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ICH S5 (R3) discusses circumstances where alternative assays are warranted in Annex 2
(ICH, 2020). These potential scenarios include:
1. where target biology or other data strongly suggest evidence of the potential for an
adverse effect on embryo-fetal development (EFD)
2. toxicity in animal species precludes reaching clinically relevant systemic exposures
3. as support for a weight of evidence assessment when there are equivocal findings in
animal studies
4. as partial support for clinical trials including up to 150 WoCBP for up to 3 months
duration
5. pharmaceuticals being developed for certain severely debilitating or life-threatening
diseases or late-life onset diseases
Although no specific assays are endorsed by ICH S5 (R3), the guideline does allow for
alternative assays to be used as part of a weight of evidence approach. In addition, the guide-
line includes information on the expectations for a qualified assay, and provides illustrative
examples of alternative assays as part of an integrated DART risk assessment strategy. While
alternative assays are often suitable for small molecules (e.g., whole embryo culture for tera-
togenicity assessment), it is unclear how the current in vitro assays/models would be used
for biologics given the need for target engagement and/or immune cell interaction.
With the COVID pandemic exacerbating the already limited NHP supply, FDA issued
Nonclinical Considerations for Mitigating Nonhuman Primate Supply Constraints Arising
from the COVID-19 Pandemic Guidance for Industry in 2022 (FDA, 2022). The guideline
expired with the end of the Public Health Emergency in May 2023, but the Federal Register
notes that “COVID-19 pandemic-related NHP supply constraints affecting pharmaceutical
development are expected to persist beyond the termination of the COVID-19 public health
emergency.” The Federal Regi ster goes on to say “FDA intends to revise and replace the guid-
ance with any appropriate changes” (FDA, 2022). Overall, the FDA guideline aligns with ICH
S5(R3) in offering alternatives to the use of NHP during the reduction in supply. For DART
assessments, it suggests the scientifically justified use of species-specific surrogates when
NHP have been determined to be the only relevant species. It also allows, on a case-by-
case basis, for the use of literature reviews in combination with repeat dose toxicity data
to generate a weight of evidence assessment of DART risk in cases where there is a clear
risk (e.g., mechanism of action related) or negligible risk (e.g., viral or bacterial targets)
(FDA, 2022; Rocca et al., 2018). Making DART studies a postmarketing commitment where
WoCBP are unlikely to be the targeted patient population is also discussed. Lastly, sponsors
are strongly encouraged to discuss proposed DART program strategy with regulators in
advance of study conduct.
Studies for the assessment of reproductive toxicity
The goal for a robust DART program should be to gather data to understand the potential
hazards due to treatment at all the stages of reproduction. ICH S5(R3) discusses reproductive
toxicity assessment based on three in vivo studies that cover the seven stages of reproduction
(see Fig. 3.1).
3. Regulatory guidelines and their application in the nonclinical evaluation of biological medicines76
I. Development of biopharmaceuticals
These studies are: (1) A fertility and early embryonic development (FEED) study, (2)
embryo-fetal development (EFD) study, and (3) a pre- and postnatal development study
(PPND). Annex 1 of ICH S5(R3) details general study design considerations for all three
studies in rodents, and typically most relevant to biopharmaceuticals, rabbits and NHP.
Fertility and early embryonic development (FEED): stages A and B
According to ICH S5(R3), the purpose of fertility studies is to test for adverse effects result-
ing from treatment from before mating (males/females) through mating and implantation
(Stages A and B). Parameters evaluated in females include potential effects on the estrous cy-
cle, tubal transport, implantation, and development of preimplantation stages of the embryo;
for males, the study will assess functional effects (e.g., libido, epididymal sperm maturation)
that may not be detected by histological examinations of the male reproductive organs (ICH,
2020). These are generally conducted in a single rodent (typically rat) species. With respect to
biopharmaceuticals, when rodents are pharmacologically relevant, fertility should be
assessed in rodents. As mating and fertility studies are not possible for nonhuman primates,
when they are the sole relevant species, reproductive tissue structure (male and female repro-
ductive histopathology), not function, can be evaluated in repeat dose toxicity studies of
3 months or more in duration. Where possible, animals on toxicity study should be sexually
mature at the start of the study. Here again, the NHP shortage may impact a sponsor’s ability
to source sexually mature animals in a timely manner to conduct chronic studies. Discussions
with health authorities may be helpful in determining whether a literature-based DART
assessment (weight of evidence assessment) may be justified for a given target, disease indi-
cation and patient population (Rocca et al., 2018; Ackley et al., 2023).
