PreHevbrio
hepatitis B vaccine (recombinant), 3-antigen
Species
Rat
Longest study
8 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat only
“Toxicology: Three toxicity studies and an intramuscular embryo-fetal developmental and pre- and post-natal reproductive toxicity study in rats were submitted.”
Why that species
Rat immunogenicity data showed the species responds to the vaccine
“The suitability of rats as a model was demonstrated by collected immunogenicity data.”
Surrogate molecule
No surrogate; earlier studies used the previous formulation (AlPO4, thiomersal), later ones the current Al(OH)3 formulation
“Earlier studies used the previous vaccine formulation (AlPO4, with thiomersal) and the remaining studies used the current vaccine formulation (Al(OH)3, without thiomersal).”
Species: general tox
Rat
“Two repeat-dose toxicity studies were performed in rats to evaluate systemic adverse effects and local tolerance, one (IBR 9100.008) using the current vaccine formulation and the other (Weizmann Report 1991) using the old vaccine formulation.”
Species: DART
Rat (combined embryo-fetal and pre/postnatal development, female)
“A GLP-compliant embryo-fetal and pre/post-natal reproductive toxicity study was conducted with the current vaccine formulation of PreHevbri in female Sprague-Dawley rats.”
Species: carcinogenicity
Not conducted (in line with applicable guidelines)
“There were no studies on genotoxicity and carcinogenicity, which is in line with applicable guidelines.”
Surrogate used in
No surrogate used
“Earlier studies used the previous vaccine formulation (AlPO4, with thiomersal) and the remaining studies used the current vaccine formulation (Al(OH)3, without thiomersal).”
Study lengthopen answer page →
Longest pivotal study
8 weeks
“For the third study, an 8-week repeated dose toxicity study, the testing facility was not GLP certified at the time the study was performed in 2004.”
Pivotal GLP studies
Non-GLP rat IM repeat-dose (doses on days 0, 14, 28; 8-week observation); GLP rat combined EFD and pre/postnatal study
“In this study, three groups of Wistar rats were dosed IM on Days 0, 14 and 28 with 0.5mL of PreHevbri (2 or 10 µg HBsAg per animal), or Al(OH)3 adjuvant alone, and were observed for signs of toxicity for 8 weeks.”
Route in tox
Intramuscular
“In this study, three groups of Wistar rats were dosed IM on Days 0, 14 and 28 with 0.5mL of PreHevbri (2 or 10 µg HBsAg per animal), or Al(OH)3 adjuvant alone, and were observed for signs of toxicity for 8 weeks.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (in line with applicable guidelines)
“There were no studies on genotoxicity and carcinogenicity, which is in line with applicable guidelines.”
Carcinogenicity
Not conducted (in line with applicable guidelines)
“There were no studies on genotoxicity and carcinogenicity, which is in line with applicable guidelines.”
Reproductive & developmental
GLP rat embryo-fetal and pre/postnatal study: no female reproductive, embryo-fetal or postnatal effects
“There were no female reproductive effects and no effects on fetal/embryonal development and postnatal development up to day 23.”
Safety pharmacology
Not conducted (in line with applicable guidelines)
“The omission of secondary pharmacodynamic and safety pharmacology studies and of the pharmacodynamic drug interaction studies are in line with the applicable regulatory guidelines.”
Genotox: Ames
Not conducted (in line with applicable guidelines)
“There were no studies on genotoxicity and carcinogenicity, which is in line with applicable guidelines.”
Genotox: in vitro mammalian
Not conducted (in line with applicable guidelines)
“There were no studies on genotoxicity and carcinogenicity, which is in line with applicable guidelines.”
Genotox: in vivo
Not conducted (in line with applicable guidelines)
“There were no studies on genotoxicity and carcinogenicity, which is in line with applicable guidelines.”
Carcinogenicity model
Not conducted (in line with applicable guidelines)
“There were no studies on genotoxicity and carcinogenicity, which is in line with applicable guidelines.”
Carcinogenicity timing
Not required (in line with applicable guidelines)
“There were no studies on genotoxicity and carcinogenicity, which is in line with applicable guidelines.”
hERG / QT
Not conducted (no safety pharmacology studies)
“The omission of secondary pharmacodynamic and safety pharmacology studies and of the pharmacodynamic drug interaction studies are in line with the applicable regulatory guidelines.”
First doseopen answer page →
First-in-human starting dose
Selection not stated; legacy dose-ranging studies (5 and 10 µg), one with an initial first-in-human part up to 20 µg
“The studies were conducted inIsrael, Thailand, and Singapore. They were open-label, comprising two dose regimens, 5 and 10 µg. One had a preliminary phase 1 FIH part with a dosage up to 20 µg.”
NOAEL / key findings
No NOAEL stated; injection-site reactions and expected lymphoid hyperplasia only, no other systemic effects
“Based on the limited data submitted, the vaccine caused typical location reactions at the injection sites but did not cause any systemic effects other than the expected lymphoid hyperplasia.”
Risksopen answer page →
Immune & cytokine safety
Slight lymphoid hyperplasia in spleen and lymph nodes, an expected immunostimulatory effect
“There were no vaccine-related adverse gross or microscopic pathologic findings observed at terminal necropsy other than isolated incidence of slight discrete lymphoid hyperplasia in the spleens and lymph nodes of the vaccine treated rats, which represented an expected immunostimulatory property of the vaccine.”
