Pfizer/BioNTech’s Late-Phase COVID-19 Vaccine Trial Speedier than Moderna, Yet Utility Conclusions Dubious from Either Trial’s Interim Analysis, Experts Say

Published : 10 Oct 2020

Although Pfizer (NYSE: PFE)/BioNTech’s (NASDAQ: BNTX) late-phase COVID-19 vaccine trial is designed to report interim data earlier and has the potential for a broader label than Moderna’s (NASDAQ: MRNA) vaccine, the former’s results could leave vaccinators unclear about which patient group would be best suited to use the vaccine. Uncertainty about how to best use both vaccines would be an issue if FDA approval comes via an Emergency Use Authorization (EUA), as premature results at such an early stage would lack detail.

Pfizer/BioNTech’s BNT162b2 and Moderna’s mRNA-1273 are two of the COVID-19 vaccine frontrunners. Both have late-phase trial designs powered to detect 60% vaccine efficacy. Although this is a low efficacy bar, experts noted the first wave of vaccines will primarily ease the burden on healthcare facilities. With the initial vaccine supply expected to be prioritized for distribution, vaccinators will need to stratify who would receive the first batch of vaccine supplies.

Pfizer/BioNTech’s Phase II/III trial (NCT04368728) has a shorter timeframe to count infection events and a relatively lower bar to trigger the reverse transcription-polymerase chain reaction (RT-PCR) test needed to confirm COVID-19, and so is set up to count infection events more quickly than Moderna’s Phase III trial (NCT04470427). However, this could be to Moderna’s advantage; even if it takes longer to collect primary endpoint results, Moderna’s data is expected to be cleaner to support the vaccine’s protection ability.

Moderna would also be able to give vaccinators more specific data because its trial is segmented according to age and risk, experts noted. However, this stratification raises the potential for Moderna to get limited subpopulation authorization. Pfizer/BioNTech’s trial only divides participants according to age, but showing positive results would translate to a broader label. Pfizer/BioNTech’s trial also covers a wider variety of disease symptoms.

Nevertheless, the number of events required to trigger interim analyses for both trials is low, leaving experts skeptical about how they would interpret such data to make vaccination decisions. While the US Centers for Disease Control and Prevention’s (CDC’s) vaccine advisory committee will finalize which subpopulations to prioritize for vaccination based on the FDA’s conditions of use, any COVID-19 vaccine receiving a EUA from the FDA based on interim analysis data is unlikely to offer the granular information needed for this decision, this news service reported 30 September.

Late-phase data for BNT162b2 is expected by the end of October, said Pfizer CEO Albert Bourla. Moderna’s mRNA-1273 will not be able to apply for authorization before 25 November, said Moderna CEO Stéphane Bancel. Still, with the US presidential election on 3 November and the FDA scheduling a public meeting for 22 October to discuss vaccine development, the race for authorization and/or licensure of a COVID-19 vaccine is the focus of a lot of attention. Neither BioNTech nor Moderna responded to requests for comment. Pfizer did not respond by press time.

Shorter lag in counting events gives Pfizer/BioNTech a speed advantage

A notable difference between Pfizer/BioNTech’s and Moderna’s trials is the latter’s primary efficacy analysis starts to count infection events 14 days after the second dose, while Pfizer/BioNTech starts counting just seven days afterward. The different timeframes could be due to each vaccine having different pharmacokinetic profiles, a Phase II/III Pfizer/BioNTech investigator explained.

While experts agreed Pfizer/BioNTech’s decision aims to provide results more quickly, they had varying viewpoints on whether Moderna’s strategy will give it a better chance at success. Moderna’s two-week window may give its vaccine more opportunity to work, said Mark Jit, Ph.D., professor, vaccine epidemiology, London School of Hygiene and Tropical Medicine, UK. However, Moderna’s longer timeframe may mean the vaccine takes longer to work, noted Nikolai Petrovsky, Ph.D., professor, College of Medicine and Public Health, Flinders University, Adelaide, Australia.

Still, the primary efficacy endpoint timeframe is somewhat discouraging for either trial, because the vaccine should ideally work as soon as possible, Jit and Petrovsky agreed. After either vaccine is administered, the person would have to wait five to six weeks from the first injection to have maximum protection likelihood, Petrovsky explained. Moderna’s trial has a secondary endpoint evaluating protection after the first dose, but Pfizer/BioNTech’s trial does not.

However, both trials are likely to collect such data, and there is logic to allowing a seven- or 14-day window, the Pfizer/BioNTech investigator said. Having this lag time will weed out protection due to nonspecific immunity by the vaccine, agreed Gordon Dougan, Ph.D., professor, Department of Medicine, Cambridge University, UK.

Moderna’s higher testing bar may mean clearer protection data

Besides counting events sooner, Pfizer/BioNTech’s other speed advantage lies in its lower threshold of symptom requirements to trigger an RT-PCR test to confirm a COVID-19 infection. However, this could benefit Moderna, as its data may offer more clarity on what symptoms its vaccine protects against.