Standard histopathological evaluation and organ weight determination are considered suf-
ficient to provide an assessment of reproductive capability in males because the majority of
reproductive toxicants cause adverse effects on gonads and/or accessory sex organs and
Stages of Reproduction
A
Premating through Conception
B
Conception through Implantation
C
Implantation through Closure of Hard
Plate
D
Closure of Hard Plate through End of
Pregnancy
E
Birth through Weaning
F
Weaning through Sexual Maturity
FEED
Stages A&B
EFD
Stages C&D
PPND
Stages C-F
FIGURE 3.1 Developmental and repro-
ductive toxicity studies and stages of
reproduction.
Studies for the assessment of reproductive toxicity 77
I. Development of biopharmaceuticals
testicular and epididymal weights and histopathology (ICH, 2009). Although assessment of
histopathology of the female reproductive tract is likely not as sensitive for detecting fertility
issues, it is still considered to be sufficient (Sanbuissho et al., 2009). If there is a cause for
concern either from mechanism of action, literature data (e.g., knockout animals) or data
from earlier studies, then additional parameters such as menstrual cycling, sperm motility,
and sperm count can be incorporated into the repeat-dose toxicity study or a specific inves-
tigative study can be designed. To assess fertility as described above, monkeys will need to be
sexually mature at the start of the study, and there are some practical and scientific consid-
erations associated with the conduct of these studies. For example, male monkeys typically
need to be 4e5 years old before they reach sexually maturity (Smedley et al., 2002). Given
that the majority of monkey repeat-dose toxicity studies have historically been conducted
in younger animals (e.g., approx. 2 years old), it may be more difficult to acquire mature an-
imals and as the historical database has been collected primarily from younger animals data
interpretation may be complicated. For situations in which there is a specific cause for
concern about potential effects on conception/implantation, evaluation using a characterized
homologous molecule may provide additional useful information.
Embryo-fetal development (EFD) and enhanced pre- and post-natal
development (ePPND): stages C and D and C through F
The purpose of the embryo-fetal study is to assess the potential adverse effects on the preg-
nant female and development of the embryo and fetus consequent to exposure of the female
from implantation to closure of the hard palate. Potential adverse effects on the pregnant/
lactating females, on the development of the conceptus, and on the offspring following expo-
sure of the female from implantation through weaning can be assessed in the pre/postnatal
study (ICH, 2020). When pharmacologically relevant, rodents or rabbits should be consid-
ered. Typically, embryo-fetal development studies are conducted in two species (rodent
and rabbit) and the same is recommended for biopharmaceuticals. However, if embryo
lethality or teratogenicity is observed in one of the species (e.g., rodent), testing in the second
species (e.g., rabbit) would not be required. In addition, if the rabbit is either not pharmaco-
logically relevant or not appropriate (e.g., unmanageable immunogenicity), it is acceptable to
assess a single rodent species. ICH S5(R3) allows for a smaller preliminary EFD (pEFD) in one
species in combination with a qualified alternative assay in a second species (ideally, rodent
for one and nonrodent for the other) to support limited enrollment of WoCBP, deferring
larger definitive studies until later in clinical development.
The type and design of the developmental toxicity studies should be tailored to the partic-
ular biopharmaceutical (i.e., its expected placental transfer (how much and when) and pre-
dicted mechanism of action). Also, as mentioned in ICH S6(R1), when there is extensive
public information with respect to a certain class of compounds, a mechanistic study which
demonstrates expected results may be conducted in place of a formal reproductive toxicity
study (Table 3.4).
