Having worked in the pharmaceutical industry since the mid-90’s, I'm often asked my opinion on the Covid-19 vaccines. such as "will you get vaccinated as soon as one is available?" and "when will that be?" Having paid little attention to the details of the myriad contenders in various stages of development, my lazy answer has been, "I’ll let you know when I see data results".

Then I learned that phase 3 protocols were released to the public when Dr. Fauci spoke last week to Governor Murphy of New Jersey. Fauci stated he was optimistic about a vaccine being available for healthcare workers in December or January and, following that it would be rolled out to the rest of the United States between the first and fourth quarters of 2021.

I got curious.

This weekend, I perused through the protocols, clinicaltrials.gov, some press releases, and created the chart above outlining high level parameters of the 4 vaccines in U.S. Phase 3 clinical development.

Here are my observations:

• None of the U.S. vaccines are being studied in children under the age of 16. Neither are they being tested in populations such as people with compromised immune systems, a history of smoking/vaping, pregnant women, etc. While this is typical for novel compounds in a new disease, it begs the questions such as "how will these vaccines allow us to re-open schools, and get us back to normal?"

On the upside:

- There is a UK arm of the Astra Zeneca trial enrolling children ages 5-12 which means data will be generated in children. If AZD1222 launches, U.S. physicians could prescribe it off-label.
- Trials can be run and/or data collected when more is known about the vaccines.
- BNT162 is including patients with chronic, stable HIV, Hepatitis B and C.

What we really need to understand, from an epidemiologist standpoint, is what percentage of the US needs to be vaccinated in order to protect those that cannot be vaccinated. In the meantime, mask wearing, testing, and contact tracing will be needed to cover this large gap.

• There is no uniform agreement upon how to define and measure prevention. The protocols describe and measure what a successful outcome can be differently. They even measure different levels of disease, for example, mRNA1273 is testing in mild to moderate disease while JNJ78436735 is testing in moderate to severe disease. Each protocol states unique (but somewhat similar) definitions along with meaningful measurements. While this is typical for novel treatments and diseases, it means we will need to carefully review data to understand what each vaccine achieves, especially if we are fortunate to have more than one vaccine. Over time, the FDA will require standardized endpoints based upon data that comes in from these trials.

• Given new FDA guidelines, companies are working to release the vaccines more than 2 years prior to their trial completion dates. To help expedite vaccine development, on June 30, 2020*, the FDA published a guidance “Development and Licensure of Vaccines to Prevent Covid-19,” which allows a company to receive emergency use authorization (EUA), of an investigational vaccine on a case by case basis.

Companies have designed their phase 3 clinical trials around this guideline ensuring statistical significance to an efficacy endpoint of preventing COVID-19 or decreasing its severity in at least 50% of people who are vaccinated. In addition, companies have scaled up production timelines to reflect much earlier dose distributions. This is unprecedented on such a large scale and raises many questions:

-Will wearing an N95 mask be more effective than getting vaccinated?
-Does this mean trials are completely halted while the drug is marketed?
-How well will trial outcomes be correlated to the market population prior to EUA?
-How is drug safety and efficacy tracked once launched?

It is possible to shorten the 2-year time-gap by other methods the FDA has in place such as rolling reviews via fast track or breakthrough therapy designations. The best way to understand the safety and efficacy of a drug is to complete the clinical trials. My concern is to what extent may the public end up being test subjects. To feel comfortable with the EUA process, more education is needed along with transparent epidemiologic analysis. I recommend The Vaccine Protocols by Derek Lowe, which helped me to better understand some of the statistical dynamics.  

A main take away from all of this is that global mask wearing, disease testing, contact tracing, social distancing, etc. will be needed for at least the next 2 years to ensure less disease spread. Who doesn’t love wearing a mask? Please post your questions and observations, I would like to hear from you!

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Deb Alper from Alper Consulting LLC, is a strategic marketing consultant who partners with early development oncology divisions, rare disease companies, and agencies to provide commercial guidance to strategic planning, new product launch preparation, early to late phase programs, life cycle planning, and portfolio prioritization.

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Chart Key:
BARDA: Biomedical Advanced Research & Dev. Authority, part of the Office of Assistant Secretary for Preparedness and Response at the US Dept of Health and Human Services (HHS)
NIAID: National Institute of Allergy and Infectious Disease
NIH: National Institute of Health
*Estimated Completion Date: is the date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (the last participant’s last visit).
Regulatory Approval process: typically occurs after the Estimated Completion Date.

*AZD1222: US trial halted on Sept. 6, 2020 to investigate an Adverse Event (AE)

*On Oct 9, 2020, post publication of this article, the FDA issued EUA for Vaccines to Prevent COVID-19 Guidance for Industry which requires ongoing Ph 3 trials to continue to demonstrate efficacy and safety, and to continue collecting placebo-controlled data.

Sources:
S1 https://s3.amazonaws.com/ctr-med-7111/D8110C00001/52bec400-80f6-4c1b-8791-0483923d0867/c8070a4e-6a9d-46f9-8c32-cece903592b9/D8110C00001_CSP-v2.pdf
S2 https://clinicaltrials.gov/ct2/show/NCT04516746
S3 https://www.beckershospitalreview.com/pharmacy/astrazeneca-releases-covid-19-vaccine-protocol.html
S4 https://www.modernatx.com/sites/default/files/mRNA-1273-P301-Protocol.pdf
S5 https://clinicaltrials.gov/ct2/show/NCT04470427
S6 https://pfe-pfizercom-d8-prod.s3.amazonaws.com/2020-09/C4591001_Clinical_Protocol_0.pdf
S7 https://www.cnn.com/2020/09/08/health/pfizer-biontech-vaccine-october-intl-grm/index.html
S8 https://clinicaltrials.gov/ct2/show/NCT04368728?term=BNT162&phase=2&draw=2&rank=1
S9 https://clinicaltrials.gov/ct2/show/NCT04505722?term=Ensemble&cond=Covid19&phase=2&draw=2&rank=1
S10 https://www.jnj.com/johnson-johnson-initiates-pivotal-global-phase-3-clinical-trial-of-janssens-covid-19-vaccine-candidate
S11 https://www.jnj.com/coronavirus/covid-19-phase-3-study-clinical-protocol