Jill Wechsler is BioPharm International's Washington Editor, jillwechsler7@gmail.com.

Jill Wechsler

Editor's Note: An earlier version of this article was originally published online on Oct. 6, 2020. 

As manufacturers advance Phase III testing of multiple COVID-19 vaccine candidates, industry and government authorities are focusing on the vast delivery, handling, and information systems needed to bring vital preventives efficiently to appropriate healthcare sites. Important complications are that some promising vaccines require two shots about three weeks apart and must be shipped frozen, one at sub-sub-zero temperatures. Additionally, it’s not clear how manufacturers, distributors, and public health officials will deal with multiple approved vaccines and the possibility that a later preventive will be more potent than earlier shots.

In hope of avoiding the confusion and mistakes that stymied access to diagnostic tests and personal protective equipment when the pandemic erupted six months ago, the administration’s Operation Warp Speed (OWS) has established an organization to oversee the delivery of COVID-19 vaccines, in addition to its more prominent role in funding the development of vaccines and therapeutics to combat the pandemic. A cadre of military logistics experts are monitoring production and planning for distribution of authorized medical products, headed by Gen. Gustave Perna, with support from the Centers for Disease Control and Prevention (CDC).

The OWS plan for vaccine production and distribution is outlined in its “From the Factory to the Frontlines” report to Congress issued Sept. 16, 2020 (1). The report notes that initial vaccine distribution will follow recommendations of the Advisory Committee on Immunization Practices (ACIP), which advises CDC on vaccination schedules and practices. ACIP’s recommendations will be shaped by a special panel formed by the National Academies of Science and Medicine (NASEM), which unveiled a framework on Oct. 2, 2020 for a four-phase approach to COVID-19 vaccine allocation and distribution (2). The panel called for the first phase to cover approximately 15% of the population in the United States, including front-line health workers and first responders, followed by individuals with underlying health conditions that puts them at higher risk of severe disease or death. The NASEM advisors do not support early access for minority populations per se but addresses the needs of disadvantaged groups by prioritizing early access based on health conditions and limited access to care.

Meanwhile, the CDC has provided advice to help state health departments update and expand vaccine distribution plans (3), a challenging task for local and tribal health departments charged with providing vaccines to priority populations. A CDC distribution contract with McKesson will handle initial vaccine deliveries from manufacturers to states and other jurisdictions.

While the logistics of the initial delivery process are relatively limited and straight-forward, later expanded distribution to multiple sites will be more complex. The real challenge, explained Nicolette Louissaint, executive director of logistics firm Healthcare Ready, is the “long, long dreaded last mile” within a state. The logistics really do differ, she explained at a briefing sponsored by the Alliance for Health Policy on Sept. 30, 2020, based on the population to be vaccinated and the facilities engaged. And vaccination of a broader US population in later phases will involve supplying doses to pharmacies and private practices where most individuals receive medicines and care.

The early phase of vaccine distribution is expected to run through mid-2021, followed by a second phase covering about 60–80 million essential workers and high-risk individuals. The experts don’t expect a sufficient volume of doses for the general US population until mid-2022. Distribution systems will differ for a single-dose vaccine, as opposed to two-dose products, where “it’s not just getting people to the pharmacy the first time,” Louissaint noted.

Challenging temperature-control requirements for lead vaccines developed by Moderna and Pfizer/BioNTech based on mRNA technology will limit how and where such products can be shipped. The logistics experts advise clinics and hospitals not to purchase special freezers to hold such products, as many local distributors should have such equipment. These early vaccines may have to be administered only by large hospitals and health clinics and involve more frequent deliveries of smaller supplies that can be administered before the product deteriorates.

Similarly, all parties face dealing with multidose vials that have to be used within hours of opening due to a lack of preservatives. The larger vials can be shipped and stored more efficiently, but administration may challenge many providers.

Even though CDC and most medical systems and distributors have advanced data systems for tracking vaccines, a main challenge will be integrating these systems and newly expanded federal IT programs designed to identify patients at risk and to track vaccine administration and individual responses. CDC is developing a new Vaccine Administration Management System (VAMS) to support existing state operations, with added capabilities for patient scheduling and supply management. But the new system is confusing, and integration may take some time.

