What flexibility did FDA and EMA accept for approved vaccines?

“The omission of non-clinical toxicity studies with RIV4 for the licensure of RIV4 in Europe is consistent with the CHMP Scientific Advice (EMEA/H/SA/3849/1/2018/III) and the EMA guidelines on influenza vaccines.”

“Of note, the dosing schedule used was not in accordance with the proposed clinical schedule (the dose ratio of SARS-CoV-2 rS nanoparticle/Matrix-M1 used is different: 50/50 in the study vs 5/50 in the clinical situation).”

“No male fertility studies were performed given no adverse observations in male reproductive organs were observed in the GLP repeat-dose toxicology study.”

“The omission of secondary pharmacodynamic and safety pharmacology studies and of the pharmacodynamic drug interaction studies are in line with the applicable regulatory guidelines.”

“According to the Applicant, pharmacokinetic studies were not performed or required, as this vaccine is not considered a new vaccine (containing antigens that have been previously described in the European Pharmacopoeia (Ph. Eur.)).”

“Animal reproduction studies have not been conducted. This information has been included in the SPC.”

“Therefore, given that there were no signs of CNS, respiratory, cardiovascular and renal effects for the 9vHPV vaccine, a nonclinical safety pharmacology study was deemed to be not necessary for the 9vHPV vaccine. This was found acceptable by the CHMP under the current requirements.”

“Toxicology studies of AAHS alone were not performed because this adjuvant has been used before in several other Merck vaccines and has an established safety profile.”

“Theoretically, lymphoid stimulatory effect seen in repeat-dose toxicity study might cause/exacerbate autoimmune diseases, but such a risk can only be characterized in post-marketing setting in humans.”

“Safety pharmacology studies were not performed. However in the toxicological studies safety daily monitoring for physical signs did not reveal any notable respiratory problems. This approach is in accordance with Note for guidance on preclinical pharmacological and toxicological testing of vaccines (CPMP/SWP/465/95).”

“The Merck Aluminium Adjuvant (aluminium hydroxyphosphate sulphate adjuvant) is used in other vaccines, which are approved in Europe, and it is agreed that no further studies on the adjuvant are required according Guideline on adjuvants in vaccines for human use (CHMP/VEG/134716/2004).”

“Theoretically, the vaccine could give rise to antibodies, which cross-react to self-structures, resulting in autoimmune events. Such possibility is not readily studied in experimental animal models, but can only be studied in the clinical situation.”

“Repeated dose toxicity has thus been evaluated in one relevant animal species (rabbits) and the studies have been conducted according to the relevant WHO and EMA guidelines, including recommendations on dose (full human dose), number of doses (exceeding proposed number in the clinic) and of route of administration (IM is proposed route of administration for licensure).”

“Previous CHMP scientific advice pointed out that a justification for the choice of the rat should be provided as according to ICH S7B the rat is not considered being an appropriate species for investigation for the potential to prolong the QT interval (the ionic mechanisms of repolarization in adult rats and mice differ from larger species). This is no longer needed in view of the pivotal dog study.”

“Toxicokinetic data were not generated since the determination of circulating levels of antigens is not required for vaccines. This is in line with the Guideline on the nonclinical evaluation of vaccine adjuvants and adjuvanted vaccines (WHO, 2013). The absence of toxicokinetic data is considered acceptable.”

“The mutagenic and carcinogenic potential of the Cervarix vaccine was not further evaluated, which is accepted since the vaccine is based on L1 protein and HPV oncoproteins are absent.”

“However, concerning is that the incidence of ventricular septal defect in both studies is higher than in the historical control and did not occur in concurrent control groups.”

“and developmental toxicity studies were not included in this Application since the RTS,S/ AS01E candidate vaccine containing, AS01E, MPL, QS-21 is not intended for administration to women of childbearing potential.”

“Pharmacokinetic studies are normally not required for a vaccine. Pharmacokinetic study of the vaccine antigen was not studied which is considered acceptable by the CHMP.”