Jill Wechsler

Despite shortages in critical components and experienced staff, vaccine manufacturers anticipate significant boosts in output in the coming weeks for these innovative products. The companies with the first Emergency Use Authorizations (EUAs) for vaccines to combat the pandemic produced only 63.7 million doses as of January 31, 2021, far less than the initial goal of 300 million doses, raising skepticism of even meeting the 200 million-dose goal for the end of March 2021. But in recent weeks, the prospects for greater vaccine output have brightened, and the entry of Johnson & Johnson into the market should help. To prevent future production delays of critical products, the Biden administration is examining supply chain vulnerabilities for pharmaceutical ingredients as part of a longer-range consideration of products important to public health.

Efforts to expand production of vaccines to combat COVID-19 have had to overcome a wide range of shortages in materials, qualified facilities, and experienced workers such as engineers and quality control managers. A particular problem is scarce supplies of the ionized lipid nanoparticles needed for the Pfizer-BioNTech and Moderna mRNA vaccines. Only a handful of companies previously produced very small amounts of lipids, most for clinical trials involving rare disease treatments. More contract manufacturers now are licensing the lipid technology, but production scale-up has been a slow process. In addition, finish-fill operations have emerged as serious bottlenecks due to shortages affecting key components for new and revised operating lines plus requirements for high levels of sterility.

At a recent hearing before the House Energy & Commerce subcommittee on Oversight & Investigations, leading vaccine makers outlined efforts to enhance production and packaging processes. Pfizer chief business officer John Young summarized company plans for boosting vaccine shipments from 5 million to 13 million doses per week by the middle of March. Similarly, Moderna president Stephen Hoge outlined efforts to deliver millions of doses by the end of March and other increases leading to a total of 700 million doses this year.

Johnson & Johnson now expects to provide 100 million doses of its single-dose adenovirus vaccine by the end of June 2021, starting with 20 million doses by late March, following FDA granting Emergency Use Authorization (EUA) for the product. Janssen vice president Richard Nettles described for the House committee how the company had to assess nearly 100 potential production sites to find eight able to support its accelerated development timeline. Drug substance production takes about two months and is being done at Emergent BioSolutions in Maryland and at Janssen’s Netherlands plant and another facility in India, Nettles explained. And another five to six weeks are needed to produce, test and release the drug product, which is occurring at U.S. sites in Indiana, Michigan and Pennsylvania, plus operations in Spain, Italy, India and Africa.

Pfizer/BioNTech now projects 2021 global production to reach 2 billion doses, almost double early estimates. Some of that increase is due to FDA approval for extracting 6 doses per vial, as opposed to 5 doses originally approved. Pfizer CEO Albert Bourla provided further details on company production scale-up in conjunction with President Joe Biden’s visit to Pfizer’s Kalamazoo, MI manufacturing facility on February 19, 2021.

 Bourla cited plans to add new formulation suites and lipid production in Kalamazoo and at its research site in Groton, CT. Additional finish/fill lines have been established at its McPherson, KS site. This expansion, together with contracts with two additional U.S. contract manufacturers and improved processes, will enable Pfizer to reduce the time needed to produce vial-ready product from 110 days to 60 days. Innovations involve doubling batch size to increase yield and utilizing more efficient lab test methods to reduce release times.

In addition, Pfizer’s vaccine will be easier to ship and store with FDA approval of higher temperatures—that is sub-zero (-15 to -25C), as opposed to the ultra-cold level initially authorized. That change is based on stability studies conducted over the past nine months and should facilitate distribution to pharmacies and smaller health facilities.

Moderna’s production gains arise from added efficiencies in creating batches of the drug substance at its facility in Norwood, MA and at the Portsmouth, NH plant operated by contract manufacturing partner, Lonza, Ltd. Moderna also is expanding its fill-finish process agreement with Catalent and looking to contract with another partner. And the company expects to speed up manufacturing runs with FDA approval of providing 15 doses per vial, filling up the empty space in vials that currently hold 10 doses.

The difficulties for manufacturers in securing critical ingredients for vaccine production, packaging and delivery has prompted the Biden administration to assess the situation as part of a larger review of shortages related to components of critical industrial products. In an Executive Order issued Feb. 24, 2021, President Biden initiated a comprehensive review of supply chain risks for active pharmaceutical ingredients (APIs), critical minerals, semi-conductors and large-capacity batteries.

 The aim is to identify factors underlying shortages and supply interruptions of these products and steps the government can take to address relevant problems in the short term. Pharmaceutical products are considered particularly vulnerable in a pandemic or other global crisis due to the high proportion of offshore production of APIs.