Tracking a two-dose vaccination schedule adds to the difficulties. To ensure that individuals receive the right shots at the right time, vaccine resupply will have to occur within the allotted time frame, and information systems must track and record when an individual is vaccinated, with which product and where. Even for vaccines that require only one shot, it will be important to record every individual dose in order to identify any adverse events, patient illnesses, and the extent of immunity provided over at least two years.

“From the Factory to the Frontlines, The Operation Warp Speed Strategy for Distributing a COVID-19 Vaccine,” 

Report to Congress, Sept. 16, 2020.
2. NASEM, 

Framework for Equitable Allocation of COVID-19 Vaccine 

(Washington, DC, The National Academies Press).
3. COVI-19 Vaccination Scenarios for Jurisdictional Planning–Phase 1, Q4 2020, Aug. 26, 2020, https://int.nyt.com/data/documenttools/phase-1-vaccination-planning-scenarios-8-27/e0b519d686f4dda5/full.pdf 


Volume 44, Number 11
November 2020
Pages: 14–15

When referring to this article, please cite it as J. Wechsler, "COVID-19 Vaccine Distribution Raises Multiple Challenges," 

Articles

Experts fear confusion over allocation processes, cold-chain requirements, and IT systems needed to bring a COVID-19 vaccine to market.

COVID-19 Vaccine Distribution Raises Multiple Challenges

With nearly a thousand research programs for cell and gene therapies moving through the regulatory pipeline, FDA’s Center for Biologics Evaluation and Research (CBER) is struggling to monitor and advance these critical treatments while also providing advice and oversight of the safety and efficacy of vaccines to combat the pandemic. Regulatory officials predict FDA will approve 10–20 cell and gene therapies during the next few years, for a total of some 40–60 innovative products over the decade. Many of these treatments fall under FDA’s high-profile program for vetting regenerative medicine advanced therapies (RMATs), which also calls on CBER’s Office of Tissues and Advanced Therapies (OTAT) to provide extra support for those cellular and gene products that meet standards for RMAT designation.

At BIO’s digital annual conference in June 2020, OTAT Director Wilson Bryan outlined the “huge escalation” in his office’s workload prior to the pandemic, with a tripling of investigational new drug applications (INDs) for gene therapies in the past three years. Back in January 2019, then-FDA Commissioner Scott Gottlieb said that FDA expected to receive more than 200 INDs a year for advanced therapies, building on its current total of more than 800 INDs for cell-based or directly administered gene therapies then on file (1). And while research in these categories has slowed in recent months due to COVID-19, Bryan noted that it has been offset by manufacturers looking to tap cellular therapies and intravenous immunoglobulin to combat the pandemic.

Continued advances in this field were seen with the July 2020 approval of tecartus from Gilead subsidiary Kite Therapeutics, a new treatment for rare mantel cell lymphoma in adults not responding to other treatment and Kite’s second CAR T therapy (2). Novartis’ Kymriah led the field with FDA approval in August 2017, followed by three other cutting-edge treatments. Sarepta Therapeutics is advancing a gene therapy for muscular dystrophy, but FDA has delayed approval of BioMarin’s much anticipated hemophilia treatment. These and other development programs have been assisted by extensive guidance from FDA, as seen in a packet of six guidance documents published in January 2020. These advisories finalized agency policy on developing gene therapies to treat hemophilia, rare diseases, and retinal disorders and on providing long-term follow-up for these relatively untried products (3). A new draft guidance addresses the tricky issue of when similar gene therapies are sufficiently different for the purposes of gaining orphan drug designation and extended exclusivity (4). Manufacturers and other stakeholders recently filed comments on this proposal, seeking more specific examples and information from FDA on this important commercial policy.

A fairly lengthy final guidance addresses the need to provide sufficient chemistry, manufacturing, and control (CMC) information in applications, particularly on critical quality attributes and master cell banks (5). The advisory describes the importance of establishing manufacturing systems able to scale up from initial production of test products to commercial operation, noted CBER Director Peter Marks at the DIA virtual global annual meeting in June 2020. He observed that difficulties in establishing a reliable method for moving from laboratory production to a viable commercial process “without a hitch” can delay product approval. Strategies for dealing with variability and improved analytical methodologies can support product characterization, Marks added, as will efforts to establish standards in this area.