If there is a concern with respect to maternal toxicity, pregnancy maintenance, and em-
bryo-fetal loss, a single embryo-fetal development (EFD) study in a limited number of ani-
mals could confirm the hazard for early pregnancy. For other biopharmaceuticals whose
3. Regulatory guidelines and their application in the nonclinical evaluation of biological medicines78
I. Development of biopharmaceuticals
mechanism of action is not expected to cause pregnancy loss but may affect later fetal devel-
opment (e.g., immunomodulators), the standard EFD study in which nonhuman primates are
dosed from early pregnancy up to GD50 with cesarean sections around GD100 would not be
expected to be representative of human fetal exposure throughout pregnancy for a parenter-
ally administered pharmaceu tical IgG.
Only when nonhuman primates are the sole relevant species should developmental
toxicity studies be conducted in nonhuman primates. ICH S5(R3) allows for ePPND studies
to be utilized instead of EFD and standard PPND studies in such instances. If immunoge-
nicity precludes dosing for the appropriate duration for full assessment of development
toxicity, timed dose interval cohorts can be considered. For instance, dosing would be initi-
ated on successive days across the pregnancy period using different cohorts of animals.
Therefore, all periods of organogenesis could be exposed to the biopharmaceutical without
the presence and possible interference of neutralizing antibodies (Martin et al., 2009). If the
biopharmaceutical is immunogenic in all species, including nonhuman primates, then con-
ducting a study with species-specific surrogates or transgenic models may be an option,
although ICH S5(R3) cautions against calculating safety margins relative to human exposures
with species specific surrogates. Where no relevant model can be utilized, sponsors should
proactively discuss a justification and a thorough literatu re-based weight of evidence risk
assessment with health authorities (Rocca et al., 2018; ICH, 2020; FDA, 2022; Ackley et al.,
2023).
Given the long half-life of a monoclon al antibody, exposure may continue after dosing is
discontinued. Therefore, for products in which nonhuman primates are the only relevant spe-
cies, a single study which can incorporate several stages of development represents the more
scientifically valid approach. This “enhanced” pre- and postdevelopment (ePPND) study, is
not simply a combined EFD and PPND study (i.e., twice the group sizes with cesare an sec-
tions) but is designed specifically for the biological characteristics of the biopharmaceutical.
On the plus side, this design is mindful of 3Rs principles and NHP shortages, and should
reduce the number of the nonhuman prima tes needed versus conducting two separate
studies (i.e., EFD and PPND). Nonhuman primates are dosed from GD20 (confirmed preg-
nancy) to birth and the study design incorporates endpoints from both studies as shown
in Fig. 3.2. It is not recommended to dose maternal animals after delivery since maternal
TABLE 3.4 Default species for DART studies.
Study type Small-molecule compound Biotherapeutic
Fertility Rodent Rodent
a
EFD Rodent and rabbit Rodent and rabbit
b
PPND Rodent Rodent
c
ePPND NA NHP
a
Only if pharmacologically relevant. If not, assess special endpoints in chronic toxicity study in sexually mature
nonhuman primate.
b
Only if relevant. If not, assess whether other species are relevant and if none then consider homolog.
c
Only if relevant. If not move to ePPND study in nonhuman primate.
Studies for the assessment of reproductive toxicity 79
I. Development of biopharmaceuticals
IgG is only excreted in the colostrum. The length of the postnatal phase will depend on the
mechanism of action, tissue cross-reactivity or data from general toxicity studies. For
example, evaluation of the development of the immune system incorporating immunopheno-
typing and immune function analysis should be incorporated for immunomodulatory mono-
clonal antibodies. The specific immune functional assays chosen should be relevant to the
specific monoclonal antibody (Stewart, 2009; Buse et al., 2003; Chellman et al., 2009).
The size of the groups required to detect a hazard should be based on the known fre-
quency of abortions in cynomo lgus monkeys in order to obtain a sufficient number of infants
(typically 6e8) necessary to assess postnatal development and any special functional evalu-
ations. ICH S5(R3) recommends a minimum of 16 pregnant females for at least two dosing
groups (including 1 control). Although there will be inter-laboratory variations, pregnancy
losses in cynomolgus monkeys tend to be highest before GD50 and also increase at parturi-
tion (Jarvis et al., 2010). If studies are performed at a contract research organization, obtaining
historical control data on spontaneous pregnancy loss in the periods bracketing and during
the study are helpful for understanding background versus treatment-related differences.
