Male and female reproductive inclusion criteria in phase 3 studies
Raphaelle Beau-Lejdstrom, PhD
Jan 31, 2021
Feb 21, 2021
Irène Fermont,MD, MSc
Question: In the BioNtech/Pfizer protocol C4591001 for the Phase 3 study of Comirnaty (below), the Appendix 4 describes strict male and female reproductive inclusion criteria.
Are all these precautions standard precautions in all vaccine trials?
Strict criteria on male and female participants reproductive inclusion can be found in the three Covid19 vaccines protocols of Phase 3 that have been approved under emergency authorization worldwide (BioNtech/Pfizer, Moderna and AstraZeneca).
The most likely reason for such restrictive criteria can be found in the AstraZeneca AZD1222 - D8110C00001 protocol (ref protocol in the folder) p35:
“The study will exclude females who are pregnant or breast-feeding and individuals less than 18 years of age. Women who are pregnant or breast-feeding are excluded at this point as nonclinical developmental and reproductive toxicity studies to support vaccinating these individuals have yet to be performed.”
In order to produce quality evidence on the efficacy and safety of these vaccines in a timely manner in the context of the current pandemic, reproductive toxicity studies were only conducted or completed after the start of Phase 3 trial. International (ICH) and FDA guidance on the conduction or trials in pregnant women (refs in the folder) recommend that these studies should be conducted prior to the start of the trial to allow the inclusion of pregnant women and in males without restriction on reproductive inclusion criteria.
The Risk Management Plan (EMA ref) for the Pfizer/BioNtech vaccine explains that “No vaccine-related effects on female fertility or the development of fetuses or offspring were observed in a DART study of BNT162b2 in rats” (DART= developmental and reproductive toxicity).
Some vaccine trials are less restrictive on male and female reproductive inclusion criteria as the reproductive toxicity studies in animals have been conducted previously.
To this day, a very limited amount of data is available for the use of covid19 vaccine in pregnant women and the drug manufacturers committed to collect more information on the vaccination of pregnant women
However, because of the occurrence of several cases of severe forms of COVID-19 in pregnant women, some associations of gyneco-obstetricians have recommended vaccinating pregnant and breastfeeding women. This has led some regulatory authorities to adopt this advice. This is the case in the USA, Israel and WHO, after a preliminary contradictory position.
Male fertility is not a subject of concern raised in the FDA or EMA documents released on the evaluation of the Pfizer/BioNtech vaccine.