The differing criteria could lead to the trials potentially reporting their conclusions differently, noted Dougan. An RT-PCR test is triggered in the Moderna study when a volunteer has at least two milder symptoms like fever or headache or has one more severe symptom of either shortness of breath or clinical or radiographic evidence of pneumonia. The Pfizer/BioNTech trial only requires one COVID-19 symptom to trigger a test.

By testing Pfizer/BioNTech volunteers with just one symptom, events for analysis would be found more quickly, said Dr. Hildegund Ertl, professor, Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania. In contrast, Moderna’s higher symptom bar would mean the trial could take longer to reach its event target, said Don Diamond, Ph.D., professor, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, California.

Pfizer/BioNTech’s lower bar could mean its data would potentially have a wider variety of disease severity for analysis, noted Gary Kobinger, Ph.D., head, Vector Design, and Immunotherapy Special Pathogens, Medical Microbiology, University of Manitoba, Canada. Moderna’s choice to be selective about which volunteers to test may lead to more limited conclusions, added the Phase III Moderna investigator. In fact, Moderna’s more stringent criteria could mean it is less confident the vaccine would cover a wider variety of disease manifestations, added Petrovsky.

However, Moderna’s trial is appealing since its data will be more robust to understand whether the vaccine protects against more severe manifestations of the disease, added Jit. Moderna’s trial would weed outpatients with fewer symptoms and eliminate any symptoms not caused by SARS-CoV-2, noted Ertl. In this case, Pfizer/BioNTech’s lower bar would be a disadvantage due to the cost and time involved in running tests in volunteers who may not have COVID-19, Diamond added.

Still, some experts noted the difference between both criteria is relatively minor, with the Moderna investigator noting the definitions for what triggers an RT-PCR test are roughly equivalent. Judgment about which volunteer gets an RT-PCR test will come down to the investigator, considering information regarding COVID-19 symptoms is evolving, the Pfizer/BioNTech investigator added.

Moderna’s stratification of at-risk younger people allows data detail

In many countries, vaccines are likely going to be prioritized for high-risk people first, Jit said. Moderna’s trial would be better able to inform rollout strategies for this group, compared to Pfizer/BioNTech’s trial design, he noted. Moderna’s 30,000-participant trial has three strata for randomization: ages 65 years and older, under 65 years old and at increased risk for COVID-19 complications, and under 65 years old and at less risk. At-risk volunteers are those with chronic lung disease, significant cardiac disease, severe obesity, diabetes, liver disease, and human immunodeficiency virus. The Pfizer/BioNTech 43,998-volunteer trial only randomizes by age, younger or older than 55 years old.

In the US, Phase Ia of vaccine rollout would be for healthcare personnel, with Phase Ib covering essential workers, people with high-risk medical conditions, and adults ages 65 years and older, according to a 22 September presentation by the CDC’s Advisory Committee on Immunization Practices. A decision about how Phase Ib would be implemented has been delayed, with decisions to be based on the FDA’s conditions of use of the authorized vaccine.

However, Moderna’s subcategorization increases the chances of its vaccine being approved in a specific subpopulation, Dougan said. Furthermore, the vaccine should ideally be efficacious in as wide a variety of people as possible, Petrovsky added.

The interim analysis will limit the severity of the secondary endpoint

Data interpretability concerns are made worse by the potential for these vaccines to get a EUA based on an interim analysis. Interim analyses may not provide enough events to power answers for more specific questions, noted the Pfizer/BioNTech and Moderna investigators.

Early data is unlikely to have enough detail on whether the vaccines can protect against different disease severities, experts said. Both Pfizer/BioNTech and Moderna trials have secondary endpoints evaluating vaccine efficacy in preventing severe COVID-19. Both trials have similar definitions of severe events, such as if the volunteer has clinical signs of severe systemic illness, a respiratory rate of 30 per minute, a SpO2 of ?93% on room air at sea level, or a PaO2/FIO2 of <300mmHg.

An interim analysis is designed around primary endpoints, so the ability to make a statement on secondary endpoints would be challenging, said Natalie Dean, Ph.D., assistant professor, Department of Biostatistics, College of Public Health & Health Professions, University of Florida, Gainesville. If a trial reaches the number of events needed for interim analysis, and if none of these patients are classified as severe, then there would be no information about the vaccine’s protection against severe COVID-19, added Kert Viele, Ph.D., senior statistical scientist, Berry Consultants, Lexington, Kentucky. This is a critical secondary endpoint, especially as easing the burden of disease on healthcare facilities is the practical success benchmarks of these vaccines, the Pfizer/BioNTech investigator added.

The first interim analysis in the BNT162b2 trial can be conducted after 32 volunteers have been confirmed to have contracted the virus, whereas the mRNA-1273 trial is designed to wait until 53 events are reached.

Pfizer has a USD 202.55bn market cap, while BioNTech’s is USD 16.88bn and Moderna’s is USD 27.25bn.

Source: GlobalData.com