Given this potential increase near birth, ePPND studies are typically designed to accrue preg-
nant animals over time. Interim statistical analyses can facilitate decisions when to add ani-
mals to a study and also to help determine whether a group or entire study should be
stopped because an adverse effect has been adequately identified. Since these studies are con-
ducted in nonhuman primates and are used for hazard identification, the number of dose
levels should be jus tified rather than a default to the standard low-, mid-, and high-dose
levels. In a situation in which clinical efficacy requires complete target saturation, a single
high-dose level that exhibits both target saturation and includes at least a tenfold margin
over clinical exposure may be justified.
Mating- Day 20
Treatment to delivery Postnatal phase
Pregnancy
Ultrasound
Fetal Growth
Infant
Immunophenotyping*
Growth & behavior
External malformations
Delivery
Infant & maternal TK & ADA
Infant
Clinical pathology
Immunophenotyping*
Immunoglobin
Behavior
X-ray assessment
Ophthalmology
Infant
Clinical pathology
Growth, behavior & development
Learning test*
Immunophenotyping*
Immune function assays*
Visceral morphology
Organ weights
Histopathology
Immunohistochemistry
Duration of
dosing
incorporates
duration of EFD
to delivery
Postnatal phase duration &
endpoints designed to address
drug-specific concerns (e.g.,
ontogeny of immune system,
CNS development, etc.)
FIGURE 3.2 Potential endpoints for an “enhanced” pre- and postdevelopment study. ADA, antidrug antibody;
EFD, embryo-fetal development; TK, toxicokinetics. *Endpoints added only if cause for concern.
3. Regulatory guidelines and their application in the nonclinical evaluation of biological medicines80
I. Development of biopharmaceuticals
The timing of the reproductive/developmental toxicity studies are detailed in ICH
M3(R2), ICH S5 (R3), ICH S6 (R1), ICH S9, and Nonclinical Considerations for Mitigating
Nonhuman Primate Supply Constraints Arising from the COVID-19 Pandemic Guidance
for Industry (ICH, 2009; ICH, 2020; ICH, 2011; ICH, 2010; FDA, 2022). Assuming there are
adequate precautions to prevent pregnancy and nonhuman primates are the only relevant
species, an EFD or ePPND study can be conducted during Phase III with the report submitted
at the time of marketing application. When it is not possible to ensure that there are sufficient
precautions in place, either a completed EFD study or interim report from an ePPND study
should be submitted prior to initiation of Phase III. As mentioned above, the FDA Guidance
for Industry around NHP Supply also gives some recommendations on points to discuss with
health authorities when determining the timing of DART studies. In addition, if there is a
serious concern for embryo-fetal developmental toxicity, a label reflecting that concern could
obviate the need to conduct the study in nonhuman primates. The recommendation in the
label would likely be to avoid administration of the drug to women of childbearing potential
unless the benefits of therapy outweigh the potential risks. Since these ePPND studies need to
be individually designed, consultation and agreement with the relevant health authorities
should be reached before proceeding with the approach.
Genotoxicity and carcinogenicity
Genotoxicity
Data from genotoxicity studies determine the potential for a chemical to cause DNA or
chromosomal damage. However, recombinant proteins and monoclonal antibodies,
composed of endogenous amino acids, are unlikely to react with DNA or other chromosomal
material and therefore evaluation for genotoxicity is not needed. Products that contain linkers
may be one of the few circumstances in which a genotoxicity assessment might be
recommended.
Carcinogenicity
Biopharmaceuticals are not genotoxic and therefore would not be expected to be “com-
plete carcinogens”; however, chronic administration could potentially lead to tumor promo-
tion or progression of specific neoplasm(s) based on mechanism of action (Vahle et al., 2010).
