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

Jill Wechsler

After a highly publicized dispute over FDA requirements for authorizing a vaccine to protect individuals from COVID-19, the agency was able to publish updated requirements for vetting and approving an Emergency Use Authorization (EUA) for new coronavirus preventives. In spelling out the data expected for such authorization, agency officials emphasized the importance of fully vetting the safety and efficacy of any new coronavirus vaccine through a highly transparent process to boost public confidence in the ability of vaccines to save lives. This review process, though, makes it unlikely that any vaccine currently in late-stage testing will be fully vetted and available to patients before mid-November, and more likely early next year.

 following several weeks of delay due to administration opposition. 

 spells out FDA’s standards for issuing an EUA, including median follow-up data for at least two months after vaccination of Phase III clinical trial participants, safety data on over 3000 vaccine recipients, plus reports on a total of five or more severe COVID-19 cases in the placebo group to address concerns about possible vaccine-induced respiratory disease.

FDA submitted the proposed guidance to the White House budget office in late September, only to meet objections from President Trump that it was “a political move more than anything else” to delay public access to a vaccine before the election. The President later stated that vaccine makers also opposed FDA’s stricter standards, but industry leaders rejected this claim. Pfizer CEO Albert Bourla stated that his company had not discussed vaccine guidelines with the White House, as that would undermine FDA’s independence. The Pharmaceutical Research and Manufacturers of America (PhRMA) and the Biotechnology Innovation Organization (BIO) further backed FDA’s clarifying guidance and transparency in the vaccine review process. And Moncef Slaoui, leader of the White House’s Operation Warp Speed initiative, added support for FDA’s plan to request adequate safety information.

Through the debate, officials in the Center for Biologics Evaluation and Research (CBER) emphasized that the EUA safety data requirement was already well known to vaccine manufacturers and that one aim was to assure manufacturers that FDA would hold all vaccine development programs to the same standards. CBER director Peter Marks further emphasized that the guidance sought to reassure the public that granting an EUA would not be a rushed decision on vaccine safety and efficacy to meet political goals, and that a vaccine EUA would require more data than for the more usual emergency authorizations for therapeutics and other medical products.

The release of the actual EUA guidance was almost anti-climatic, as CBER had provided most of the specifics the day before as background material for upcoming deliberations by the FDA Vaccines and Related Biological Products Advisory Committee (VRBPAC) 

. That session will discuss overall data requirements, which will be applied to all vaccine applications and be scrutinized publicly by this expert panel before any product is approved for broader patient use.

In several recent presentations, Marks explained the cost-benefit reasoning for authorizing faster, emergency-use of COVID vaccines, as opposed to requiring the more extensive data needed to file a Biologics License Application (BLA) usually required for vaccines. While the longer process is the gold standard for FDA vaccine approval, Marks noted at a meeting sponsored by the Friends of Cancer Research in late September that COVID vaccine trials will obtain sufficient data on safety and efficacy, as spelled out in guidance issued in July, but will not “require the bar to be so high as to cost lives.” The data in an EUA has to come from a well-designed Phase III trial that provides compelling information on efficacy, permitting the regulators to move forward without all the “bells and whistles” FDA normally requires. And authorities will be able to detect later safety signals due to the more advanced public health surveillance systems that were not established in the 1970s for the swine flu epidemic.

In an online interview with the Journal of the American Medical Association (JAMA), Marks described more fully the vaccine review and approval process, noting that even though the data in an EUA is stripped down from a BLA, it still can run to thousands of pages of line and tabular listings. An EUA review could take several weeks, as opposed to many months for a BLA, as there may be less extensive discussion between FDA and the EUA sponsor, but the submission will contain much of the same information on clinical studies and manufacturing. And with an accelerated review process, FDA will want to see a safety profile that is “incredibly clean,” Marks emphasized, for a vaccine to be used by millions of people.

In discussing CBER priorities at the annual meeting of the Food and Drug Law Institute (FDLI) this week, Marks explained that requesting clinical trial safety data for two months after final vaccine administration should provide enough time to capture most adverse events, while not extending the research so long as to delay access to a vaccine that can save lives. Most adverse events of concern show up within a six-weeks to two-months period after vaccination, justifying the two-months follow-up period.

