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Zabransky DJ, Yarchoan M, Elizabeth M, Jaffee EM. Strategies for Heating Up Cold Tumors to Boost Immunother-
apies, vol. 7; 2023. p. 149e70. https://doi.org/10.1146/annurev-cancerbio-061421-040258.
Zhang X, Yang B, Ni Q, Chen X. Materials engineering strategies for cancer vaccine adjuvant development. Chem Soc
Rev 2023;52(9):2886e910. https://doi.org/10.1039/d2cs00647b.
Zhao T, Cai Y, Jiang Y, et al. Vaccine adjuvants: mechanisms and platforms. Sig Transduct Target Ther 2023;8:283.
https://doi.org/10.1038/s41392-023-01557-7.
Zheng J, Shi W, Yang Z, Chen J, Qi A, Yang Y, et al. RIG-I-like receptors: molecular mechanism of activation and
signaling. Adv Immunol 2023;158:1e74. https://doi.org/10.1016/bs.ai.2023.03.001.
6. Introduction to vaccines and adjuvants226
II. Vaccines
7
Regulatory aspects of nonclinical
vaccine development
Lisa M. Plitnick
MRL, Merck & Co., Inc., Rahway, NJ, United States
OUTLINE
Introduction 227
Regulatory guidelines 228
Alternate approaches 230
Repeat-dose toxicity evaluation 231
Developmental toxicity 233
Biodistribution 234
Environmental risk assessment 234
Genotoxicity and carcinogenicity 235
Safety pharmacology 235
Neurovirulence 236
Conclusion 236
References 236
Introduction
Nonclinical toxicity studies are an integral part of vaccine development and provide an
assurance of safety prior to administration of a vaccine to humans in clinical trials. The
studies are designed to identify any potential adverse effects of the vaccine antigens, ad-
juvants, components of the formulation, impurities or contaminants, or interactions
thereof. These data are used to define a No Adverse Effect Level (NOAEL), or a dose at
which no adverse findings were identified and the resultant safety margins. This
CHAPTER
227
Nonclinical Development of Biologics, Vaccines and
Specialty Biologics, Second Edition
https://doi.org/10.1016/B978-0-443-13344-2.00009-2
© 2025 Elsevier Inc. All rights are reserved, including those for text
and data mining, AI training, and similar technologies.
information is used by clinicians to determine a safe starting dose and, in conjunction with
available pharmacology data, the highest projected clinical dose. The type and duration of
studies varies based on vaccine type, indication, components (e.g., adjuvants), etc. and are
based on speci fic clinical plans. To aid in the design of the development programs, world-
wide regulatory guidelines are available and provide specificguidancetovaccine
manufacturers.
This chapter will focus on the regulatory aspects of nonclinical development of vac-
cines. While regulatory guidelines are helpful in providing recommendations regarding
vaccine development, timely interactions with Health Authorities (HAs) are highly rec-
ommended to propose any alternative approaches and/or to ensure alignment of nonclin-
ical plans with regulatory expectations, particularly since requirements may vary between
regions.
Regulatory guidelines (Table 7.1)
Vaccines were traditionally considered inherently safe and routine nonclinical toxicity
evaluations were not required. W ith the advent of newer technologies allowing the devel-
opment of novel vaccine modalities, adjuvants, and delivery systems, widely accepted,
comprehensive guidelines were implemented. The firstofthesewastheEuropeanMedi-
cines Agency (EMA) guideline approved in 1 998 (EMA, 1995). While this guideline has
since been rescinded, numerous guidelines applicable to vaccines have been drafted and
range from general guidance applicable worldwide (WHO, 2005)tosomethatarecountry-
(India, 2005; China, 2010; Japan, 2022) or vaccine-specific(FDA, 2020; WHO, 2007, 2013,
2018). These guidelines provide detail on aspects of nonclinical toxicity evaluations such
as the types of studies needed, animal models, stu dy design (dose, route of administration,
dosing schedule, etc.), and relevant endpoints. They also contain high-level information on
nonclinical testing, which has since been supplemented by additional guidelines that
outline the regulatory expect ations for traditional (e.g., live virus, subunit) as well as novel
(e.g., mRNA) types of vaccines (WHO, 2014, 2021, 202 2; FDA, 2020; Japan, 2016a,b; EMA,
2001, 2010, 2018; FDA, 1985, 1992, 2007) as well as vaccines intended for specificpopula-
tions (ICH, 2020a; FDA, 2006).
