Jill Wechsler

The much-anticipated meeting of FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) last month addressed a number of critical issues related to testing and approval of vaccines to prevent COVID-19 infection, including policies and data requirements for determining that a pandemic vaccine can be considered safe and effective, particularly when based on more limited, early clinical trial data. A main goal for FDA officials was to reassure the public that it will take all precautions to ensure the safety of any vaccine approved under an Emergency Use Authorization (EUA).

The deliberations may have been shaped by halts in two major vaccine trials at the time due to unspecified safety issues. While studies sponsored by AstraZeneca and Johnson & Johnson’s Janssen unit resumed soon after the meeting, the study pauses were described by researchers as a sign that clinical trial safety systems were working as intended, as the analysts determined the adverse events were unrelated to the test vaccine candidates.

FDA standards for documenting vaccine safety was an important topic for VRBPAC review. The agency’s Center for Biologics Evaluation and Research (CBER) specified in its recent guidance document that it expects an EUA application to provide two months or more of safety data for at least half of the participants in a 

 following completion of the full vaccination regimen (see: https://bit.ly/36azRXc). As most serious side effects appear within six weeks of individual vaccination, this timeframe was designed to provide a sufficient period for detecting rare events such as vaccine-induced enhanced respiratory disease and to distinguish such conditions from COVID-19.

A particularly challenging issue for the advisors was how granting EUA status to an initial product could interfere with further assessment of the vaccine’s safety and with ongoing trials for other preventives. FDA and the expert panel advised that the sponsor of an authorized vaccine should continue blinded follow-up assessments for months following an initial authorization. The aim is to gain further information on vaccine efficacy and side effects, including rare adverse events and fuller comparisons among patient groups with differences in age, sex, comorbidities, and ethnic characteristics. And because information on how long immunity will last will be limited in initial data, both manufacturers and regulators look for additional guidance on determining what data needs to be collected further to indicate when boosters or additional vaccination would be advisable.

However, sponsors raised concerns that it may be unethical to retain trial participants in a placebo arm following EUA approval, raising an important consideration for the research community and health authorities.

At the same time, unblinding a trial could hinder continued development of alternative vaccines, as it would be difficult to enroll new subjects in randomized trials after a vaccine comes to market. Scientists and vaccine developers emphasize that it’s vital for research to continue on multiple preventives, as certain products may affect certain populations differently, and varying formulations may be more suitable for distribution in certain regions.

Most analysts, moreover, expect that some vaccines likely to gain approval in subsequent months may be more effective or provide stronger protection than the early products.

While randomized, placebo-controlled clinical trials are necessary to understand the true effects of a medical product on larger populations, individual participants may gain limited benefit and added risk in the face of a lethal pandemic where the risks are more stark.

An alternative research approach may be to use a newly authorized vaccine as a control in testing subsequent preventives, as a form of noninferiority trial. Such studies may take much longer and cost more to produce results, but could reduce the need for large placebo control arms that deny treatment for thousands.

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FDA’s Vaccines and Related Biological Products Advisory Committee addresses issues related to testing and approval of potential COVID vaccines.

Early Vaccine Authorization Raises Ethical and Logistical Challenges for Trial Sponsors

President-elect Joe Biden hit the ground running this week with initiatives to combat the widening coronavirus pandemic. The first public announcement from the Biden-Harris transition team was to name members of a 

 charged with initiating policies and actions to combat the fast-rising infection rate in the U.S.

The 13-member panel includes well-known scientists, physicians, and public health experts. Former FDA commissioner David Kessler is one of three co-chairs, in addition to former surgeon general Vivek Murthy and Yale University public health professor Marcella Nunez-Smith. The task force also includes former director of the Biomedical Advanced Research and Development Agency (BARDA) Rick Bright, former FDA official and national security advisor Luciana Borio, health policy advisors Ezekiel Emanuel and Atul Gawande, and infectious disease experts Eric Goosby and Michael Osterholm. The group has the task of advising the incoming Biden administration on initial public actions and communications related to the pandemic. It will consult with state and local officials on public health and economic steps to get the virus under control, along with ways to provide relief to families and to reopen schools and businesses safely.

In addition, the incoming Biden administration has formed a special coronavirus transition team to lay the groundwork for responding to the pandemic before and immediately after the official inauguration of the new president in January. This much larger task force includes transition officials from several federal agencies involved in dealing with COVID-19. This team of more than 50 federal officials is headed by a central coordinating group to oversee activities related to domestic programs, national security and foreign policy issues, and technical and legal policies. One aim is to set priorities for gathering information from the Departments of Health and Human Services (HHS), Homeland Security and State, among others, once the Biden transition team gains access to federal agency data and resources—normal and expected actions still being delayed by the Trump White House.