For FDA to continue to oversee and advance these innovative and challenging development programs efficiently, industry, patient groups, and research organizations are urging policy makers to increase CBER funding as part of recently launched user fee negotiations. So far, CBER has coped by shifting personnel and resources to meet user fee approval goal dates, Marks noted at the BIO conference. Some early meetings intended to assist sponsors in designing research programs for new therapies have had to be delayed or cancelled, he acknowledged, but most regulatory activities have moved forward.

However, CBER officials acknowledge that it will be difficult to maintain its schedule for supporting innovative therapies while also overseeing a growing number of COVID-19 vaccines moving into clinical trials, along with more new or updated vaccine manufacturing operations. All eyes are on FDA to fully assess the safety and quality of these critical preventives and to ensure the appropriate design and conduct of clinical studies.

CBER currently receives only a small portion of the annual user fee payments, about $135 million this year compared to $680 million for the Center for Drug Evaluation and Research (CDER), based on a much smaller number of biologics license applications CBER usually reviews compared to CDER (6).

But now the surge in INDs and applications for new cellular and gene therapies promises to narrow that disparity. Both CDER and CBER seek to recruit and train additional staff to assess the rising volume of innovative products and have been working to add some 200 agency reviewers and scientists to their offices. But efforts to expand staff in a very tight job market and through the agency’s cumbersome hiring process has been difficult, and the unique skills sought by CBER make recruiting particularly challenging.

1. S. Gottlieb, “Statement from FDA Commissioner Scott Gottlieb, MD and Peter Marks, MD, PhD, Director of the Center for Biologics Evaluation and Research on New Policies to Advance Development of Safe and Effective Cell and Gene Therapies,” 

, Jan. 15, 2019.
2. FDA, “FDA Approves First Cell-Based Gene Therapy for Adult Patients with Relapsed or Refractory MCL,” Press Release, July 24, 2020.
3. FDA, Search for FDA Guidance Documents, 

Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations, Draft Guidance for Industry

Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs), Guidance for Industry

Five-Year Financial Plan, Fiscal Years 2018-2019-2020-2021-2022, 2020 Update for the Prescription Drug User Fee Act Program, Report 


Volume 44, Number 9
September 2020
Pages: 14–15

When referring to this article, please cite it as J. Wechsler, "Surge in Cellular and Gene Therapies Challenges FDA," 

Regulators strive to review flood of advanced treatments while also vetting COVID-19 vaccines.

Surge in Cellular and Gene Therapies Challenges FDA

With the national election taking place at a time of desperate hope for new vaccines and therapies to combat the lethal coronovirus, FDA officials are struggling to maintain the credibility and independence of its drug regulatory process amidst accusations of intentionally delaying clinical testing for political reasons. In response to calls from Democrats for better strategies to prevent and treat COVID-19, President Trump ramped up charges that FDA staff look to limit access to needed therapies.

On August 22, Trump blasted FDA for blocking efforts to test and approve a COVID vaccine before election day. The entire research community acknowledges that sponsors and public health authorities are moving at record speed to test potential vaccines, enabling several sponsors to launch Phase III trials for promising products. While some early data may appear this fall, its unlikely that the public will see clear results on efficacy and safety from these very large studies in just two months. And with many of the early studies being conducted overseas, FDA would face challenges in approving a vaccine based on foreign clinical trial data.

 on August 22, 2020 that the “deep state” at FDA was “making it very difficult for drug companies to get people in order to test the vaccines and therapeutics.” The aim of agency staffers, he said, was to “delay the answer until after November 3”. 

To be able to claim some victory in tackling the pandemic on the eve of the Republican convention, the President trumpeted progress in treating patients with COVID convalescent plasma (CCP) from recovered individuals. At a Sunday evening press conference on August 23, 2020, FDA Commissioner Stephen Hahn joined President Trump and Health and Human Services (HHS) secretary Alex Azar to announce it had issued an 

emergency use authorization (EUA) for convalescent plasma

 that would make it easier to provide this treatment to COVID-19 patients. Trump heralded the move as “truly historic” and that FDA “really stepped up, especially over the last few days” to take this action.