While there may be slight differences in regulatory requirements for nonclinical toxicity
testing of various types of vaccines or in specific countries, there are commonalities in the
type and design of studies required to support clinical development. These are distinct
from those required for small molecules and large molecules as described in Chapter 1 and
are generally quite streamlined compared with other modalities. For example, from a strict
regulatory perspective a polysaccharide vaccine with a well-characterized aluminum adju-
vant indicated for infants should only require one repeat-dose GLP toxicity study in a single
species to support the program through registration. This is of course provided there are no
formulation or other changes that may trigger additional evaluations, etc. Considering
different vaccine types or indications, additional studies such as Developmental Toxicity, bio-
distribution and/or genetic toxicity studies may be required. More detail on when these
studies may be needed is included below.
7. Regulatory aspects of nonclinical vaccine development228
II. Vaccines
TABLE 7.1 Regulatory Guidelines.
Vaccine type Guideline
All vaccines Worldwide: WHO Guidelines on Nonclinical Evaluation of Vaccines (2005)
India: Drug and Cosmetics Act (1940); Drug and Cosmetics Rule (1945) (2005)
China: State Food and Drug Administration, China Technical guidelines for
preclinical research on preventive vaccines. Notice No. 140 (2010)
Japan: Japanese Guideline for Non-clinical Studies of Vaccines for Preventing
Infectious Diseases (2022 e DRAFT)
Adjuvanted vaccines Worldwide: WHO Guidelines on Nonclinical Evaluation of Vaccine Adjuvants and
Adjuvanted Vaccines (2014)
Vaccines for pregnant women
and WCBP
FDA: Guidance for Industry. Considerations for Developmental Toxicity Studies for
Preventative and Therapeutic Vaccines for Infectious Disease Indications (2006)
ICH S5(R3) Detection of Reproductive and Developmental Toxicity for Human
Pharmaceuticals (2020b)
mRNA vaccines WHO: Evaluation of the quality, safety and efficacy of messenger RNA vaccines for
the prevention of infectious diseases: regulatory considerations (2022 e DRAFT)
DNA vaccines FDA: Guidance for Industry. Considerations for Plasmid DNA Vaccines for
Infectious Disease Indications (2007)
Guidelines on the quality, safety and efficacy of plasmid DNA vaccines. (2021,
Replacement of Annex 1 of WHO Technical Report Series, No. 941)
EMA: Note for Guidance on the Quality, Preclinical and Clinical Aspects of Gene
Transfer Medicinal Products (2001)
Recombinant DNA vaccines FDA: DRAFT Points to consider in the production and testing of new drugs and
biologicals produced by recombinant DNA technology (1985)
FDA: Supplement to DRAFT Points to consider in the production and testing of new
drugs and biologicals produced by recombinant DNA technology (1992)
Viral vectored vaccines EMA: Guideline on quality, nonclinical and clinical aspects of live recombinant viral
vectored vaccines (2010)
Lipid based vaccines Japan: Guideline for the Development of Liposome Drug Products (2016a)
Japan: Reflection paper on nucleic acids (siRNA)-loaded nanotechnology-based
drug products (2016b)
EMA: Guideline on the quality, non-clinical and clinical aspects of gene therapy
medicinal products (2018)
Vaccine-specific FDA Development and Licensure of Vaccines to Prevent COVID-19. Guidance for
Industry (2020)
Guidelines to assure the quality, safety and efficacy of live attenuated rotavirus
vaccines (oral). WHO Technical Report Series No. 941 (2007)
Guidelines on the quality, safety and efficacy of dengue tetravalent vaccines (live,
attenuated). WHO Technical Report Series No. 979 (2013)
Guidelines on the quality, safety and efficacy of Ebola vaccines. WHO Technical
Report Series, No. 1011 (2018)
Regulatory guidelines 229
II. Vaccines
Alternate approaches
There may be situations where toxicity studies may be waived or conducted following
the initiation of clinical studies if, for example relevant data from a similar vaccine are avail-
able (i.e., a platform approach, FDA, 2020; WHO, 2022) or when employing the “animal
rule” (established by FDA to facilitate licensure of new products for life-threatening condi-
tions whe n traditional effi cacy trials in humans are unethical or impractical (FDA, 2015)).
