HBVaxPro
hepatitis B vaccine (rDNA)
Sources:EMA assessment report ↗
Species
RatMouse
Longest study
n/a
Genotox
Not stated Not stated
Carcinogenicity
Not stated Not stated
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat (repeat-dose); mouse and rat (single-dose), using the HBsAg-containing combination vaccine HEXAVAC
“The absence of toxicity was evaluated after repeated administrations in the rat according to treatment schedules mimicking a human vaccination scheme (i.e., 3 injections at monthly intervals).”
Why that species
Not stated in public reviews
The reviews list the species but not why. For biologics, ICH S6(R1) asks for species in which the product is pharmacologically active (target binding and activity), usually a cynomolgus monkey.
“A relevant species is one in which the test material is pharmacologically active due to the expression of the receptor or an epitope (in the case of monoclonal antibodies).”
✓ VerifiedICH 2011: ICH S6(R1): Preclinical Safety Evaluation of Biotechnology-Derived…, p. 7Source ↗
Surrogate molecule
No surrogate; thiomersal-free HBsAg bulk tested as part of the HEXAVAC combination vaccine
“The tested substance was Hep B Thiomersal-Free Bulk Vaccine as Part of HEXAVAC development which was carried out in accordance with the current guideline (CPMP/SWP/465/95) for preclinical pharmacological and toxicological testing of vaccines.”
Species: general tox
Rat
“The absence of toxicity was evaluated after repeated administrations in the rat according to treatment schedules mimicking a human vaccination scheme (i.e., 3 injections at monthly intervals).”
Species: DART
Not conducted
“Animal reproduction studies have not been conducted.”
Species: carcinogenicity
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.
Surrogate used in
No surrogate; nonclinical data extrapolated from the HEXAVAC and PROCOMVAX combination vaccines
“The data from the HEXAVAC and PROCOMVAX studies can be extrapolated to the monovalent, thiomersal-free hepatitis B vaccine.”
Study lengthopen answer page →
Longest pivotal study
Not stated (rat, 3 injections at monthly intervals)
“The absence of toxicity was evaluated after repeated administrations in the rat according to treatment schedules mimicking a human vaccination scheme (i.e., 3 injections at monthly intervals).”
Pivotal GLP studies
GLP-era rat repeat-dose study of HEXAVAC, 3 injections at monthly intervals mimicking the human schedule
“The absence of toxicity was evaluated after repeated administrations in the rat according to treatment schedules mimicking a human vaccination scheme (i.e., 3 injections at monthly intervals).”
Route in tox
Subcutaneous (considered equivalent to the intramuscular clinical route); intraperitoneal in the rat single-dose study
“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).”
Skipped studiesopen answer page →
Genotoxicity
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.
Carcinogenicity
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.
Reproductive & developmental
Not conducted
“Animal reproduction studies have not been conducted.”
Safety pharmacology
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.
Genotox: Ames
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.
Genotox: in vitro mammalian
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.
Genotox: in vivo
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.
Carcinogenicity model
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.
Carcinogenicity timing
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.
hERG / QT
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 doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of HBVaxPro don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for vaccines outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: No toxicologically significant findings in rat; changes attributed to the vaccine properties of test and reference vaccines (EMA assessment report, p. 4)
NOAEL / key findings
No toxicologically significant findings in rat; changes attributed to the vaccine properties of test and reference vaccines
“revealed changes attributed to the vaccine properties of the reference and tested vaccines. None of these findings had a toxicological significance.”
Risksopen answer page →
Immune & cytokine safety
No autoimmune reactions, kidney or vascular lesions, or immune complex deposition in the rat repeat-dose study
“Based on the design of this repeated dose toxicology study, no immuno-toxicological findings such as autoimmune reactions were observed. It is noted that this animal study revealed no kidney or vascular lesions justifying further examinations or indicating potential immune complex deposition.”
Biodistribution & persistence
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.
Modality-specific risk
Anaphylaxis to residual yeast antigen contaminants: none detected across multiple lots
“In addition, a special assay was run to test for possible anaphylactic reactions to potential yeast antigen contaminants of the HBs vaccine. No anaphylactic reactions were detected when multiple lots of the vaccine were tested.”
Anti-drug antibodies: animals
C3H mouse immunogenicity at least equivalent with and without thiomersal
“The comparative mouse immunogenicity test performed with the hepatitis B vaccine with and without thiomersal indicates that there is at least equivalent immunogenicity of both products.”
Anti-drug antibodies: patients
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.
Tox packageopen answer page →
Before first-in-human
First-in-human: where
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.
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
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of HBVaxPro don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for vaccines outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: No toxicologically significant findings in rat; changes attributed to the vaccine properties of test and reference vaccines (EMA assessment report, p. 4)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Rat repeat-dose study (HEXAVAC), 3 injections at monthly intervals; duration and recovery not stated
“The absence of toxicity was evaluated after repeated administrations in the rat according to treatment schedules mimicking a human vaccination scheme (i.e., 3 injections at monthly intervals).”
Pivotal GLP studies
GLP-era rat repeat-dose study of HEXAVAC, 3 injections at monthly intervals mimicking the human schedule
“The absence of toxicity was evaluated after repeated administrations in the rat according to treatment schedules mimicking a human vaccination scheme (i.e., 3 injections at monthly intervals).”
DART package
Species: DART
Not conducted
“Animal reproduction studies have not been conducted.”
Reproductive & developmental
Not conducted
“Animal reproduction studies have not been conducted.”
PPND / ePPND: when
Animal reproduction studies not conducted
“Animal reproduction studies have not been conducted.”
Carcinogenicity
Species: carcinogenicity
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.
Carcinogenicity model
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.
Carcinogenicity timing
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.
Safety marginopen answer page →
Safety margin at NOAEL
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.
NOAEL / key findings
No toxicologically significant findings in rat; changes attributed to the vaccine properties of test and reference vaccines
“revealed changes attributed to the vaccine properties of the reference and tested vaccines. None of these findings had a toxicological significance.”
Efficacy evidenceopen answer page →
Efficacy evidence
C3H mouse potency (ED50) testing versus the licensed thiomersal-containing vaccine
“In-vivo potency testing in C3H mice showed the thiomersal-free vaccine to be highly potent and comparable to that of the thiomersal-containing formulation.”
Why that model
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.
Reviewer's view of the efficacy data
Mouse immunogenicity at least equivalent, but extrapolation to humans is controversial
“The comparative mouse immunogenicity test performed with the hepatitis B vaccine with and without thiomersal indicates that there is at least equivalent immunogenicity of both products. However, it is controversial to what extent these data can be extrapolated to humans.”
Flexibilityopen answer page →
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.”
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