To reduce such problems in the future, the White House plans to examine more broadly U.S. supply chain issues related to products important for public health and biological preparedness, as well as for national defense, communications technology, food production and the industrial base for energy, transportation and communications sectors. Federal agencies will review goods and materials vulnerable to supply chain disruptions, locations of key manufacturing and production assets, the availability of alternative sources for critical goods, and issues arising from a failure to develop needed domestic capabilities. This initial review of supply chain vulnerabilities leaves off the more strident “Buy American” rhetoricof the Trump administration, but it opens the door to further initiatives to support more “on-shoring” of biopharmaceutical production.

https://energycommerce.house.gov/committee-activity/hearings/hearing-on-pathway-to-protection-expanding-availability-of-covid-19

https://pfe-pfizercom-d8-prod.s3.amazonaws.com/2021-02/Biden%20Visit%20Press%20Statement%20-02.19.21.pdf?0_.cWRfs1JDNo1JfJR9EQHDmb7.Okaa2

https://www.whitehouse.gov/briefing-room/statements-releases/2021/02/24/fact-sheet-securing-americas-critical-supply-chains/

Articles

Vaccine manufacturers anticipate significant boosts in output in the coming weeks.

COVID-19 Vaccine Makers Overcome Challenges to Ramp Up Production

In a highly publicized challenge to unbalanced marketing of an opioid painkiller, FDA issued a public statement and press release, along with a sharp warning letter rebuking AcelRx Pharmaceuticals for its glib and simplistic messaging on painkiller Dsuvia.

 The admonishment signals FDA’s intent to take strong action against misleading promotion of high-risk medicines, perhaps also seeking to deflect outside criticism of acting commissioner Janet Woodcock for supporting the approval of certain risky pain medicines when director of the Center for Drug Evaluation and Research (CDER).

FDA’s main objection in this case is that AcelRx’ s “tongue and done” headline highlights Dsuvia’s easy administration, while also minimizing product risks. FDA cites banner headlines with large type and illustrations touting a one-step administration process. At the same time, the message requires viewers to scroll through paragraphs of text to find limitations of use and important safety information.

 Such skewed messages here are doubly troubling to FDA, as this pain medicine is subject to a risk evaluation and mitigation strategy (REMS) to restrict its use, and its label carries a boxed warning highlighting the need to avoid misuse through careful monitoring and administration.

The agency’s criticism of this unbalanced presentation of risk/benefit information reflects a common complaint of pharma promotions and follows a 2009 draft guidance on the topic.

 This warning letter is the first compliance action taken by CDER’s Office of Prescription Drug Promotion (OPDP) this year and could be a signal of more actions of this sort to come. OPDP has been fairly quiet in recent years in challenging industry marketing activities, but this announcement aims to signal the agency’s “commitment to combat inappropriate opioid use” and its willingness to challenge violative marketing for high risk products in general, and opioid therapies in particular.

OPDP also is responding to changes brought by pandemic by doing more to challenge misleading or inaccurate messages related to treatments for COVID-19, according to a review of the Office’s annual report. In outlining priorities and programs for this year, acting OPDP director Katie Gray also notes a continued focus on ensuring balanced communications on high-risk drugs.

https://www.fda.gov/drugs/drug-safety-and-availability/fda-issues-warning-acelrx-making-false-and-misleading-claims-about-risks-and-benefits-dsuvia?utm_medium=email&utm_source=govdelivery

https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/acelrx-pharmaceuticals-inc-613257-02112021

https://www.fda.gov/drugs/news-events-human-drugs/opdp-reflects-2020-looks-forward-2021-it-helps-ensure-prescription-drug-promotion-truthful-balanced

FDA issues a sharp warning letter rebuking AcelRx Pharmaceuticals for its ”glib and simplistic” messaging on painkiller Dsuvia.

FDA Blasts Misleading Opioid Promotion

Despite critical disruptions and added challenges posed by the coronavirus pandemic this past year, FDA annual reports on drug regulatory programs and policies confirm successful efforts for meeting review time frames and updating policies and programs. These reviews of FDA initiatives and activities recapitulate efforts to assess and approve new drugs, generic drugs, and biologics and strategies for advancing new initiatives, which appear timely as FDA continues to renegotiate revisions and expansion of user fees paid by manufacturers to support FDA oversight and review activities.

Several reports from the Center for Drug Evaluation and Research (CDER) summarize efforts to ensure drug quality and to maintain a steady pace in new drug review and approvals despite limitations and pressures imposed by the pandemic. A report on new drug approvals in 2020 documents the 53 novel drugs and biotech therapies approved in 2020, describing a range of innovative oversight strategies to evaluate product safety and efficacy.

 The report also notes approval of additional uses for certain existing therapies, evaluation of new biosimilars, and the importance of expedited review programs in facilitating patient access to critical medicines.

More specific demographic information on the clinical trials supporting the review and approval of these novel drugs is provided in the 2020 Drug Trials Snapshots Summary Report.