The platform approach applies when nonclinical toxicity data are available for a prede-
cessor vaccine utilizing a particular platform, which may be used to support clinical trials
and potentially registration of a new vaccine using the same platform. This may be used for
individual studies or an entire nonclinical program including repeat-dose GLP toxicity,
developmental toxicity, biodistribution, and/or genetic toxicity studies (FDA, 2020;
WHO, 2022).
The most recent example of vaccine types to which the platform approach has been
applied is mRNA vaccines introduced during the COVID-19 pandemic. These types of
vaccines are considered a platform technology as they contain mRNA within the same
lipid nanoparticle (LNP) and the mRNA (with similar modifications) can readily be
changed without requiring changes in manufacture or control of the resulting new prod-
uct. In this case, adoption of a platform approach allowed manufacturers to accelerate
vaccine development based on knowledge gained from similar products manufactured
with the same well-characterized platform technology (FDA, 2020; W HO, 2022 ). Between
the speed with which mRNA vaccines may be developed inherent in the technology and
the use of the platform approach, these vacc ines were available in record time and the
impact on the COVID-19 pandemic was immeasurable. Additional examples of vaccines
that may utilize a platform approach are circular RNA vaccines ( based on the same prin-
ciples as mRNA/linear vaccines) and viral vectored vaccines where the vector remains the
same but the protein insert encodes for a different antigen. An example of this approach
for a viral vectored vaccine was with ERVEBO, the vesicular stomatitis virus (VSV)-
vectored Ebola vaccine developed during the 20 13e 16 Ebola virus disease (EVD)
outbreak. This was the largest EVD outbreak to date and the third Public Health Emer-
gency of International Concern in history. Nonclinical efficacy and toxicity data were
available for a similar VSV-based HIV vaccine and these data were used to support the
start of clinical trials. Toxicology, immunogenicity and efficacy studies with ERVEBO
were performed in parallel with clinical development. Utilizing this approach and capital-
izing on regulatory pathways allowing accelerated development and approval (i.e.,
PRIME [Priority Medicines] designation in the EMA and Breakthrough Therapy Designa-
tion in the US) allowed this development program to be significantly shorter than tradi-
tional vaccin e programs (Wolf et al., 2021; Coller et al., 2017).
While the platform approach allows for waivers for nonclinical toxicity studies, manufac-
turers may choose to conduct a non-GLP study with the candidate vaccine (e.g., inclus ion of
in-life toxicity endpoints on a non-GLP pharmacology study) prior to initiation of clinical tri-
als as a confirmation of safety prior to administration to humans but this is not required.
Again, taking these approaches may require input from HAs, at least when these approaches
are proposed for initial programs.
7. Regulatory aspects of nonclinical vaccine development230
II. Vaccines
Repeat-dose toxicity evaluation (Table 7.2)
Nonclinical toxicity studies are typically designed once initial pharmacology studies in
mice, rabbits and/or nonhuman primates (NH Ps) have identified an appropriate antigen
dose and adjuvant dose (if included) to be proposed for clinical trials. If there are no
immunogenicity data in the model selected for the toxicity studies (e.g., rat), a non-GLP
immunogenicity study may be conducted to ensure the rat is a relevant model (i.e., mounts
a vaccine-specific immune response) in which to evaluate toxicity of the particular vaccine
being studied. This study may also serve to provide reagents for species-specific immunoge-
nicity assay development required for the GLP toxicity study. In addition, if for example, the
vaccine contains a novel adjuvant with an unknown toxicity profile making it challenging to
select doses for the GLP toxicity study, several dose levels of the vaccine and/or adjuvant and
the adjuvant alone may be studied and clinical observations, and clinical and anatomic pa-
thology endpoints may also be included. This information will provide some confidence in
selecting doses for the GLP toxicity study, reducing the risk of not identifying a NOAEL
and potentially delaying clinical studies.
Once an appropriate animal model has been selected, a repeat-dose toxicity study under
Good Laboratory Practices (GLP) conditions (21CF R 58) is conducted. In general, a single
relevant species (typically rat or rabbit) is acceptable. Care should be taken if the rabbit is
selected as the nonclinical toxicity model. Se llers et al., have reported that study-related pro-
cedures can induce stress-related biomarkers and histological changes in cardiac tissues that
TABLE 7.2 Repeat-dose toxicity evaluation.
