Flublok
influenza vaccine, recombinant hemagglutinin
Species
RatDog
Longest study
5 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 for repeat-dose toxicity and DART (trivalent RIV3); dog and rat for safety pharmacology
“The pivotal repeat-dose toxicity study was conducted with the SC route. Results showed that five weekly SC injections with RIV3 were locally and systemically well tolerated in rats.”
Why that species
Rat mounts antibody responses to all vaccine strains at the human dose; dog relevance questioned (no immunogenicity evidence)
“RIV3 at the human dose induced an active immune response to the three strains in all rat dams from the vaccine group. The exposure of foetuses and pups to vaccine-specific maternal antibodies was also demonstrated.”
Surrogate molecule
No surrogate; toxicity studies used the trivalent formulation (RIV3), bridged to quadrivalent RIV4
“No non-clinical toxicity studies have been performed with RIV4. The applicant supports the non-clinical safety evaluation of RIV4 based on a number of toxicology studies conducted with RIV3.”
Species: general tox
Rat
“The pivotal repeat-dose toxicity study was conducted with the SC route. Results showed that five weekly SC injections with RIV3 were locally and systemically well tolerated in rats.”
Species: DART
Rat (fertility, embryo-fetal and early postnatal development, combined study)
“In DART study conducted in female rats, three IM injections (31 and 12 days before mating and on Gestation Day 6) of RIV3 did not induce maternal toxicity, and there were no adverse effects on mating performance or fertility, embryo-foetal development (including an evaluation of teratogenicity) and an early post-natal development.”
Species: carcinogenicity
Not conducted
“No genotoxicity and carcinogenicity studies were carried out in line with relevant guidelines. Studies evaluating genotoxicity and carcinogenicity are normally not required for viral vaccines.”
Surrogate used in
No surrogate used; all toxicity studies used RIV3 (trivalent), bridged to RIV4
“No non-clinical toxicity studies have been performed with RIV4. The applicant supports the non-clinical safety evaluation of RIV4 based on a number of toxicology studies conducted with RIV3.”
Study lengthopen answer page →
Longest pivotal study
5 weeks
“The pivotal repeat-dose toxicity study was conducted with the SC route. Results showed that five weekly SC injections with RIV3 were locally and systemically well tolerated in rats.”
Pivotal GLP studies
GLP rat repeat-dose study, five weekly SC injections of RIV3; rat IM DART; single-dose, local tolerance studies
“The pivotal repeat-dose toxicity study was conducted with the SC route. Results showed that five weekly SC injections with RIV3 were locally and systemically well tolerated in rats.”
Route in tox
SC for the pivotal repeat-dose study (7-day interval) instead of the clinical IM route; IM for DART
“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.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (not normally required for viral vaccines; no adjuvant)
“No genotoxicity and carcinogenicity studies were carried out in line with relevant guidelines. Studies evaluating genotoxicity and carcinogenicity are normally not required for viral vaccines.”
Carcinogenicity
Not conducted (not normally required for viral vaccines; no adjuvant or novel excipients)
“Studies evaluating genotoxicity and carcinogenicity are normally not required for viral vaccines. Since no adjuvants or novel excipients are used in this product absence of those studies is considered acceptable.”
Reproductive & developmental
Rat fertility, embryo-fetal and early postnatal study (three IM doses, pre-mating and GD6): no adverse effects
“In DART study conducted in female rats, three IM injections (31 and 12 days before mating and on Gestation Day 6) of RIV3 did not induce maternal toxicity, and there were no adverse effects on mating performance or fertility, embryo-foetal development (including an evaluation of teratogenicity) and an early post-natal development.”
Safety pharmacology
Dedicated single-dose SC studies: dog cardiovascular, rat respiratory and CNS; no effects
“Results of safety pharmacology studies showed that a single SC injection with RIV3 did not adversely affect the blood pressure, heart rate, ECG parameters (in beagle dogs), respiratory parameters (in rats) as well as FOB, locomotor activity or body temperature (in rats).”
Genotox: Ames
Not conducted (not normally required for viral vaccines)
“No genotoxicity and carcinogenicity studies were carried out in line with relevant guidelines. Studies evaluating genotoxicity and carcinogenicity are normally not required for viral vaccines.”
Genotox: in vitro mammalian
Not conducted (not normally required for viral vaccines)
“No genotoxicity and carcinogenicity studies were carried out in line with relevant guidelines. Studies evaluating genotoxicity and carcinogenicity are normally not required for viral vaccines.”
Genotox: in vivo
Not conducted (not normally required for viral vaccines)
“No genotoxicity and carcinogenicity studies were carried out in line with relevant guidelines. Studies evaluating genotoxicity and carcinogenicity are normally not required for viral vaccines.”
Carcinogenicity model
Not conducted (not normally required for viral vaccines; no adjuvant or novel excipients)
“Studies evaluating genotoxicity and carcinogenicity are normally not required for viral vaccines. Since no adjuvants or novel excipients are used in this product absence of those studies is considered acceptable.”
Carcinogenicity timing
Not required: viral vaccine without adjuvant or novel excipients
“Studies evaluating genotoxicity and carcinogenicity are normally not required for viral vaccines. Since no adjuvants or novel excipients are used in this product absence of those studies is considered acceptable.”
hERG / QT
Single SC dose in beagle dogs: no effect on blood pressure, heart rate or ECG
“Results of safety pharmacology studies showed that a single SC injection with RIV3 did not adversely affect the blood pressure, heart rate, ECG parameters (in beagle dogs), respiratory parameters (in rats) as well as FOB, locomotor activity or body temperature (in rats).”