 That report presents data on demographic groups participating in these key studies and how such enrollment may inform product safety and efficacy. In addition, CDER activities for protecting public health during the pandemic are outlined in an annual Drug Safety annual report that describes efforts to ensure appropriate tracking and reporting of safety issues, some related to broader uses of the agency’s Sentinel System.

Separately, an annual report from CDER’s Office of Product Quality (OPQ) highlights the use of alternative tools for on-site facility inspections to support the timely approval of new drugs, an effort that avoided the need for 153 site visits.

 OPQ notes its role in advancing CDER’s emerging technology program and efforts to advance continuous and semi-continuous manufacturing and continued development of its knowledge-aided assessment and structured applications (KASA) program for evaluating new drugs, starting with solid oral dosage forms. Another main goal is to move forward with a new framework for assessing and identifying mature quality management systems by manufacturers.

OPQ also cites its efforts to support the approval of 942 generic drugs last year, including more first generics, complex generic therapies, and biosimilars. This involves coordination with CDER’s Office of Generic Drugs (OGD) in bringing new generics to market quickly and efficiently, especially to offset shortages in medicines critical to treating patients infected by COVID-19, as is outlined in the OGD annual report.

 It discusses efforts to update the OrangeBook, publish guidances on specific product development standards, advance the science on complex generics, and collaborate with foreign regulatory authorities to support wider global access to generic drugs. OGD is poised for a major reorganization beginning this year, which aims to update operations to better handle a steady rise in abbreviated new drug applications (ANDAs).

The challenges in continuing to speed new oncology therapies to patients are presented in an annual report from FDA’s Oncology Center for Excellence (OCE), which enumerates its achievements last year in overseeing the approval of multiple new indications and market approval of cancer treatments, including several new formulations.

 OCE director Richard Pazdur emphasizes the importance of addressing the needs of cancer patients during the pandemic with initiatives to permit more flexible clinical trials and remote communications. OCE also is continuing its Project Orbis collaborative review of new cancer therapies with other regulatory authorities to speed access to cancer treatments around the world.

Similarly, the annual report from the Center for Biologics Evaluation and Research (CBER) outlines how it met milestones for reviewing new therapies and for ensuring product safety.

 CBER director Peter Marks highlights the Center’s involvement in the development and evaluation of vaccines against COVID-19. In addition, CBER approved several novel biologics and blood reagents, provided advice to sponsors through virtual meetings, and continued to support pilot programs to advance modern manufacturing and regenerative medicine. Separately, Marks issued CBER’s list of new guidances slated for release in 2021.

 This relatively short list of only 14 planned advisories reflects the considerable progress made last year in issuing more than 20 guidances, including several related to development and emergency use of new COVID-19 vaccines and therapies.

In January, CDER also published a much longer list of planned guidances for 2021—more than a hundred, including 42 new items.

The largest categories involve clinical studies, generic drugs and agency procedures, and new categories were added for biosimilars, compounding, pharmacology/toxicology and the animal rule. New guidances on the list involve the use of real-world data, developing antisense drug products, and demonstrating efficacy in a single trial.

FDA may gain some added resources for its evaluation of new treatments to combat COVID-19 from a Congressional proposal to make an extra $500 million available to the agency this year, on top of its budget for 2021 headed for final approval on Capitol Hill. The funding boostrecognizes the considerable added work that FDA has taken on to support the development and oversight of new vaccines, therapeutics and medical products, as multiple applications for EUAs and product approvals have overloaded the agency.

https://www.fda.gov/media/144982/download

https://www.fda.gov/media/145718/download?utm_medium=email&utm_source=govdelivery

https://www.fda.gov/media/145716/download

https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/office-pharmaceutical-quality

https://www.fda.gov/drugs/generic-drugs/office-generic-drugs-2020-annual-report

https://www.fda.gov/about-fda/oncology-center-excellence/oce-annual-report

https://www.fda.gov/vaccines-blood-biologics/fy-2020-report-director

https://www.fda.gov/media/120341/download

https://www.fda.gov/media/134778/download

Despite challenges and disruptions posed by the coronavirus pandemic this past year, FDA annual reports on drug regulatory programs and policies confirm successful efforts for meeting review time frames and updating policies and programs.

FDA Documents Recent Achievements, Maps Plans for Continued Progress

With two innovative vaccines beginning to provide protection against the coronavirus for Americans and people around the world, and more on the way, scientists and policy-makers are looking more sharply at the lag in identifying and producing medicines to moderate early infections and to treat seriously ill patients. And the demand for effective therapies has escalated with the emergence of new COVID-19 variants.

Much of the blame for limited progress in this area lies with the lack of collaborative, centralized research programs able to identify and collect valid data on existing and new therapies. Instead, hundreds of researchers and clinicians have launched multiple trials of available drugs, most without adequate controls and size needed to yield useful evidence. Moreover, the focus on developing monoclonal antibodies (mAbs) that are delivered intravenously has created difficulties for patients and providers.

Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), noted in a recent interview with JAMA that while some available therapies have been effective in treating some patients, there has been no “knock-out punch” against the virus. Administering mAbs, he explains, means a patient has to go to a hospital or infusion center, which are ill-suited for treating outpatients in early disease stages. What is needed, he said, is a “concerted effort” for developing effective combination antiviral agents that can suppress COVID-19 completely, as done for HIV and hepatitis C.

Moncef Slaoui, former co-director of Operation Warp Speed (OWS), similarly acknowledged the need for mAbs with formulations that permit subcutaneous or intramuscular injection to facilitate outpatient delivery to patients with mild infections. He lamented that the centralized approach for developing vaccines did not work for therapeutics, where multiple researchers have launched hundreds of small trials, most with no controls.

One sign of progress is FDA’s recent authorization of a mAb cocktail from Eli Lilly that features a notably shorter infusion time frame than other similar treatments. FDA granted emergency use authorization (EUA) for this combination of bamianivimab and etesevimab with an infusion time of 16 minutes, instead of an hour.

 And ongoing tracking of testing for therapeutics to treat COVID-19 by BioCentury anticipates the release of data from late-stage studies on nearly 30 therapies, including 10 immune modulators in phase 3 or 4 trials plus studies on antimicrobials and antithrombotics.

Several immune modulators are participating in the collaborative ACTIV-1 IM trial organized by the National Institutes of Health (NIH). More notable is the RECOVERY trial in the United Kingdom, which has yielded important clinical results on potential pandemic therapies, including a recent study showing that the rheumatoid arthritis treatment Tocilizumab from Roche can reduce deaths in hospitalized COVID-19 patients when combined with the steroid dexamethasone. Equally important is earlier RECOVERY findings that the much touted malaria drug hydroxychloroquine was not beneficial.

But aside from a handful of such collaborative studies, most COVID-19 research on potential therapeutics has been sponsored by individual biopharma companies and academic research centers. Janet Woodcock, who has directed OWS therapeutic development this past year on leave from her position as director of the Center for Drug Evaluation and Research (CDER), reports that only 5% of the more than 400 clinical trials underway worldwide could be considered sufficiently “randomized and adequately powered” to achieve statistical significance. At a webinar in January 2021 hosted by the Clinical Trials Transformation Initiative (CTTI), Woodcock, now FDA acting commissioner, lamented the waste and duplication created by a “plethora of small, single-center trials,” most without control arms and sufficient size and structure to yield results.

 Moreover, the situation has created shortages in research supplies and in personnel, as well as competition for patients at medical centers, she added.

Former FDA commissioner Rob Califf, now with Verily and Google Health, similarly reported that of thousands of interventional studies to test COVID-19 therapies listed on the ClinicalTrails.gov website, most have just a few sites and have been slow to enroll patients. And many trials continue to study questionable treatments, such as hydroxychloroquine and convalescent plasma.

An FDA report on the accomplishments of its Pandemic Recovery and Preparedness Plan (PREPP) last year noted that there are no new FDA-approved therapies for COVID-19, despite nearly 3000 clinical trials on record through data from Clinical.trails.gov and the World Health Organization as of November 2020. The report concludes by calling for broader use of adaptive trial designs and master protocols to avoid such waste and redundancy.

At the CTTI conference, research experts reported on progress in expanding collaborative research programs in the U.S., such as NIH’s ACTIV-3 and ACTIV-4 studies and the REMAP-CAP multi-center trial. A group of leading biopharma companies formed the COVID R&D Alliance last summer to collaborate in identifying and testing repurposed and new compounds through platform trials and data sharing. And the emergence of new virus variants is raising the need for more joint efforts, as FDA prepares new guidance to facilitate the testing and modification of vaccines, diagnostics and therapeutics to combat new pathogens, with an eye to encouraging more productive clinical research methods. Such initiatives aim to address the critical problems that have delayed effective development of COVID-19 treatments so far and to build support for more coordinated centralized clinical testing programs before the next pandemic.

https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-monoclonal-antibodies-treatment-covid-19-0

https://www.biocentury.com/article/634179

https://www.ctti-clinicaltrials.org/briefing-room/meetings/fastest-path-effective-covid-19-treatments-using-master-protocol-studies

https://www.fda.gov/media/145129/download

R&D on medical treatments lags notable success with vaccines.

Jill Wechsler

Articles

COVID-19 Vaccine Makers Overcome Challenges to Ramp Up Production

FDA Blasts Misleading Opioid Promotion

FDA Documents Recent Achievements, Maps Plans for Continued Progress

Where Are the Therapeutics to Combat COVID-19?