At the press briefing, Hahn said the agency was encouraged by “promising data” from recent studies, and that analysis indicated that potential benefits of administering CCP outweigh risks. The evidence came from early reports on two small trials and a large expanded access protocol sponsored by the Mayo Clinic, which has provided plasma to more than 70,000 patients. A Clinical Memorandum from the Office of Blood Research and Review (OBRR) in the Center for Biologics Evaluation and Research (CBER), 

 showing that CCP “may be effective,” but that patients will benefit more if CCP is administered early in the course of disease and has higher antibody levels

Such “optimal patients” treated with plasma at the highest antibody titers showed “significant clinical benefit” in survival, Hahn said. But he sidestepped the White House claim that CCP was a “powerful therapy” that reduced mortality by 35%, noting that data so far did not come from randomized trials.

The EUA approval followed considerable analysis and debate within FDA and other federal health agencies over the scope and timing of an authorization. Last week, FDA indicated it would hold off on an EUA due to objections from leaders of the National Institutes of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID) that evidence of efficacy was too limited and that an EUA would make it harder to obtain clear risk-benefit information on how best to use this treatment. While some 150 clinical trials are testing plasma treatment, few are sufficiently randomized and controlled to produce clear data. Additional information on testing and developing convalescent plasma treatments is 

While some public health authorities support the EUA as not likely to harm patients and may be beneficial, recent events raise fears that the administration will continue to press for approval of a COVID vaccine before all the evidence is in. Hahn and his deputies have maintained that FDA will “rigorously” evaluate all the evidence on vaccine safety and efficacy and will refer to the agency’s earlier guidance recommending that vaccines be at least 50% more effective than placebo in preventing COVID-19 infection. And to ensure a transparent, unbiased, science-based evaluation, the agency will discuss clinical trial data on vaccine candidates with its advisory committee on vaccines, starting with a meeting tentatively scheduled for October 22, 2020.

All eyes will be on CBER Director Peter Marks, who 

 that he would resign if policy makers seek to approve a vaccine before data shows that it is safe and effective. According to press reports, Marks emphasized that so far FDA has not faced such political pressure, but that efforts to put something unsafe or ineffective through the approval process was his “red line.” Marks also said he would respond similarly if parties sought political gain by delaying approval of a vaccine shown to work safely.

Any perception that FDA approval decisions on vaccines and therapeutics reflect political pressures—as opposed to scientific evidence—stands to further undermine public confidence in the benefits and safety of any COVID vaccine. The already accelerated pace of product development has fueled anti-vaccine campaigns, and caveats raised by President Trump may further encourage vaccine hesitancy. Biopharma companies, research leaders and the medical community recognize the importance of an independent and credible FDA that maintains worldwide respect for its science-based regulatory decisions. Political moves that challenge the agency’s authority will only hinder efforts to address today’s world health crisis and the economic turmoil and public health catastrophe affecting billions.

FDA announced it had issued an emergency use authorization for convalescent plasma that would make it easier to provide this treatment to COVID-19 patients. 

FDA Caught in Political Crossfire

	Pharmaceutical companies developed, and FDA approved, dozens of new drugs and biotech therapies in 2019, as new discoveries in genomics and drug development continue to bear fruit. Even if 2019 approval numbers don’t set new records, the list includes notable breakthroughs, including Novartis’ controversial gene therapy Zolgensma; Vertex’s triple combo for cystic fibrosis; and new treatments for cancer, migraine, light-sensitivity, Parkinson’s disease, pneumonia, rheumatoid arthritis, tuberculosis, and urinary tract infections. The steady rise in applications for investigational therapies has made it difficult for the Center for Biologics Evaluation and Research (CBER) to keep pace, while the Center for Drug Evaluation and Research (CDER) continued to reorganize its Office of New Drugs (OND) to better assess and process a growing volume of submissions requiring special attention.

	At the same time, high price tags on transformative therapies heightened challenges for prescription drug reimbursement and payment strategies. Health plans, payers, and policy makers continue to debate multiple proposals for reforming drug coverage and pricing, ranging from wider importing of less costly products from abroad, federal government price negotiations, and specific limits on annual price increases and patient out-of-pocket costs. There’s much talk of “value-based pricing,” but legal and technical difficulties limit this approach. The resulting uncertainties make it difficult for manufacturers to plan research programs, devise pricing and marketing strategies, and commit to upgrades in production operations.