The decision whether to evaluate carcinogenic potential for a new drug entity as outlined
in ICH S1A depends on both its intended clinical use (i.e., length of treatment and severity of
disease) and specific concerns based on its pharmacological properties, including genotoxic-
ity (ICH, 1995). In accordance with ICH S1A, long-term rodent carcinogenicity studies should
be considered for biopharmaceuticals when the recombinant product exhibits biological ef-
fects that are different from those of the natural product, when there are structural differences
between the recombinant product and the natural product, and when recombinant products
are administered at pharmacologic doses that exceed endogenous levels. These refer to
recombinant proteins (e.g., growth factors, hormones, interferons) intended for replacement
or augmentation therapy but do not address other novel biopharmaceuticals such as
monoclonal antibodies and fusion proteins (ICH, 1995).
Genotoxicity and carcinogenicity 81
I. Development of biopharmaceuticals
In the original ICH S6 guideline, the often quoted first statement “Standard carcinogenicity
bioassays are generally inappropriate for biotechnology-derived pharmaceuticals” refers spe-
cifically to the conduct of the 2-year rodent bioassays, not to carcinogenicity assessment in
general. The intent was to discourage a default to long-term animal studies, even if techni-
cally feasible, not to rule them out completely. In keeping with the case-by-case philosophy
of ICH S6, the objective of this section was to provide flexibility in assessment of the carcino-
genic potential and request that sponsors employ an adequate scientific approach. The ICH
S6 amendment provides greater clarity based on the accumulated experience with bio-
pharmaceuticals since the original guideline was published in 1997 (Vahle et al., 2010;
Cavagnaro, 2008a, 2008b). The ICH S1B(R1) Addendum describes factors to consider in an
integrated weight of evidence when developing a carcinogenicity assessment strategy
(ICH, 2022). Of these, perhaps the most relevant to biologics is evidence of immune modula-
tion. In this case, the guidance suggests that while broad immunosuppression may provide
sufficient cause for concern, standard rat or mouse studies are unlikely to further inform on
human risk.
In a review of marketed biopharmaceuticals, assessment for either carcinogenicity poten-
tial or tumor promotion was available for only a minority (29/80) of those products reviewed
(Vahle et al., 2010). Standard 2-year bioassays (mouse and rat or rat only) were conducted
more frequently with peptide hormones than other products, whereas only one standard
2-year mouse bioassay was conducted for a monoclonal antibody (Orencia). In vitro cell pro-
liferation assays tended to be used for growth factors and/or hematology factors and one
alternative carcinogenicity model was found. It should be noted, however, that in a number
of cases, in particular for monoclonal antibodies, a lack of species relevance and/or immuno-
genicity was often the reason for not conducting 2-year bioassays. No single study or set of
studies were identified as potential “defaults” with which to evaluate carcinogenic potential
nor was any approach completely discounted. The importance of understanding the mecha-
nism of action, pharmacology, theoretical consequences of target engagement, and experi-
mental data was emphasized (Vahle et al., 2010). ICH S6(R1) continues to recommend a
product-specific approach and when an assessment of carcinogenic potential is needed, the
design of an appropriate nonclinical safety package should be based on emerging nonclinical
and clinical data and a review of the relevant literature. Although not specifically recommen-
ded in ICH S6 R1, development of the product-specific risk assessment carcinogenicity strat-
egy should begin early in development so that additional endpoints, if necessary to evaluate
potential effects on cell proliferation, can be added to the chronic repeat-dose toxicity study
and shoul d be based on a weight of evidence approach.
In addition, the carcinogenicity strategy document should be periodically updated as new
data or information become available. The following should be considered:
• Review the literature to obtain information such as target location (e.g., gene
expression databases), animal models of disease, human genetic diseases, downstream
effects of a target using genetically modified ani mals (e.g., knockout, knock-in mice,
etc.)
• Review available data from existing in vivo studies (e.g., pharmacology or efficacy
models), including general toxicity studies with careful attention to any suggestion of
proliferative changes.
3. Regulatory guidelines and their application in the nonclinical evaluation of biological medicines82
I. Development of biopharmaceuticals
• Examine information on related drugs (in-house, competitor molecules, marketed
products).