Parameter Details
Species Single relevant species in which immune response demonstrated is acceptable (typically rat or
rabbit)
Potential additional nonrodent study for novel adjuvants or if employing platform approach
# Doses
administered
Should match or exceed number of doses planned for clinical studies
(n ¼ 1orn þ 1)
Route of
administration
Match clinical route and device, if appropriate
Dose volume Match clinical volume (if possible)
Treatment groups Full human dose (FHD) or multiple doses up to Maximum Feasible Dose that exceeds the FHD
on a per kg basis
Control (e.g., PBS, adjuvant alone)
Treatment interval May be shorter than clinical interval. Typically, 2e3 weeks apart with 4-week treatment-free
period
Routine endpoints Full antemortem and postmortem evaluations and immunogenicity
Repeat-dose toxicity evaluation 231
II. Vaccines
may confound the interpretation of the histopathology data (Sellers, 2017). There may be in-
stances where the NHP may be considered the only relevant model in which to evaluate
toxicity (e.g., viral vaccines where viral replication and a resultant immune response are
only observed in the NHP or the vaccine will be administered via intranasal administration
using a specific device). In these cases, a discussion with HAs is prudent to ensure all alter-
natives have been vetted as use of NHP s is generally not preferred. In some cases (i.e., novel
adjuvants in which activity may be more potent in NHPs) it may be necessary to conduct a
study in a second species. One approach to this is to include nonterminal toxicity endpoints
on a non-GLP NHP pharmacology study. The benefit to this approach is that it allows a
toxicity evaluation in a nonrodent without requiring necropsies and terminal endpoints.
This serves to reduce NHP use, consistent with the 2022 FDA guidance on considerations
for mitigating NHP supply constraints (FDA, 2022) and an overall commitment to the prin-
ciples of the 3Rs of animal use (reduction, refinement and replacement) (https://www.nc3rs.
org.uk/who-we-are/3rs).
The GLP toxicity study is de signed to match clinical study plans as closely as possible
regarding route (typically intramuscular or subcutaneous though oral, intradermal o r
intranasal routes may also be used), dose (in absolute terms vs. on a dose per kg basis uti-
lized for other modalities), formulation and device (if needed). The number of doses
administered is equal to or greater than the number of doses planned clinically. Given
the clinical dosing interval may be quite extended (i.e., months), the frequency of dosing
in animal studies may be shortened relative to that proposed for clinical trials a nd based
on the kinetics of the immune response rather than matching the clinical dosing schedule.
To this end, doses are typically administered at defined intervals of 2e3 weeks. One or
more control groups (PBS or buffer control and/or adjuvant alone controls if a novel adju-
vant is utilized) are typically include d to aid in interpretation of the study findings. A sin-
gle dose level equivalent to the full hum an dose is also acceptable but in cases where
issues with tolerability are anticipated, multiple dose levels may be prudent to ensure a
NOAEL is established. Toxicity endpoints included on the study are consistent with those
for small molecules or large molecules with a particular emphasis on immune system or-
gans and injection sites. In-life endpoints are collected following the first and last dose to
evaluate toxicity following single and multiple doses, respectively. Immunogenicity eval-
uations are typically included following the first and last dose on all studies to determine
whether the model mounts an immune response to the vaccine, thus confirming the spe-
cies selected is an appropriate model in which to evaluate t oxicity. While immunogenicity
assays may be conducted under non-GLP conditions, it is recommended the laboratory
follow good scientific practices, in alignment with the following to ensure the quality
and integrity of the data generated: (1) Good Documentation Practices meeting ALCOA
(attributable, legible, contemporaneous, original, accurate) principles, equivalent to those
defined in GLP, (2) Qualified or fit-for-purpose serology assays, including appropriate
controls, and conducted under department SOPs following GLP principles, (3) Personnel
who are skilled in the processes being executed, with documented training, and (4) Equip-
ment, which is calibrated and maintained. It should also be noted that unlike other modal-
ities, vaccine-specific immunogenicity in vaccine studiesisadesirableresponseand
although it is an integral part of the toxicity evaluation it is n ot intended to predict human
immunogenicity; this is the purpose of the pharmacology evaluations. Necropsies
7. Regulatory aspects of nonclinical vaccine development232
II. Vaccines
including gross and histopathologic evaluations are included approximately 3 days after
the last dose and after a recovery period (e.g., 4 weeks). Given the mechanism of action of
vaccines ( i.e., immunogenicity/inflammation), certain findings (e.g., clinical pathology
findings indicative of an inflammatory response, local injection site reactions, increased
body temperature, increased inflammatory biomarkers) that may be considered adverse
with other modalities are expected (Baldrick, 2016) and therefore are carefully considered
as the NOAEL is determined. For this reason, itiscriticaltheindividualsevaluatingthe
toxicity data are experienced in vaccine toxicity studies with an understanding of ex-
pected effects of a well-tolerated vaccine to ensure any findings are put into the proper
context.
