Jill Wechsler

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.

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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

Pressure to quickly and efficiently develop and test potential treatments for COVID-19 has led sponsors and research organizations to implement new strategies for determining product safety and efficacy in a broad range of patients. Collaboration is a leading theme as multiple biopharma companies look to study candidates in master protocols designed to compare several test therapies at the same time. More decentralized trials and adaptive studies and greater use of real-world data (RWD) and real-world evidence (RWE) are shaping protocols and revising patient recruitment and enrollment practices.

One approach is for clinical studies to identify and enroll more high-risk patients in order to accelerate data collection on product effectiveness. Eli Lilly, for example, 

 to test an experimental neutralizing antibody in nursing homes where residents and staff have been exposed to the virus. The aim is to see if the test drug (LY-CoV55), developed by AbCellera, can block the spread of infection among these highly vulnerable individuals. The plan is to enroll 2,400 patients in a Phase III study in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID) and utilizing its COVID-19 Prevention Network. Because long-term care facilities lack the infrastructure to conduct clinical trials, Lilly assembled a customized fleet of recreational vehicles with lab equipment and research personnel able to provide intravenous infusion of the test drug to patients at selected sites.

Another strategy involves studying asymptomatic adults in households with an infected individual to determine if the test drug can prevent the spread of infection to healthy individuals. 

NIAID is jointly conducting a Phase III trial with Regeneron Pharmaceutical

 that will enroll 2,000 adults in such homes to study whether its investigational REGN-COV-2 double monoclonal antibody (mAb) combination therapy can block contagion compared to placebo based on assessment of results one month following administration.

The Lilly/AbCellera mAb also is being tested in hospitalized COVID patients as part of a larger randomized controlled trial (RCT) organized by NIAID and other research entities. Based on a master protocol, the study is designed to test multiple mAb treatments, with flexibility to enroll additional patients later in the trial and shift study participants to another therapy that shows more promise. Initial participants are randomly assigned to receive a test drug or placebo and then assessed for symptom change after five days. These findings will determine whether investigators should administer the drug to larger patient cohorts and to more seriously ill individuals.

Biopharma companies are collaborating to support platform trials able to test multiple therapies. For example, the COVID R&D Alliance involving 20 biopharma companies 

announced in early August the launch of the I-SPY COVID platform trial

 to test three drugs from Amgen, AbbVie, and Takeda on seriously ill, hospitalized individuals. The aim is to determine if these anti-inflammatory treatments can provide relief by impacting the immune system of such individuals, as measured in their need for respiratory support. The trial utilizes Quantum Leap Healthcare Collaborative’s adaptive platform trial design, which aims to minimize the number of study participants and time required to obtain data by assessing multiple therapies at the same time. In utilizing features of adaptive trials, the sponsors agree to drop those drugs that don’t show effectiveness and to add new test products that show some promise, as has been applied to research on new cancer therapies.

Another goal for the research community is to use innovative research strategies to enroll more diverse racial and ethnic populations in clinical trials for COVID-19 treatments and vaccines. Although FDA has issued guidance and emphasized the importance of such efforts for years, minority participation in clinical trials has remained low. At the same time, national tracking data indicates that hospitalization rates for black and Latino groups are nearly five times that of whites. Main factors for these disparities is that minorities show a higher prevalence of debilitating health conditions (obesity, heart disease, diabetes), poor healthcare, and greater exposure to contamination through jobs and crowded living conditions.

Researchers are working to overcome decades of mistrust in government health institutions through community outreach efforts. Sponsors seek to locate clinical trial test sites in neighborhoods with high minority populations and are working with local church groups and community organizations to overcome fear of medical institutions.

a growing recognition of the importance of testing new therapies

 in large, randomized, placebo-controlled, double-blind clinical trials as necessary for determining whether an experimental medicine has any real impact on preventing or treating infection by the COVID-19 virus.

Data disproving effectiveness claims for some highly touted drugs have focused attention on the need for sound, well-controlled studies that may confirm effectiveness, but perhaps only in certain patients with less serious disease, or that treatment may lead to serious side effects for others.

A look at how real world data and real world evidence are shaping more decentralized trial designs for potential COVID-19 treatments. 

Innovative Clinical Trial Designs Emerge from Pandemic

As biopharma companies and research institutes advance the development of promising vaccines against COVID-19, policymakers and health officials have intensified deliberations on strategies for ensuring fair and equitable distribution of anticipated preventives. The issue is important to health authorities across the globe and has emerged as a seminal topic in the U.S. amidst growing debate over healthcare disparities and whether high costs will limit access to critical treatments.

To build public support for a vaccine distribution plan even before any test product gains market approval, the National Institutes of Health (NIH) and the Centers for Disease Control and Prevention (CDC) have called on a special expert panel to tackle the allocation issue. At the agencies’ request, the National Academy of Sciences, Engineering and Medicine (NASEM) has formed a blue-ribbon committee of leading bioethicists, economists, geneticists, and public health authorities to quickly 

 for priority vaccine access to assist policymakers in the U.S. and other nations achieve equitable distribution of anticipated vaccines.

This project was launched July 24 with the aim of providing a final report by early October.