Initially, the Biden transition team has indicated it plans to work with and maintain operations of the current administration’s Operation Warp Speed (OWS), which has overseen and funded the production of promising COVID-19 vaccines and is in the midst of planning the logistics for a complex vaccine distribution process as data emerges on safe and effective preventives. Biden advisors have discussed revising the OWS name to reduce any public perception that it is emphasizing speed over safety, as part of efforts to rebuild confidence and acceptance of vaccines and therapies that gain FDA approval in the coming weeks.

The Biden pandemic plan is expected to build on campaign documents that highlighted the importance of slowing community spread of the virus through greatly increased COVID testing, expanding the nation’s cadre of public health workers, ensuring access to health insurance, and providing states with 

 to distribute vaccines and therapies effectively and equitably. To combat continuing charges from the Trump White House that politics has motivated recent vaccine clinical trial efficacy announcements, Biden emphasizes the need to “put scientists in charge of all decisions on safety and efficacy,” to publicly release clinical data on any FDA-approved vaccines, and to have FDA career staff report publicly on questions related to product approvals.

Meanwhile, speculation continues over who the President-elect will name to lead HHS and other health agencies—senior roles that usually are lower priorities for new administrations but now are considered critical for the nation to combat the pandemic and restore economic health. Through his campaign, Biden consulted with a wide circle of former Obama administration public health leaders, generating much speculation about who now will play leading roles. Normally, new administrations announce main Cabinet officials first before filling out the numerous agency office directors. But in the current climate, new leaders for FDA and the Centers for Disease Controls and Prevention (CDC) may come sooner.

President-elect Biden has announced initiatives to combat the widening coronavirus pandemic including a 13-member COVID advisory board.

Tackling COVID Top Priority for New Administration

The much-anticipated meeting of FDA’s vaccine advisory committee this week is slated to address a number of critical issues related to testing and approval of vaccines to prevent COVID-19 infection. Although the Vaccines and Related Biological Products Advisory Committee (VRBPAC) will not review an application for any particular product, this panel of virologists and scientists will discuss 

policies and data requirements for determining that a pandemic vaccine can be considered safe and effective

, particularly when based on more limited, early clinical trial data.

Shaping the discussion is the current halt in two major vaccine trials due to unspecified safety issues. U.S. investigators continue to seek more information on patient illness in the AstraZeneca vaccine study announced in early September, although enrollment has restarted for AZ trials in the United Kingdom and other countries. Johnson & Johnson more recently paused its massive COVID vaccine trial due to an “unexplained illness” in a patient. The safety committee for the study has stated by examining whether the ill individual received the vaccine or was in the placebo arm. The sponsors emphasize that these research halts demonstrate their excessive caution and importance of calling on outside monitoring boards to fully investigate such cases.

FDA standards for documenting vaccine safety is an important topic for VRBPAC review, particularly as it relates to granting Emergency Use Authorization (EUA) to an experimental vaccine, an approach that agency officials consider likely and appropriate given the high costs of the pandemic in terms of public health risks and economic hardship. The Center for Biologics Evaluation and Research (CBER) specified in its 

 that it expects an EUA application to provide two months or more of safety data for at least half of the participants in a trial following completion of the full vaccination regimen. As most serious side effects appear within six weeks of individual vaccination, this timeframe is designed to provide a sufficient period for detecting events such as vaccine-induced enhanced respiratory disease and to distinguish such conditions from coronovirus disease.

A particularly challenging issue for the advisors is the how granting EUA status to an initial product could interfere with further assessment of the vaccine’s safety and with ongoing trials for other preventives. FDA says that the sponsor of an authorized vaccine should continue blinded follow-up assessments for months following an initial distribution, but there some authorities believe that an EUA sponsor should shift all participants in the placebo arm to receive treatment. While that might appear a more ethical decision, it could block efforts to gain further information on vaccine efficacy and side effects, including rare adverse events and fuller comparisons among patient groups with differences in age, sex, comorbidities and ethnic characteristics. And because of limited information about how long immunity will last from initial vaccines, both manufacturers and regulators look for additional guidance on determining what data needs to be collected further to indicate when boosters or additional vaccination would be advisable.

Most analysts expect that some vaccines likely to gain approval in subsequent months may be more effective or provide stronger protection than the early products. However, continued development of alternative vaccines may be hindered by difficulties in enrolling new subjects in randomized trials when a vaccine is on the market. Scientists and vaccine developers emphasize that it’s vital for research to continue on multiple preventives, as certain products may affect certain populations differently, and varying formulations may be more suitable for distribution in certain regions.