After examining the first few vaccines, Marks anticipates that FDA will get a better sense of how well different products generate immune response vs. clinical response, which could greatly speed up the development process. But as these initial vaccines may have different effects on different populations, a highly transparent review process can help the public understand the pros and cons and decide which vaccine they want.

's Washington Editor, jillwechsler7@gmail.com.

Articles

Bio/pharma industry leaders support FDA’s newly published EUA guidance for COVID-19 vaccine authorization.

Industry Backs Clear FDA Standards for COVID Vaccine Authorization

For decades, FDA officials have offered both carrots and sticks to encourage industry adoption of advanced manufacturing methods able to ensure product quality and avoid drug shortages. The goal is to shift away from outdated batch manufacturing systems that increase the risk of production problems and raise costs by offering reduced regulatory oversight to firms able to document high-quality manufacturing processes and reduced product defects and regulatory snafus. However, pharma companies have remained leery of required reporting of performance measures for fear of revealing proprietary information and damaging reports, even resisting the agency’s more recent proposal for voluntary submission of information that would support rankings of firms based on quality culture and target achievements.

Now this initiative may gain impetus from operational and supply issues created by the COVID-19 pandemic. Curbs on international trade and travel have highlighted the dangers of relying on Chinese and other foreign manufacturers for supplies of APIs as well as antibiotics and other vital medicines, especially as the halt in most on-site facility inspections further limited oversight of overseas suppliers. FDA has moved to assess regulatory compliance and product quality through past inspection reports, product defect and adverse event filings, recall information, and consumer complaints. The agency can evaluate product quality through sampling and testing in agency labs and also review social media postings citing drug adverse event reports or patient concerns about accessing a needed therapy. And inspection information from foreign regulatory authorities under existing mutual recognition agreements (MRAs) can supplement in-house information.

The situation has bolstered support for encouraging biopharma manufacturers to shift more production to the United States, a high-profile initiative of the Trump Administration. In a Sept. 10, 2020 opinion piece on 

, FDA Commissioner Stephen Hahn and Deputy Commissioner Anand Shah proposed that investment in modern manufacturing technologies can increase the efficiency and reduce costs of medical products, while also reducing the regulatory burden on companies through real-time assessments of drug quality (1).

This proposal follows an August posting on FDA’s website by Hahn and Shah that describes more fully how advanced manufacturing can relieve strain on medical product supply chains and ensure quality production of vital medicines (2). They cite a partnership between the Center for Drug Evaluation and Research (CDER) and the Biomedical Advanced Research and Development Authority to explore how continuous manufacturing techniques can improve capacity for rapid medical countermeasure production during emergencies. And FDA is supporting the development of an International Council for Harmonization (ICH) guideline on continuous manufacturing as part of its Q13 proposal.

FDA continues to devise strategies that encourage pharma companies to invest in modern manufacturing systems, primarily through submission of data documenting how resulting products meet or exceed FDA quality standards. CDER has gone through several iterations of such quality metrics initiatives and now has stepped back to learn more about how firms already collect quality data and how they utilize this information to improve product performance and reliability (3).

In 2019, CDER’s Office of Product Quality (OPQ) visited 15 manufacturing facilities that volunteered to demonstrate how they use quality metrics and other measures internally to promote quality production. Important early takeaways are that it can take years for a manufacturer to get quality metrics and quality programs up and running, reported Lucinda (Cindy) Buhse, director of OPQ’s Office of Quality Surveillance, in a presentation to the September regulatory conference sponsored by the Consumer Healthcare Products Association (CHPA) (4). She noted that quality metrics are challenging because companies need to establish consistent methods and definitions within a facility, among a company’s different facilities, and between the company and its contractors. A successful program involves integrating quality metrics throughout a company, “up to the CEO,” she commented, so that these measures become part of a firm’s strategic plan and include predictive analytics that can help a company prevent deviations and production issues.