The NASEM panel will contribute to similar discussions by the Advisory Committee on Immunization Practices (ACIP), which regularly advises the CDC on overall vaccination policy. An ACIP COVID working group is collecting and analyzing information on pandemic vaccines under development and has held discussions and public meetings to identify high-priority groups for initial vaccination. There was further open public meetings in August and planned for September, and the ACIP committee will collaborate with the NASEM panel to avoid confusion and build public confidence in their recommendations.

The resulting distribution framework aims to identify first-tier vaccine recipients as well as populations that should be added as more vaccine becomes available. Individuals at higher risk will include those in higher age groups, with underlying health conditions, engaged in high-risk occupations, affected by racial and ethnic disparities, and in hard-hit geographic locations.

The experts also will consider how best to communicate the allocation recommendations to promote a sense of equity and to mitigate vaccine hesitancy. 

The NASEM panel held its second meeting Aug. 7

, moving quickly in order to issue a draft report by early September and then final recommendations by early October.

The very tight timeline is designed for the panel to present its framework in time to have an impact.

At the opening meeting of the NASEM expert panel in July, NIH director Francis Collins directed the group to consider the needs of individuals at highest risk of complications from COVID-19 and of essential workers in setting a distribution policy well in advance of having an approved vaccine for the disease. Collins also proposed early access for participants in late-stage vaccine clinical trials who receive a placebo, instead of treatment.

Whether there are 10 million or 100 million doses available early on will determine how far down the priority list health authorities can go, he explained, but with taxpayer money funding vaccine manufacturing ahead of time, the aim is to have millions of doses ready to go when authorities determine that one or more vaccines are safe and effective.

Even with an agreed-on plan for equitable access to vaccines, federal and state agencies and industry face a monumental task of transporting, distributing and administering millions of vaccine doses as fast and as efficiently as possible at the appropriate time. A serious complication is that there may be more than one approved vaccine, with products carrying different indications and dosing protocols.

Delivery requirements will vary depending on product temperature, storage and handling requirements. With some vaccines requiring two doses, it will be important to keep track of who needs a second dose and when and where. Systems also are needed to track and report adverse events, as well as overall immune response.

While the CDC normally manages vaccine distribution to state agencies, especially for children, uncertainty has been generated by talk of the military stepping in to handle main logistics, as proposed by the administration’s Operation Warp Speed initiative. State and public health officials are wary of federal pandemic planning efforts so far, given the lack of coordination and effectiveness in distributing COVID-19 test kits and personal protective equipment to healthcare providers and facilities.

Shortages continue in those categories, and in supplies of those medicines that have demonstrated some effectiveness in treating sick patients.

The National Governors Association has advised state officials to start planning now for vaccine administration efforts, but acknowledges that uncertainty over who will be in charge complicates such efforts. Meanwhile, vaccine manufacturers will be looking for information on where to ship vaccines when available, initially for emergency use and more widely following product approval. That will require decisions on priority populations and locations to receive early vaccines, which hopefully will emerge in time to support efficient distribution efforts.

As biopharma companies and research institutes advance the development of promising vaccines against COVID-19, policy makers and health officials have intensified deliberations on strategies for ensuring fair and equitable distribution of anticipated preventives.

Debate Accelerates Over Who Gets COVID Vaccine First

FDA announced recently that it planned to resume “prioritized domestic inspections” for certain regulated products that had been put on hold by COVID-19 since March. The agency also would 

continue to conduct “mission critical” inspections

, utilizing methods to ensure the safety of all involved personnel. But it was unclear to biopharma companies from the July 10 press release which products and situations would warrant on-site visits and how the agency would respond where the pandemic made an inspection unsafe or unfeasible.

provides answers to such questions about when the agency will seek to visit a site and how it will respond when a needed inspection cannot be conducted safely. FDA explains that it may delay approval of new products in situations where travel restrictions and other concerns block a pre-approval inspection that the agency considers necessary.

Breakthrough therapies and regenerative medicine advanced therapies may gain approval even without a desired inspection. This policy also applies to other mission critical therapies used to diagnose, treat, or prevent a serious disease where no treatment alternative is available.

However, if an application involves a less critical medicine, and FDA has concerns about the adequacy of the facility but cannot conduct a site visit before the application’s “action date,” then FDA will issue a complete response letter that explains the reasons for delaying approval.

The agency will try to avoid such situations by utilizing other methods to access needed information on a manufacturing operation without an actual site visit. FDA will review earlier inspection reports, request records and information from the applicant and from the facility, and seek to obtain inspection reports from other trusted foreign regulatory partners. And for drugs made overseas where inspections continue to remain on hold, the agency will review product quality through sampling and testing at border control sites.

Similar assessments will apply to Bioresearch Monitoring (BIMO) surveillance of research sites, conducted to ensure that investigators follow policies to protect research subjects and to ensure the accuracy of clinical trial data. Here, FDA will continue to follow risk-based approaches that consider the nature of the application and site-specific factors.

The new guidance also provides flexibility for manufacturers looking to make changes in a facility or production process for an approved product affected by supply chain disruptions due to the pandemic. FDA will expedite such requests for drugs and biologics used in treating COVID-19 patients and for critical products in shortage situations. This will involve weighing the impact of post-approval changes and a firm’s efforts to mitigate the risk to product quality associated with a change. For critical products, FDA may permit a manufacturer to use a lower reporting category to facilitate the change and avoid C review and inspection of the changes.

FDA to resume “prioritized domestic inspections” for certain regulated products put on hold by COVID-19.

Author | Jill Wechsler