Once a NOAEL is established, a safety margin is calculated, which for vaccines is typically
established on a per kg basis. For example, a full human dose of 42 mg of a vaccine adminis-
tered to a 0.3 kg rat provides an approximate 200-fold safety margin for a 60 kg adult human
or a 17-fold margin in a 5 kg infant. While there is no specific guidance on margin calculation
for vaccines, this approach is generally accepted and in line with language in the 2005 WHO
guidelines, which indicates “. a dose that exceeds the human dose on a mg/kg basis and
that induces an immune response in the animal model may be used. In such cases, the factor
between human and animal dose should be justified.”
Developmental toxicity
As mentioned above, specific recommendations apply to vaccines administered to partic-
ular populations. An example of this is the developmental toxicity study, which is conducted
for vaccines indicated for women of childbearing potential (WOCBP) or pregnant women.
The study is conducted under GLP conditions and is designed to evaluate the effects of
the vaccine on pregnant and lactating animals. In contrast to the developmental toxicity eval-
uation supporting other modalities such as small molecules, which consists of multiple devel-
opmental toxicity studies, a single, well-designed study in a single species is generally
sufficient, the design of which is outlined in the ICH S5(R3) (ICH, 2020a) and FDA (FDA,
2006) guidelines. In general, dams are exposed to the vaccine in the premating stage to ensure
peak antibody production and thereby exposure to the vaccine-induced immune response as
well as components of the vaccine formulation during critical stages of development (e.g.,
organogenesis). The vaccine is also administered during gestation (and lactation, as needed).
In a typical study design, one subgroup of females is subjected to cesarean secti on to allow
uterine and fetal examinations and a second subgroup is allowed to litter with postnat al
follow-up of the offspring. Endpoints include maternal function in F0 dams and pre- and
postnatal evaluations of viability, growth, and development, including preweaning neurolog-
ical evaluations (e.g., pupil constriction, auditory startle reflex, surface righting reflex, and/or
air righting) of F1 animals and immunogenicity in all F0 and F1 animals to confirm species
relevance.
Generally, the developmental toxicity study utilizes the species, highest tolerated dose
and route used for repeat-dose toxicity studies. This is recommended to avoid any unantic-
ipated or overt toxicity in the pregnant animals, often more sensitive than nonpregnant an-
imals. The design of the study is the same whether it will be utilized to support inclusion of
Developmental toxicity 233
II. Vaccines
WOCBP or pregnant women in clinical studies but the timing differs. To support WOCBP,
the study may be conducted concurrent with Phase 3 clinical studies with the data available
for filing provided appropriate contraception measures are included in the clinical trial
whereas the data are required prior to enrollment of pregnant women (FDA, 2006).
Stand-alone studies for the express purpose of fertility evaluation are generally not
required (FDA, 2006). In addition, given the age de-escalation design utilize d for infant vac-
cine clinical trials in which safety in adults is evaluated prior to proceeding to adolescents/
toddlers/infants, studies in juvenile animals are generally not required (ICH, 2011b,
2020b).
Biodistribution
In vaccine studies, the antigen-specific immune response may be considered a surrogate
for toxicokinetics as it provides evidence that the animals have been exposed to the vaccine.