Also at the CHPA conference, Steve Greer, Corporate Quality Assurance External Engagement Leader at Procter & Gamble, described the benefits of participating in FDA’s site visit program in 2019. FDA raised questions about how P&G defines quality metrics, how it measures quality culture, which metrics are more predictive, and which are most important in providing insight into the health of the organization, he said (4).

One immediate need, Greer and Buhse emphasized, is for manufacturers to participate in a Dun & Bradstreet Quality Benchmarking Study funded by FDA, which aims to assess data from some 2000 industry establishments on what metrics firms use to assess manufacturing performance. D&B is partnering with the University of St. Gallen in Switzerland to conduct the study with the aim of improving global understanding of which quality management practices are most effective (5).

CDER also is moving ahead with a “feedback program” that involves FDA staffers analyzing and assessing quality data from a manufacturer and then reviewing its findings with the firm on a confidential basis. Thirteen establishments are submitting quality metric data on lot acceptance and invalidated out-of-specification rates, product quality complaints, quality culture, and process performance. CDER staffers began discussing their analyses with firms in virtual
meetings that began in May 2020 with an eye to completion by the end of this year.

This information from manufacturers, both through site visits and feedback discussions, will help FDA revise and finalize draft guidance on quality metrics. Buhse noted that manufacturers have raised concerns about data validation, how FDA will address different types of companies and products, and how the agency will deal with products made at multiple sites and sites that produce multiple products.

The larger vision for FDA is that the quality metrics program will advance from basic quality management systems to more mature, proactive quality management maturity (QMM) programs that focus on outcomes affecting patients. Buhse described QMM as a “larger umbrella” for quality metrics, involving supply chain management and change management that together provide evidence that a firm can reliably provide a drug to customers.

In a report on drug shortages in 2019, CDER makes the case that manufacturers able to demonstrate high-quality drug production, as documented through a QMM system, should be able to use this achievement as a selling point with purchasers and the public that want to avoid shortages and quality problems (6). A new pilot in 2021 may offer reduced routine monitoring to firms and facilities that demonstrate QMM. And FDA anticipates important gains if staff can spend less time and effort dealing with emergency shortages and other supply chain issues.

QMM involves meeting current good manufacturing practice standards as a minimum requirement for a firm to assure the proper design, monitoring, and control of a manufacturing process and facility. Advanced change management, as outlined by the ICH Q12 guideline on streamlining postapproval changes, requires a manufacturer to demonstrate a clear understanding of process performance.

Most important for QMM is a management commitment to maintaining a quality operation. “Management sets the tone” for a company to take ownership of quality, Buhse noted. This involves a focus on performance, on outcomes that affect patients, and on efforts to reduce those quality issues that lead to complaints. A company may need to update busines processes and be willing to invest in facility improvements, in needed equipment, in staff training, and in quality systems, while also supporting analytics able to forecast supply issues and market changes.

“Op-ed: The Coronavirus Pandemic Underscores the Need to Bring Drug Manufacturing Back to US

, Sept. 10, 2020.
2.FDA, “Investing in Advanced Manufacturing to Support Public Health Preparedness,” 

“Quality Metrics for Drug Manufacturing,” 

, accessed Sept. 10, 2020.
4.J. Ahearn, Moderator, “Creating Value Through Quality Metrics,” Conference Session at the CHPA 2020 Regulatory, Scientific, & Quality Conference, Sept. 1–3, 2020.
5.Dun & Bradstreet, “2020 Quality Benchmarking Study,” 

www.dnb.com/marketing/pharmaceutical-manufacturing-quality-study.html

Drug Shortages: Root Causes and Potential Solutions 2019

 Washington editor, jillwechsler7@gmail.com.


Volume 44, Number 10
October 2020
Pages 14–15

When referring to this article, please cite it as J. Wechsler, "Will COVID-19 Pandemic Finally Establish Drug Quality Metrics?," 

Drug shortages and supply chain challenges bolster FDA efforts to promote modern manufacturing.

Will COVID-19 Pandemic Finally Establish Drug Quality Metrics?

