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
Flublok: what flexibility did regulators accept, and why?
influenza vaccine, recombinant hemagglutinin · Influenza HA
Flexibility accepted
OtherAccepted
No nonclinical toxicity or pharmacology studies with the quadrivalent vaccine; package bridged from trivalent RIV3
Why: Same manufacturing process, no novel excipients or residuals, no post-marketing safety concerns with RIV3; consistent with EMA influenza guidelines · Within the guideline · Human data
“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.”
“Taking into account the similarity of RIV3 to RIV4, with respect to the manufacturing process with no novel excipients or process residuals and in absence of post-marketing safety concerns with RIV3, it is agreed that the non-clinical package developed to support RIV3 is relevant to support licensure of RIV4 in the EU.”
OtherCriticised but acceptedBeyond the letter
Pivotal repeat-dose study by SC route with weekly dosing instead of the clinical IM route and 2-3-week interval
Why: Extensive clinical and post-marketing experience with RIV3 identified no unexpected safety signal · Human data
“It is noteworthy that use of an alternative administration route (SC) rather than the clinically intended IM route for a pivotal toxicity study is uncommon, as is the short dosing interval of 7-days rather than a classic 2-3-weeks interval.”
“Despite the limitations observed in the pharmacodynamic or toxicology studies, it is acknowledged that extensive clinical experience with RIV3 from pre-licensure clinical trials and post-marketing surveillance safety profile did not identify any unexpected safety signal.”
Efficacy modelAcceptedBeyond the letter
No challenge-protection studies in animals; mouse immunogenicity only
Why: Mouse immunogenicity data provide proof-of-concept · Pharmacology or kinetics
“These data provide important proof-of-concept and support omission of the protection studies in animals.”
Efficacy modelAcceptedBeyond the letter
No nonclinical immunogenicity data for the added B/Yamagata strain
Why: Extensive clinical experience showed immunogenicity of each antigen in the vaccine · Human data
“Although these non-clinical data do not address immunogenicity of the 4th strain in the context of RIV4, the CHMP acknowledged the extensive clinical experience with RIV4 that showed immunogenicity of each of the 4 antigen compositions within the vaccine.”
“Therefore, the absence of non-clinical pharmacology data on the Yamagata lineage is considered acceptable.”
Safety pharmacologyCriticised but acceptedBeyond the letter
Safety pharmacology by SC route instead of IM; dog of questionable relevance without immunogenicity evidence
Why: Extensive clinical and post-marketing experience with RIV3 identified no unexpected safety signal · Human data
“However, there are limitations of this study due to the use of SC route instead of the intended IM administration in humans. In addition, relevance of the dog can be questioned due to absence of immunogenicity evidence from the model.”
“Despite the limitations observed in the pharmacodynamic or toxicology studies, it is acknowledged that extensive clinical experience with RIV3 from pre-licensure clinical trials and post-marketing surveillance safety profile did not identify any unexpected safety signal.”
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
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)
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