosimilar-user-fee-amendments

https://www.fda.gov/industry/fda-user-fee-programs/generic-drug-user-fee-amendments

While biopharma companies will pay more than $3 million to file an NDA or BLA application during fiscal year 2022, new fees for generic drugs will see modest or no increases and those for biosimilars may drop or hold even.

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 announcement by President Joe Biden 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 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 have to 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 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 ten years, so the added delay provides a “savings,” much applauded by PBMs and health insurers that currently benefit from manufacturer rebates.

https://www.whitehouse.gov/briefing-room/statements-releases/2021/08/12/fact-sheet-president-biden-calls-on-congress-to-lower-prescription-drug-prices/

https://phrma.org/resource-center/Topics/Cost-and-Value/PhRMA-Statement-on-President-Bidens-Remarks-to-Lower-Prescription-Drug-Prices

https://go.bio.org/index.php/email/emailWebview?md_id=29781

https://www.citizen.org/article/civil-society-organizations-call-on-the-department-of-health-and-human-services-to-combat-excessive-drug-prices/

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 announcement by President Biden.