With little more than a month to go until the national election, President Trump 

 designed to reduce what consumers pay for prescription drugs, while also promising to protect coverage for pre-existing health conditions

. However, analysts noted that administration-backed legal challenges to the Obama Administration’s Affordable Care Act (ACA) stand to eliminate health benefits for millions, even as Americans face a critical need for health care under the threat of infection by COVID-19.

Most surprising is the President’s plan to distribute a $200 drug benefit card to seniors. The cards would help pay prescription drug copays for 33 million Medicare beneficiaries, at an estimated cost of $6.6 billion. Because the initiative is unauthorized and unfunded, the administration proposes to implement the benefit through a demonstration program and to cover the cost with anticipated savings from its earlier plan to link Medicare drug reimbursement to a “most favored nation” calculation based on lower drug prices in Europe. Without that program, though, which has not been enacted, there are no Medicare funds to support the discount cards. Earlier, the press reported that President Trump had proposed that pharma companies underwrite $100 discount cards for seniors in exchange for the administration dropping the plan to link US drug prices to those overseas, but that manufacturers had rejected that plan. This new drug card proposal is even less attractive to industry and likely to be challenged in court if it does move forward.

Separately, the administration promoted consumer access to less costly medicines from abroad in finalizing its Safe Importation Action Plan that permits states to import certain drugs from Canada. A 

 issued Sept. 24, 2020 authorizes states, Indian tribes, and possibly pharmacies and wholesalers to create their own import plans, which must meet FDA standards and gain agency authorization.

 Importation programs can cover drugs approved by Health Canada, but not many of the most expensive biotech therapies—making it difficult for the plans to meet the requirement of providing “significant cost reductions” to American consumers. The process is complicated, potential savings are unclear, and its impact is expected to be minimal.

FDA advanced the administration’s drug import program by publishing a 

outlining the standards and procedures for drug manufacturers to be able to import their own products approved for overseas sale

. The advisory specifies the process for pharma companies to obtain a National Drug Code for certain FDA-approved prescription drugs that are manufactured and intended for sale in a foreign country to permit the firm to offer these products at lower prices in the United States. When originally proposed last July, analysts predicted that few pharma companies were likely to implement this program and that it was not expected to have any impact on the US pharmaceutical market. But consumers facing high out-of-pocket costs for medicines often see drug import programs as an appealing way to gain access to less expensive drugs.

Indications that the White House aims to distribute “some” of the $200 drug discount cards before the November 3rd election, despite unclear funding or authority, drew sharp rebukes from Democrats that the President was promoting non-existent savings on pharmaceutical outlays merely to attract voters. Even advocates of US drug pricing reform recognize that the current Trump proposals are unlikely to save money for consumers or the government and believe that it’s more important for the administration to focus its health-related efforts on combatting the COVID-19 pandemic.

With little more than a month to go until the national election, President Trump announced a revised initiative designed to reduce what consumers pay for prescription drugs, while also promising to protect coverage for pre-existing health conditions. 

Trump Health Policies Again Thrust Drug Pricing and Access into the Spotlight

With all eyes on efforts to research and test potential vaccines and therapies to combat the coronavirus pandemic, fears about overly accelerated development programs has heightened demands for wider access to information on study protocols, statistical analysis plans, and early results. One aim is to address concerns that political pressure from the White House might lead to FDA authorization or approval of a COVID-19 vaccine before Phase III data have been fully evaluated.

Leading vaccine manufacturers have responded by taking the unusual step of disclosing full clinical study protocols for their late-stage randomized, blinded, placebo-controlled studies. After the CEO’s of nine companies pledged to collect sufficient data to demonstrate product safety and efficacy before seeking FDA approval, Moderna CEO Stephane Bancel made public its 135-page protocol specifying its plan for randomization of 30,000 patients, how they are selected based on age and likely risk, and listing of all recruitment sites in the United States. The document specifies the plan for blinding, randomized assignment to placebo, efficacy assessments, and statistical analysis plan for determining when the study meets its endpoints and that an independent data monitoring committee is slated to compare efficacy of vaccine to placebo initially when 53 and 106 cases are confirmed, and then after 151 cases of infection. An 

 is slated to compare efficacy of vaccine to placebo initially when 53 and 106 cases are confirmed, and then after 151 cases of infection