Biodistribution & persistence
No pharmacokinetic studies; accepted by CHMP
“Pharmacokinetic studies were not performed with PreHevbri. This was considered acceptable by the CHMP.”
Modality-specific risk
Aluminium adjuvant injection-site reaction: mononuclear infiltration, myodegeneration and Al(OH)3 deposits
“The analysis of the injection site at four weeks showed essentially a mononuclear cell infiltration with signs of myodegeneration and depositions of Al(OH)3 in all groups.”
Anti-drug antibodies: animals
Rat seroconversion 100% (10 µg) and 70% (2 µg) in repeat-dose study, confirming immune response
“In the repeated dose toxicity study, 100% and 70% seroconversion were observed for the 10 µg and 2 µg HBsAg dose level, respectively, when administered IM on a 3-dose schedule (Days 0, 14 and 28).”
Anti-drug antibodies: patients
Intended response: seroprotection rate 91.4% vs 76.5% with Engerix-B
“The SPR was 91.4% (95% CI: 89.1, 93.3) in the PREHEVBRIO group and 76.5% (95% CI: 73.2, 79.5) in the ENGERIX-B group.”
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Israel, Thailand and Singapore: legacy dose-ranging studies, one with a first-in-human part up to 20 µg
“The studies were conducted inIsrael, Thailand, and Singapore. They were open-label, comprising two dose regimens, 5 and 10 µg. One had a preliminary phase 1 FIH part with a dosage up to 20 µg.”
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Selection not stated; legacy dose-ranging studies (5 and 10 µg), one with an initial first-in-human part up to 20 µg
“The studies were conducted inIsrael, Thailand, and Singapore. They were open-label, comprising two dose regimens, 5 and 10 µg. One had a preliminary phase 1 FIH part with a dosage up to 20 µg.”
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Non-GLP rat IM study: necropsy 2 days after last dose (week 4) or at 8 weeks after recovery
“Animals were sacrificed 2 days after the last dose (= 4-week time point) or at 8 weeks following recovery.”
Pivotal GLP studies
Non-GLP rat IM repeat-dose (doses on days 0, 14, 28; 8-week observation); GLP rat combined EFD and pre/postnatal study
“In this study, three groups of Wistar rats were dosed IM on Days 0, 14 and 28 with 0.5mL of PreHevbri (2 or 10 µg HBsAg per animal), or Al(OH)3 adjuvant alone, and were observed for signs of toxicity for 8 weeks.”
DART package
Species: DART
Rat (combined embryo-fetal and pre/postnatal development, female)
“A GLP-compliant embryo-fetal and pre/post-natal reproductive toxicity study was conducted with the current vaccine formulation of PreHevbri in female Sprague-Dawley rats.”
Reproductive & developmental
GLP rat embryo-fetal and pre/postnatal study: no female reproductive, embryo-fetal or postnatal effects
“There were no female reproductive effects and no effects on fetal/embryonal development and postnatal development up to day 23.”
PPND / ePPND: when
Combined embryo-fetal and pre/postnatal study in rat (GLP) completed before the marketing application
“A GLP-compliant embryo-fetal and pre/post-natal reproductive toxicity study was conducted with the current vaccine formulation of PreHevbri in female Sprague-Dawley rats.”
Carcinogenicity
Species: carcinogenicity
Not conducted (in line with applicable guidelines)
“There were no studies on genotoxicity and carcinogenicity, which is in line with applicable guidelines.”
Carcinogenicity model
Not conducted (in line with applicable guidelines)
“There were no studies on genotoxicity and carcinogenicity, which is in line with applicable guidelines.”
Carcinogenicity timing
Not required (in line with applicable guidelines)
“There were no studies on genotoxicity and carcinogenicity, which is in line with applicable guidelines.”
Safety marginopen answer page →
Safety margin at NOAEL
DART: rats given a dose equivalent to the adult human dose; no numeric multiple stated
“Developmental toxicity study has been performed in female rats at a dose equivalent to the adult human dose.”
NOAEL / key findings
No NOAEL stated; injection-site reactions and expected lymphoid hyperplasia only, no other systemic effects
“Based on the limited data submitted, the vaccine caused typical location reactions at the injection sites but did not cause any systemic effects other than the expected lymphoid hyperplasia.”
Efficacy evidenceopen answer page →
Efficacy evidence
Immunogenicity in mice and rats; no challenge model
“The pharmacology studies clearly establish the immunogenicity of PreHevbri in immunized mice and rats.”
Why that model
Rodents used because they respond to HBsAg
“The suitability of rodent species for these studies was supported by their responsiveness to HBsAg.”
Reviewer's view of the efficacy data
Mouse i.p. route a clear limitation; immunogenicity established from rat IM studies with dose-response
“The results of mice studies were generated for the i.p. route, which represents clear limitation of these studies. However, the conclusion that PreHevbri is immunogenic can be established from the rat toxicity studies, where the IM route was employed and a dose-response relationship was established.”
Flexibilityopen answer page →
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.”
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