These issues raise important ethical considerations for the research community and health authorities. While randomized, placebo-controlled clinical trials are necessary to understand the true effects of a medical product on larger populations, individual participants may gain limited benefit and added risk. And in the face of a lethal pandemic, the risks are even more stark. An alternative research approach may be to use a newly authorized vaccine as a control in testing subsequent preventives, a form of noninferiority trial. Such studies may take much longer and cost more to produce results but could reduce the need for large placebo control arms that deny treatment for thousands.

This week's much-anticipated meeting of FDA’s vaccine advisory committee will address critical issues related to the testing and approval of vaccines to prevent COVID-19 infection.

Early Vaccine Authorization Raises Ethical & Logistical Challenges for Trial Sponsors

Growing public concerns about politics playing a role in vetting potential vaccines and therapies to combat the COVID-19 pandemic has prompted sponsors of leading clinical trials to make public their study protocols and statistical analysis plans. One aim of such extensive disclosure of research methods is to address fears that a push for speedy results from the White House might lead to FDA authorization or approval of a COVID vaccine before Phase III data has been fully evaluated. Regulatory authorities and industry leaders have loudly proclaimed their adherence to good science, and vaccine sponsors pledged to collect sufficient data to demonstrate product safety and efficacy before seeking FDA approval. But the debate continues.

Several recently issued research protocols specify numbers of participants in the late-stage clinical trials, age and sub-group goals, enrollment procedures, plans for blinding, randomized assignment to placebo, and efficacy assessments. Details include dosing schedules and adverse event assessments.

Moderna CEO Stephane Bancel led the move toward greater transparency in August by issuing the 

135-page plan for its study for mRNA-1273 SARS-CoV-2 vaccine

. It specified 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. With two doses of the vaccine needed to achieve desired immunity, Moderna says it does not expect full study results until late November.

Pfizer and AstraZeneca similarly released detailed trial protocol documents, acknowledging the need for greater transparency in COVID vaccine research. Pfizer specifies the vaccine candidate and dose for Phase II/III testing and that it expects to assess nearly 44,000 participants, with half receiving the vaccine. 

The expectation is that this will yield 164 primary-endpoint cases within six months

AstraZeneca’s protocol indicated that statistical confidence will be met when 150 trial participants become ill.

 The plan calls for only one interim analysis, and that the trial might be halted early if the vaccine shows effectiveness with fewer cases of contamination. However, AstraZeneca’s timeframe for enrolling and assessing study participants was delayed by the need to address the report of a serious adverse event in its Phase III study. Although the sponsor resumed its vaccine trials in the UK, Brazil, and South Africa, US testing remained on hold as officials at the National Institutes of Health (NIH) moved to investigate further the cause and nature of the adverse event and whether it was triggered by the vaccine or an unhappy coincidence. US authorities were concerned that the sponsor failed to reveal specifics on the safety issue, which outside clinicians identified as the rare spinal inflammatory disorder transverse myelitis.

In launching its Phase III ENSEMBLE study a few weeks later for its vaccine candidate, Johnson & Johnson’s Janssen unit also unveiled its 

 to assess its recombinant adenoviral vector vaccine in 60,000 participants, with 30,000 receiving a placebo. A main advantage of this shot is that it only requires one dose, which stands to accelerate the testing and data analysis process considerably. J&J will monitor trial participants until 154 COVID-19 related events occur to assess whether the vaccine provides sufficient protection against COVID-19.

Novavax announced on Sept. 24 that it, too, had initiated its first 

 to evaluate its COVID-19 vaccine candidate, which has demonstrated high potency in early testing. It is being first tested in 10,000 volunteers in the UK, with plans for a second 30,000-patient study in the. At that time, the company said it planned to publish its UK study protocol to support transparency. Its initial announcement indicated that this first study has two primary endpoints, as compared to one for other vaccine trials, which may increase the time needed to demonstrate efficacy in moderate or severe disease.

The disclosure of these usually confidential details on research endpoints, assessment timeframes, and study analysis plans aim to promote information sharing among vaccine developers, and also build public confidence. Although vaccine study sponsors had provided the usual public information on study sites and enrollment plans, more details on statistical analysis efforts should facilitate outside assessment of decisions by sponsors to seek input from independent data safety monitoring boards or to stop a trial early. And with the US government providing billions in support of most of these vaccine development programs, independent scientists believe the public has the right to such information.

Sponsors are beginning to make their study protocols public as pressure for a COVID-19 vaccine rises.

Jill Wechsler

Articles

Early Vaccine Authorization Raises Ethical and Logistical Challenges for Trial Sponsors

Tackling COVID Top Priority for New Administration

Early Vaccine Authorization Raises Ethical & Logistical Challenges for Trial Sponsors

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