Pfizer and AstraZeneca similarly released their trial protocols, acknowledging the need for greater transparency in COVID-19 vaccine research. The Pfizer document specifies the vaccine candidate and dose for Phase II/III testing and the number of trial participants, including age groups and evidence of infection before vaccination. It describes dosing schedule, adverse event assessment, and the plan for interim analyses of data. Here, the sponsor will utilize an internal Pfizer committee to review data plus an external data monitoring committee to review cumulative unblinded data throughout the study. Pfizer 

a total of nearly 44,000 participants, half receiving the vaccine, in anticipation that this will yield 164 primary-endpoint cases within six months

a goal of 50% effectiveness, with statistical confidence to be met when 150 trial participants become ill

. The plan calls for only one interim analysis, compared to more for the other manufacturers, and it might be halted early if the vaccine is 50% effective with fewer cases of contamination.

These disclosures came on the heels of efforts to resolve a report of a serious adverse event in the AstraZeneca trial that halted its Phase III study, generating criticism of the company for failing to reveal specifics on the safety issue, which outside clinicians termed a rare spinal inflammatory disorder called transverse myelitis. Although clinical trials for the vaccine resumed quickly in the United Kingdom, Brazil, and South Africa, US studies remained on hold as officials at the National Institutes of Health (NIH) urged delay pending further investigation into the cause and nature of the adverse event and whether it was triggered by the vaccine or an unhappy coincidence. US authorities said they wanted to examine tissue or blood samples from the British patient to evaluate the case further and hopefully avoid increased vaccine hesitancy in the US.

The disclosure of usually confidential details on research plans responded to concerns raised by leading scientists and research authorities about the need for more transparency in vaccine studies to promote public confidence in the independence and reliability of clinical research on pandemic vaccines and therapies. Although vaccine developers were providing the usual public information on study sites and enrollment plans, experts continued to seek more details on statistical analysis plans that would allow more public assessment of adverse events and research outcomes. And they wanted to know when sponsors were likely to seek input from independent data safety monitoring boards on whether to stop a trial early—either to assess a safety issue or to file an emergency use authorization (EUA) with FDA. With the federal government providing billions in support of vaccine development programs, independent scientists insist that the public should have that kind of information.

Fears about overly accelerated development programs has heightened demands for wider access to information on study protocols, statistical analysis plans, and early results.

COVID-19 Vaccine Concerns Prompt Clinical Trial Transparency

President Trump has taken on the pharmaceutical industry in a surprise move making significant cuts in reimbursement for drugs covered by Medicare. The White House

Sunday, Sept. 13, 2020 implementing a policy to link payments for medicines provided through Medicare to prices charged in other industrial countries

. This time, though, the “most-favored-nation” pricing policy affects medicines administered through both Part D drug plans and in doctors’ offices under Medicare Part B—a major escalation from the administration’s earlier proposals affecting only Part B drugs.

In issuing an executive order to establish an International Pricing Index, President Trump looks to avoid a lengthy rule-making process that could take months, or years, to implement. Using this approach to establish this kind of innovative policy change clearly aims to appeal to voters before the looming national elections. Such a broad change is unlikely to go into effect by November 3 but can become a prominent campaign promise.

The Pharmaceutical Research and Manufacturers of America (PhRMA) issued a 

 blasting the administration’s “misaligned incentives” and “reckless attack on the very companies working around the clock to beat COVID-19.” 

The proposal “threatens America’s innovation leadership” as well as access to medicines for millions of seniors, PhRMA states.

Manufacturers are expected to file suit to block implementation of the policy if it goes forward. Meanwhile, other administration drug cost-cutting proposals remain in limbo, including efforts to legalize drug imports from Canada and to ban or limit rebates to pharmacy benefit managers (PBMs). This action by Trump clearly signals that earlier efforts to negotiate a price control deal with companies has failed and that the administration is willing to take on the pharmaceutical industry to bolster the President’s appeal to voters.