First doseopen answer page →
First-in-human starting dose
Antigen content of quadrivalent product matched licensed trivalent vaccine plus a second B strain; no separate dose-finding
“The quantity of each HA antigen and excipients of RIV4 was equivalent to that of the US licensed trivalent recombinant influenza vaccine manufactured by PSC with the addition of the second B strain.”
NOAEL / key findings
No NOAEL stated; no systemic toxicity in rats, only transient injection-site microscopic changes
“There were no local reactions and no signs of systemic toxicity including clinical pathology parameters, organ weights and macroscopic findings. The main related findings were transient microscopic changes at the injection sites, which is expected.”
Risksopen answer page →
Immune & cytokine safety
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.
Biodistribution & persistence
Not conducted; pharmacokinetic studies not required for vaccines
“In accordance with current guidelines, pharmacokinetic studies are not required for the vaccine assessment. No non-clinical pharmacokinetic studies have been performed to evaluate absorption, distribution, metabolism and excretion of the active ingredients of RIV4.”
Modality-specific risk
Local tolerance: transient injection-site inflammation after IM injection only
“Transient microscopic inflammation at injection sites was observed after IM injection only, which was expected.”
Anti-drug antibodies: animals
All vaccinated rat dams mounted antibodies to the three strains; maternal antibodies reached fetuses and pups
“RIV3 at the human dose induced an active immune response to the three strains in all rat dams from the vaccine group. The exposure of foetuses and pups to vaccine-specific maternal antibodies was also demonstrated.”
Anti-drug antibodies: patients
One IM dose immunogenic (HAI) for each vaccine strain in adults 50 years and older
“Overall, one 0.5 mL IM dose of RIV4 is demonstrated immunogenic for each vaccine strain in subjects ≥50 years of age”
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
Antigen content of quadrivalent product matched licensed trivalent vaccine plus a second B strain; no separate dose-finding
“The quantity of each HA antigen and excipients of RIV4 was equivalent to that of the US licensed trivalent recombinant influenza vaccine manufactured by PSC with the addition of the second B strain.”
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Rat, five weekly SC injections of RIV3; recovery phase not stated
“The pivotal repeat-dose toxicity study was conducted with the SC route. Results showed that five weekly SC injections with RIV3 were locally and systemically well tolerated in rats.”
Pivotal GLP studies
GLP rat repeat-dose study, five weekly SC injections of RIV3; rat IM DART; single-dose, local tolerance studies
“The pivotal repeat-dose toxicity study was conducted with the SC route. Results showed that five weekly SC injections with RIV3 were locally and systemically well tolerated in rats.”
DART package
Species: DART
Rat (fertility, embryo-fetal and early postnatal development, combined study)
“In DART study conducted in female rats, three IM injections (31 and 12 days before mating and on Gestation Day 6) of RIV3 did not induce maternal toxicity, and there were no adverse effects on mating performance or fertility, embryo-foetal development (including an evaluation of teratogenicity) and an early post-natal development.”
Reproductive & developmental
Rat fertility, embryo-fetal and early postnatal study (three IM doses, pre-mating and GD6): no adverse effects
“In DART study conducted in female rats, three IM injections (31 and 12 days before mating and on Gestation Day 6) of RIV3 did not induce maternal toxicity, and there were no adverse effects on mating performance or fertility, embryo-foetal development (including an evaluation of teratogenicity) and an early post-natal development.”
PPND / ePPND: when
Rat reproductive study with pre- and postnatal phase completed; final report reviewed for the original licence
“Reproductive toxicity study for FluBLOk, recombinant trivalent influenza vaccine: final report, review memorandum”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No genotoxicity and carcinogenicity studies were carried out in line with relevant guidelines. Studies evaluating genotoxicity and carcinogenicity are normally not required for viral vaccines.”
Carcinogenicity model
Not conducted (not normally required for viral vaccines; no adjuvant or novel excipients)
“Studies evaluating genotoxicity and carcinogenicity are normally not required for viral vaccines. Since no adjuvants or novel excipients are used in this product absence of those studies is considered acceptable.”
Carcinogenicity timing
Not required: viral vaccine without adjuvant or novel excipients
“Studies evaluating genotoxicity and carcinogenicity are normally not required for viral vaccines. Since no adjuvants or novel excipients are used in this product absence of those studies is considered acceptable.”
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 NOAEL stated; no systemic toxicity in rats, only transient injection-site microscopic changes
“There were no local reactions and no signs of systemic toxicity including clinical pathology parameters, organ weights and macroscopic findings. The main related findings were transient microscopic changes at the injection sites, which is expected.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse immunogenicity (HAI and neutralizing antibodies) with monovalent rH3 and trivalent RIV3; no challenge studies
“The results from these studies show that RIV3 and rH3 are immunogenic and can induce serum HAI and nAb antibodies against the influenza strains present in the vaccine.”
Why that model
Extensive human pharmacodynamic data with RIV3 and RIV4; no animal immunogenicity or challenge studies with RIV4
“No specific non-clinical pharmacology studies including immunogenicity and challenge-protection studies in animal models have been performed with RIV4. There is large amount of pharmacodynamics data available in humans with both RIV3 and RIV4, both licensed in the US and manufactured using the same manufacturing process as that intended for EU.”
Reviewer's view of the efficacy data
Mouse immunogenicity data accepted as proof-of-concept, supporting omission of animal protection studies
“These data provide important proof-of-concept and support omission of the protection studies in animals.”
Flexibilityopen answer page →
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.”
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