Arexvy
respiratory syncytial virus vaccine, adjuvanted (AS01E) · RSV preF3; TLR4 (AS01E adjuvant)Toxicity studies used AS01B adjuvant (double immunoenhancer dose) instead of the clinical AS01E formulation
HBVaxPro: what flexibility did regulators accept, and why?
hepatitis B vaccine (rDNA) · HBsAg VLPs
Flexibility accepted
OtherAcceptedBeyond the letter
No dedicated nonclinical studies with HBVaxPro; data extrapolated from HEXAVAC, PROCOMVAX and the thiomersal-containing vaccine
Why: Separate studies would not provide new knowledge on the preclinical safety profile · Class precedent · Weight of evidence
“Pre-clinical data are considered to be sufficent. The data from the HEXAVAC and PROCOMVAX studies can be extrapolated to the monovalent, thiomersal-free hepatitis B vaccine. Separate studies would not provide any new knowledge on the pre-clinical safety profile of HBVAXPRO.”
Study lengthAcceptedBeyond the letter
Rat repeat-dose study omitted the fourth (booster) dose of the human schedule
Why: Second and third injections sufficient to boost the immune response and reveal adverse reactions · Pharmacology or kinetics
“The fourth dose which was administered 6 months to 1 year after the third dose in the human vaccination scheme for HEXAVAC® was not included in this toxicology study design. However, it is considered that the second and the third injections were sufficient to boost the immune response and to reveal potential adverse reactions.”
OtherAcceptedBeyond the letter
Repeat-dose toxicity given subcutaneously rather than by the intramuscular clinical route
Why: Subcutaneous route considered equivalent in bioavailability to the intramuscular route · Pharmacology or kinetics
“The subcutaneous route was considered equivalent in terms of bioavailability to the intramuscular clinical route and a dose level of 5 human doses per kg was tested (human dose level: 0.17 human dose/kg of human body weight).”
DARTVerdict not stated
No animal reproduction studies
“Animal reproduction studies have not been conducted. This information has been included in the SPC.”
Same question, other vaccines
Cervarix
human papillomavirus bivalent (types 16, 18) vaccine, recombinant, AS04-adjuvanted · HPV 16/18 L1 VLPs; TLR4 (AS04 adjuvant)No genotoxicity or carcinogenicity studies with the vaccine (MPL adjuvant genotoxicity tested only)
Cyfendus
anthrax vaccine adsorbed, adjuvanted · B. anthracis PA; TLR9 (CpG 7909 adjuvant)Effectiveness established from animal post-exposure survival studies under the Animal Rule instead of human efficacy trials
Fendrix
hepatitis B vaccine (rDNA), AS04C-adjuvanted · HBsAg VLPs; TLR4 (AS04C adjuvant)No distribution or excretion data for the final vaccine or AS04C adjuvant
Flublok
influenza vaccine, recombinant hemagglutinin · Influenza HANo nonclinical toxicity or pharmacology studies with the quadrivalent vaccine; package bridged from trivalent RIV3
Gardasil
human papillomavirus quadrivalent (types 6, 11, 16, 18) vaccine, recombinant · HPV 6/11/16/18 L1 VLPsNo dedicated safety pharmacology studies; physical signs monitored within toxicity studies
Gardasil 9
human papillomavirus 9-valent vaccine, recombinant · HPV 9-valent L1 VLPsNo safety pharmacology study
Heplisav-B
hepatitis B vaccine (recombinant), adjuvanted · HBsAg; TLR9 (CpG 1018 adjuvant)Adjuvant-alone 8-week repeat-dose study designs not representative of the clinical dose regimen
Mosquirix
RTS,S/AS01 malaria vaccine · P. falciparum CSP-HBsAg (RTS,S) VLPs; TLR4 (AS01 adjuvant)No reproductive and developmental toxicity studies
Nuvaxovid
COVID-19 vaccine, recombinant spike protein nanoparticle, Matrix-M-adjuvanted · SARS-CoV-2 spike (nanoparticle)Rat DART used Matrix-M1 below the absolute human dose (maximum volume of clinical formulation)
PreHevbrio
hepatitis B vaccine (recombinant), 3-antigen · HBsAg S/pre-S1/pre-S2 VLPsPivotal repeat-dose toxicity study in rats not GLP-compliant
Shingrix
zoster vaccine recombinant, AS01B-adjuvanted · VZV glycoprotein E; TLR4 (AS01B adjuvant)Vaccine DART only in rats at 40% of the human dose; no full-human-dose rabbit study