The White House issued an executive order Sunday, Sept. 13, 2020 implementing a policy to link payments for medicines provided through Medicare to prices charged in other industrial countries. 

Trump Escalates Drug Pricing War

In the wake of developments that have undermined public confidence in independent and science-based decision-making by FDA, industry leaders insist they will maintain high standards for clinical trials and regulatory submissions for new vaccines and therapeutics to combat COVID-19. Biopharma companies have invested enormous resources in developing new pandemic therapies but realize that Americans will reject new vaccines and treatments without strong confidence in the safety and efficacy of these products.

On September 3, eight prominent biotech industry executives 

the importance of rigorous clinical research and complete study data to support any authorization or approval of a new COVID vaccine or treatment. Issued by the Biotechnology Innovation Organization (BIO), the letter also calls on FDA to maintain its “historic independence as the gold-standard international regulatory body” to assure the public that its decisions reflect the “highest standards of scientific and medical integrity”

. Biotech leaders also urged politicians on both sides of the aisle to ensure that politics do not influence the development and approval of new medicines.

At the same time, five pharma CEOs stated they would not seek early authorization or approval of a new COVID treatment without a clear demonstration of product safety and efficacy from randomized clinical trials. During a 

 organized by the Geneva-based International Federation of Pharmaceutical Manufacturers and Associations (IFPMA)

, Pfizer chairman Albert Bouria stated that his company “will not cut corners” or take any action that would tarnish Pfizer’s scientific reputation. Eli Lilly will publish all data and “subject it to scientific scrutiny,” stated chairman David Ricks, also IFPMA president. Merck chairman Kenneth Frazier and others urged reliance on FDA advisory committees to gain added transparency to approval decisions and to guard against political influence.

Most recently, the CEO’s of nine biopharma companies currently developing COVID vaccines 

pledged to seek approval or emergency use authorization

 only after demonstrating product safety and efficacy through a Phase 3 clinical study that meets FDA requirements. The signers include AstraZeneca, BioNTech, GlaxoSmithKline, Johnson & Johnson, Merck, Moderna, Novavax, Pfizer and Sanofi

Separately, Moncef Slaoui, the top vaccine scientist on the administration’s Operation Warp Speed (OWS) initiative, publicly acknowledged that there is “very, very low” chance of successful vaccine results by October, and that he would resign “immediately” if there is outside interference in the vaccine vetting process.

These statements aim to offset fears that FDA might soften its approval standards due to pressure from the White House to make available a COVID vaccine in October. FDA commissioner Stephen Hahn recently said in an interview that a COVID-19 vaccine could be authorized for emergency use in some populations before the completion of Phase III studies. That followed questionable statements by Hahn supporting the Trump Administration’s characterization of convalescent plasma as a major advance in treating COVID patients. Continuing predictions from the White House about a vaccine being available in two months, and instructions from the Centers for Disease Control and Prevention (CDC) that state public health departments should be prepared to distribute a vaccine by the end of October, heightened concerns that political pressure will lead to some kind of authorization of a new vaccine before the November 3 election.

Hahn later tried to show his independence by posting an apology for exaggerating efficacy claims for convalescent plasma. The Trump Administration responded by dismissing health policy communications advisor Wayne Pines, evidently for encouraging Hahn’s plasma retraction. Hahn then removed top FDA press and external affairs staffers, who had been placed at the agency by administration officials and were seen as responsible for shaping Hahn’s enthusiasm for convalescent plasma.

The bottom line for FDA and for industry is to protect the integrity of the drug approval process from outside political agendas as vaccine data moves through the pipeline. Manufacturers recognize that premature approval of any products would erode FDA’s coveted gold-standard reputation, an imprimatur that is critical to market acceptance of complex and costly therapies around the world. Biopharma companies have much to gain from producing and distributing effective treatments able to slow or halt the lethal COVID pandemic, but even more to lose in reputation as well as financial health from providing patients with sub-potent or risky products.

Editor's Note: This article was updated to include information on response from some pharmaceutical companies.

Industry leaders insist they will maintain high standards for clinical trials and regulatory submissions for new vaccines and therapeutics to combat COVID-19. 