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
PreHevbrio: what flexibility did regulators accept, and why?
hepatitis B vaccine (recombinant), 3-antigen · HBsAg S/pre-S1/pre-S2 VLPs
Flexibility accepted
GLPCriticised but acceptedBeyond the letter
Pivotal repeat-dose toxicity study in rats not GLP-compliant
Why: Study reliable on audit; considerable safe human experience with the vaccine, including infants · Human data
“The Applicant provided a clear justification for the absence of GLP for the pivotal 4-week repeat-dose toxicity study in rats and potential consequences of non-compliance. The study was considered to be reliable without restrictions.”
“Together with availability of considerable human experience with PreHevbri, showing a safe and well-tolerated profile in varying age groups including infants, consistent with these nonclinical toxicity studies, the CHMP agreed that additional GLP-compliant repeat-dose toxicity study with PreHevbri is not necessary.”
OtherCriticised but acceptedBeyond the letter
Main repeat-dose study lacked full-organ histology and reversibility assessment; groups not adequately sized
Why: Considerable human experience showing a safe, well-tolerated profile · Human data
“The CHMP considered that the main repeat-dose toxicity study did not include histology analysis of the full list of organs and tissues or assessment of reversibility of the microscopic changes in selected vital organs, and study groups were not adequately sized.”
“Together with availability of considerable human experience with PreHevbri, showing a safe and well-tolerated profile in varying age groups including infants, consistent with these nonclinical toxicity studies, the CHMP agreed that additional GLP-compliant repeat-dose toxicity study with PreHevbri is not necessary.”
OtherCriticised but acceptedBeyond the letter
Two of three toxicity studies used a non-clinical formulation and dosing regimen; no conclusions could be drawn
Why: Prior clinical experience outside the U.S. for several years · Human data
“In the first two toxicity studies, the dosing regimen did not mimic the proposed trial and the test article was not the intended clinical formulation, therefore no conclusions could be drawn.”
“Despite the deficiencies in the general toxicology studies, prior clinical experience with the vaccine outside the U.S. for several years was sufficient to support further development under the U.S. IND.”
Safety pharmacologyAccepted
No safety pharmacology, secondary pharmacodynamic or drug interaction studies
Why: In line with applicable regulatory guidelines · Within the guideline
“The omission of secondary pharmacodynamic and safety pharmacology studies and of the pharmacodynamic drug interaction studies are in line with the applicable regulatory guidelines.”
BiodistributionAccepted
No pharmacokinetic studies
Why: Not a new vaccine (antigens described in Ph. Eur.); in accordance with CPMP, WHO and ICH S6 guidelines · Within the guideline · Class precedent
“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.)).”
“This is in accordance with relevant regulatory guidelines (CPMP/SWP/465/95, WHO 2005, WHO 2014, ICH S6). Overall, it is supported that no pharmacokinetic studies are warranted with PreHevbri.”
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
HBVaxPro
hepatitis B vaccine (rDNA) · HBsAg VLPsNo dedicated nonclinical studies with HBVaxPro; data extrapolated from HEXAVAC, PROCOMVAX and the thiomersal-containing vaccine
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)
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