Blinding and Masking Issue in Covid-19 Vaccine Clinical Trials

Clinical trials for Covid-19 vaccine development are moving into the critical late phase stage. The front runners right now are Moderna (in collaboration with NIAIH), Oxford University (in collaboration with AstraZeneca), and BioNTech (in collaboration with Pfizer). All three had published the positive results from their phase 1/2 studies to demonstrate that the Covid-19 vaccines can generate utilizing antibodies against SARS-COV-2 virus and vaccines are tolerable and generally safe in healthy volunteers. 

• Moderna Phase 1 results: Jackson et al (2020) An mRNA Vaccine against SARS-CoV-2 — Preliminary Report NEJM 
• Oxford/AstraZeneca Phase 1/2 results:  Folegatti et al (2020) Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet
• BioNTech/Pfizer Phase 1/2 results: Mulligan et al (2020) Phase 1/2 Study to Describe the Safety and Immunogenicity of a COVID-19 RNA Vaccine Candidate (BNT162b1) in Adults 18 to 55 Years of Age: Interim Report. medRxiV

The confirmatory studies are about to begin to demonstrate the efficacy and safety of the Covid-19 vaccines. The requirements for study design, efficacy endpoint, and safety endpoints are laid out in FDA's guidance "Development and Licensure of Vaccines to Prevent COVID-19"

Moderna is supposed to announce the start of phase 3 study next week. The other two will follow. The phase 3 studies from these three companies have already been registered in clinicaltrials.gov. The table below lists key parameters from these three studies. BioNTch/Pfizer had phase 1/2/3 studies combined in the same study protocol where the results from the phase 1 portion of the study have been published (see above Mulligan et al) 

	Moderna/NIAIH	Oxford/AstraZeneca	BioNTech/Pfizer
Protocol Title	A Phase 3, Randomized, Stratified, Observer-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Immunogenicity of mRNA-1273 SARS-CoV-2 Vaccine in Adults Aged 18 Years and Older	A Phase 2/3 Study to Determine the Efficacy, Safety and Immunogenicity of the Candidate Coronavirus Disease (COVID-19) Vaccine ChAdOx1 nCoV-19	A Phase 1/2/3, Placebo-Controlled, Randomized, Observer-Blind, Dose-Finding Study to Evaluate the Safety, Tolerability, Immunogenicity, and Efficacy of SARS-COV-2 RNA Vaccine Candidates Against COVID-19 in Healthy Adults
Phase	Phase 3	Phase 2/3	Phase 1/2/3
Sample Size	30,000	10,260	32,000
Treatment Groups	mRNA-1273 Placebo	ChAdOx1 nCoV-19 (Abs 260) MenACWY vaccine ChAdOx1 nCoV-19 (Abs 260) + 2.2x10^10vp (qPCR) boost Two dose MenACWY vaccine ChAdox1 n-CoV-19 (Abs 260) vaccine low dose ChAdOx1 nCoV-19 (qPCR) ChAdOx1 nCoV-19 plus 5x10^10vp boost (qPCR)	BNT162b1 BNT162b2 BNT162b3 Placebo
Age Groups	18 years and older	18 years or older 18-55 years 70 years and older 5-12 years inclusive	18-55 years of age 65-85 years of age 18-85 years of age
Number of Doses	100 microgram 2 doses (on day 1 and day 29)	1 or 2 doses	Low, low-mid, mid, or high doses 1 or 2 doses
Randomization	Randomized	Randomized	Randomized
Control Group	Placebo [0.9% sodium chloride (normal saline) injection]	MenACWY vaccine (also named Menveo or Nimenrix)	Placebo [a sterile saline solution for injection (0.9% sodium chloride injection, in a 0.5-mL dose)]
Blinding/Masking	Quadruple (Participant, Care Provider, Investigator, Outcome Assessor)	Single (Participant)	Triple (Participant, Care Provider, Investigator)

With the side-by-side comparison, we can see the clear difference in selecting the control group and how the blinding/masking is handled. In studies by Moderna and BioNTech, the control group is a placebo consisting of only the normal saline. But the quadruple and the triple masking (beyond the double-blind) are used to prevent the potential unblinding. 

 In the study by Oxford, the control group is another vaccine, MenACWY vaccine that is approved for protecting against meningococcal disease (meningitis and blood poisoning (septicaemia)) caused by serogroups A, C, W, and Y. The single blinding is used and the participants (volunteers) will not know whether they receive Covid-19 vaccine or MenACWY vaccine. 

In order to prevent potential unblinding - the participants become knowing which treatment they have received, using an active vaccine such as MenACWY that have been approved to be safe seems to be better and more adequate. In the publication of their phase 1 study results, they explained why it's necessary to use MenACWT vaccine as control. 

"MenACWY was used as a comparator vaccine to maintain blinding of participants who experienced local or systemic reactions, since these reactions are a known association with viral vector vaccinations. Use of saline as a placebo would risk unblinding participants as those who had notable reactions would know they were in the ChAdOx1 nCoV-19 vaccine group."

Placebo with saline as the control group is acceptable to FDA. In FDA's guidance "Development and Licensure of Vaccines to Prevent COVID-19", it says "Later phase trials, including efficacy trials, should be randomized, double-blinded, and placebo controlled" even though there is no mention about the requirement for the component of the placebo. 

With placebo (saline) as the control group, no matter whether the triple or quadruple blinding is used, there is still a potential unblinding by the participants because the participants can guess which treatment (Covid-19 vaccine or placebo) they have received based on the adverse events they may experience.

The published early phase results indicate that participants receiving Covid-19 vaccine experience more frequent adverse events in local injection site reactions and systemic reactions. BioNTech/Pfizer study says: 

"pain at the injection site was the most frequent prompted local reaction, reported after Dose 1 by 58.3% (7/12) in the 10 μg, 100.0% (12/12 each) in the 30 μg and 100 μg BNT162b1 groups, and by 22.2% (2/9) of placebo recipients. After Dose 2, pain was reported by 83.3% and 100.0% of BNT162b1 recipients at the 10 μg and 30 μg dose levels, respectively, and by 16.7 % of placebo recipients."

"Reports of fatigue and headache were more common in the BNT162b1 groups compared to placebo. Additionally, chills, muscle pain, and joint pain were reported among BNT162b1 recipients and not in placebo recipients."

After vaccination, participants may be able to guess they have received Covid-19 if they experience adverse events such as local injection site pain and systemic side effects such as fatigue, headache, chills, muscle pain,... They will be able to guess (pretty accurately) that they have received Placebo (saline) if they don't experience any local reactions or systemic side effects. 

If participants become aware of the treatment they have received, will it have an impact on their behavior? Will participants knowing to receive Covid-19 vaccine feel they have some protection, therefore maybe let loose their guard against Covid-19? I hope this will not be the case, otherwise, the biases induced by the behavior change because of the potential unblinding will have an impact on the efficacy results (most likely toward the null hypothesis of no difference).