Therefore, traditional pharmacokinetic evaluations are not routinely required. However, bio-
distribution studies, potentially including tissues which may result in shedding, may be
required for viral vectored vaccines, mRNA vaccines, DNA vaccines, novel adjuvants or vac-
cines delivered via alternative routes of administration (WHO, 2014, 2021, 2022). While there
are no specific guidelines regarding the design of biodistribution studies for vaccines or vac-
cine adjuvants, the general guidance in ICH S12: Nonclinical Biodistribution Considerations
for Gene Therapy Products (2023) may be useful in designing these studies. The need for and
timing of these studies is considered on a case-by-case basis and information from the liter-
ature or from previous vaccine candidates may be used to support the requirement for these
studies. In general, biodistribution studies are conducted in a single relevant species and a
single dose is administered at either the full human dose or a dose level known to be well
tolerated. Necropsies are conducted at early and late timepoints to evaluate both bio-
distribution and persistence (duration of tissue exposure). A general tissue list is evaluated
but additional tissues may be included if a particular biodistribution profile is of concern
(e.g., if there is a concern for distribution to the neurological system, spinal cord tissues
may be included). An evaluation of biodistribution may theoretically be included on a
repeat-dose toxicity study, however there are limitations to this approach given the frequency
of dosing (every 2e3 weeks) may not allow a thorough evaluation of persistence so this
should be addressed if this approach is taken. If there is a concern that a vaccine may inte-
grate into the host genome, an evaluation of integration may also be included. In general,
early conversations with HAs to ensure alignment on study design and timing are
recommended.
Environmental risk assessment
In cases of recombinant viral vaccines or vectors that could result in the release of recom-
binant microorganisms into the environment or vaccines considered genetically modified or-
ganisms (GMOs), studies evaluating environmental risk may be required (WHO, 2013, 2018).
There are specific model systems utilized to evaluate the risk of transmission between
7. Regulatory aspects of nonclinical vaccine development234
II. Vaccines
humans or other hosts. For example, for vaccines based on or containing viruses anticipated
or known to be spread by arthropod vectors such as mosquitoes, studies may be conducted to
evaluate transmissibility from vaccinees to mosquitoes and the capacity of the vaccine virus
to grow within mosquitos. In addition, mosquitoes may be fed blood meals or injected with
the vaccine followed by the measurement of virus in various compartments (Troyer et al.,
2001). For viruses pathogenic in livestock and suspected of having shedding potential, trans-
mission studies may also be conducted in animals such as swine (Morozov et al., 2021)to
evaluate animal-to-animal spread of the vaccine virus.
Genotoxicity and carcinogenicity
Genotoxicity and carcinogenicity studies are also generally not required for vaccines given
the antigens are generally biological in nature (e.g., polysaccharides, virus-like particles, inac-
tivated viruse s, etc.). Notable exceptions are genotoxicity studies for novel excipients or novel
adjuvants that are or contain novel chemical entities (NCEs) (WHO, 2005, 2014) or contain
structural alerts that may trigger genotoxicity evaluations. If it is determined that genotoxic-
ity studies are required, a full genotoxicity evaluation should be conducted per ICH S2(R1)
(ICH, 2011a). When conducting these evaluations, careful consideration needs to be given
to formulation buffers and compatibility with the buffer matrix used for the in vitro genotox-
icity assays as interference may confound the interpretation of the data. This information will
aid in buffer and/or top concentration selection. In general, if the adjuvant contains an NCE,
it is best practice to study just the NCE in the in vitro studies while the formu lated adjuvant
will be studied in vivo to most closely mimic how humans will be exposed to the adjuvant. In
addition, the anticipated increases in body temperature and/ or inflammation following
administration of a novel adjuvant may confound the interpretation of an in vivo chromo-
some damage assay and result in inc reases in micronuclei or chromosome aberrations that
are due to an inflammatory response rather than genotoxicity. Inflammation and hyperther-
mia are recognized as confounding factors for an in vivo chromosome damage assessment
(Tweats et al., 2007; ICH, 2011; OECD, 2016; Downs et al., 2012; Westbrook et al., 2009)
and can create challenges for the genotoxicity assessment of vaccine adjuvants that are
designed to stimulate the imm une response. As genetic toxicity studies are rarely conducted
for vaccine programs, it would be recommended that the need for these studies be confirmed
and any deviation from the studies outlined in ICH S2(1) be discussed with HAs.
Safety pharmacology
Safety pharmacology studies are generally only needed if data from nonclinical or clinical
studies suggest the vaccine may affect physiological parameters such as central nervous sys-
tem (CNS), respiratory, cardiovascular (CV) or renal function (WHO, 2005, 2014). If it is
determined these evaluations are needed, ICH S7A (ICH, 2000) may be reviewed for general
guidance but an interaction with HAs would likely be prudent as there may be justification to
incorporate these endpoints in the planned repeat-dose GLP toxicity study rather than con-
ducting stand-alone studies.
Safety pharmacology 235
II. Vaccines
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