	A main cause of delay in bringing cutting-edge therapies to market in recent months has been difficulties in ensuring that production systems can ensure product safety and quality. The transition from pilot-scale to commercial manufacturing of gene and cellular therapies can be challenging and costly, observed CBER Director Peter Marks at the PDA/FDA Joint Regulatory Conference in September 2019. He emphasized the need for high-quality manufacturing of these new products, noting that treatments made from living cells or tissues often are not easily characterized, are susceptible to microbial contamination, and involve complex manufacturing materials and processes.

	CBER published several guidances on testing and producing new cellular and gene therapies and has promoted additional assistance for manufacturers of advanced technologies, Marks added. But limited gene therapy manufacturing capacity will continue to be a major problem as multiple new products gain market approval, particularly those for treating chronic conditions in larger patient populations.

	Such hurdles have prompted leading manufacturers such as Pfizer and Sanofi to make major investments in new biotech manufacturing sites. In addition, firms of all sizes look to work with contract manufacturing organizations with capacity for quality biotech production. To address these needs, as well as the difficulties of smaller developers of treatments for rare conditions, Marks backs the creation of a public-private consortium that can produce quality materials for preclinical and clinical studies more reliably and at lower cost.

	While manufacturing issues delayed access to new breakthrough therapies, such problems also continued to disrupt production of many common, low-cost medicines that are important for treating many serious health conditions. In response to concerns from Congress and the public, FDA issued a report in October 2019 examining the financial, manufacturing, and policy issues underlying short supplies of important prescription medicines in the United States. The analysts found that of 163 drugs that first went into shortage between 2013 and 2017, 62% of supply disruptions were associated with manufacturing or product quality issues; only a few had problems due to increased demand or natural disasters (1).

	A lead proposal from FDA officials is that manufacturers able to ensure a reliable supply of high-quality therapies should be able to command higher prices, an approach designed to encourage companies to invest in modern production systems able to avoid shortages, particularly for the low-priced, low-profit sterile injectables that companies often decide to abandon, rather than commit to the long-term upgrades needed to meet standards. To support this approach, FDA Acting Commissioner Ned Sharpless and CDER Director Janet Woodcock called for a system able to measure and rate a facility’s “quality management maturity” that can inform the public about its commitment to reliable quality production (2).

	In addition, the report included more common actions to prevent and address ongoing shortages, such as permitting longer expiration dates where justified or increasing penalties on firms that fail to provide timely and adequate notification of a likely interruption in production. FDA also could require manufacturers of certain drugs to conduct periodic risk assessments to identify vulnerabilities in supply chains and plans to mitigate such risks. And new international standards for harmonizing post-approval changes in drug manufacturing and formulation, as proposed in a new guideline (Q12) developed by members of the International Council for Harmonisation (ICH), would make it easier for manufacturers to modernize or alter a production facility that serves multiple markets.

	Manufacturers should “sell quality-not just medicine,” Woodcock stated in an FDA “voices” posting (3). Even though industry strongly opposed an earlier CDER effort to establish a system for rating companies on their ability to achieve quality drug manufacturing, Woodcock  maintained that a firm’s ability to reliably make a product in sufficient quantities and with sufficient speed to “ensure that supply consistently meets demand over sustained periods of time” should be a strong selling point. This discussion will continue in 2020.

Report–Drug Shortages: Root Causes and Potential Solutions

, Oct. 29, 2019.
	2. N. Sharpless and J. Woodcock, “Statement on FDA’s New Report Regarding Root Causes and Potential Solutions to Drug Shortages,” Press Release, Oct. 29, 2019.
	3. J. Woodcock, “T

o Help Reduce Drug Shortages, We Need Manufacturers to Sell Quality-Not Just Medicine


	Vol. 43, No. 12
	December 2019
	Page: 14

	When referring to this article, please cite it as J. Wechsler, "Quality Issues Offset Biomedical Advances," 

Problems in assuring reliable drug quality and supply dampens progress in bringing lifesaving therapies to market.  