• Understand any potential issues with drug class (e.g., immunomodulators, growth
factors, etc.).
Integration of the information to produce a coherent strategy may be difficult, particularly
for targets in which extensive information is available. For example, multiple publications
that describe knockout animal data with the same target may provide conflicting data; the
question is which one to choose? Also, in particular with cytokines such as interleukin-10,
molecules that exhibit pleiotropic activity can result in apparently contradictory biology
(i.e., they can be antimetastatic in certain cell lines but prometastatic in others) (Rosenblum,
2002). These examples highlight that the carcinogenicity assessment should be based on a
weight-of-evidence approach.
There will be cases in which sufficient data exist to provide an adequate risk assessment
without the need for additional nonclinical studies. For example, there may be no toxicity
data from either the chronic toxicity studies or alerts from a literature review (including
knockout animals, target biology) that indicate a potential carcinogenic risk of the biophar-
maceutical candidate, and the target’s biological activity is not involved in either growth po-
tential or cell proliferation. A monoclonal antibody directed against a specific growth factor
may be an example. Similarly, recombinant proteins identical to the native protein sequence
used as replacement therapies such as coagulation factors are examples of drugs that most
likely wo uld not require additional studies.
There will, however, be biopharmaceuticals whose mechanism of action poses a theoretical
carcinogenic risk (e.g., immunosuppressive agents and growth factors) and those for which
there is insufficient available information or that target engagement can produce both anti-
proliferative and proliferative signals. A common approach to attempt to assess the theoret-
ical risk posed by growth factors is to incubate the biopharmaceutical with transformed cells
and when the in vitro data indicate a positive effect, follow up with a relevant in vivo animal
model (e.g., murine xenograft model). This strategy has been used for a number of bio-
pharmaceuticals and in some cases has resulted in either inconsistent or inconclusive data
or in other cases, even when all the data have been negative, it has not impacted the label;
the potential theoretical concerns are still highlighted (Vahle et al., 2010). This illustrates
the importance in understanding the relevance of animal carcinogenicity models (both short
term and long term) to human.
Another class of biopharmaceuticals that has generated extensive discussion is the immu-
nomodulatory agents in which the concern for chronic use is the potential impairment of tu-
mor surveillance, particularly as it is generally accepted that there is a correlation between
long-term immunosuppression and increased malignancy (Vahle et al., 2010). Although an
association between immunosuppression and reactivation of latent viruses resulting in an
increased risk of malignancy has been suggested as a surrogate model, conflicting results
from animal experiments question the clinical relevance (Vahle et al., 2010). Therefore, given
the variable results in nonclinical studies and apparent lack of relevance to the clinical situ-
ation, ICH S6(R1) recommends that with these types of compounds, the potential hazard
would be best addressed through appropriate product labeling and clinical risk management
practices.
Genotoxicity and carcinogenicity 83
I. Development of biopharmaceuticals
There will be targets, particularl y novel ones, in which insufficient data are available with
which to conclude that no additional nonclinical data are needed. In this case, a more exten-
sive evaluation may be necessary and may include the option of additional nonclinical
studies such as the 2-year rodent bioassay. The types and designs of studies need to be care-
fully considered with respect to the relevance of the animal data to humans. Animal studies
should only be conducted when the data are expected to mitigate the concern; if they do not
then the label should reflect the concern.
In conclusion, there is no single default that is appropriate to evaluate the potential carci-
nogenicity of a biopharmaceutical and different scenarios need to be considered, as shown by
Table 3.5. In any case, the product-specific strategy should be discussed with health author-
ities to insure their acceptance.
Special considerations for anticancer drugs
This section describes the principles, special considerations, and differences related to
nonclinical progra ms to support the development of anticancer biopharmaceuticals (See
also Chapter 11). An international guideline, ICH S9, which discusses the implementation
of principles for the development of anticancer agents, was finalized in 2009. ICH S9 and
ICH S9 Q&A apply to biopharmaceuticals that are in development to treat patients with
advanced, late-stage cancer (ICH, 2010; ICH , 2018). In addition, other ICH guidelines should
be considered when a particular topic of the nonclinical program strategy is not directly
addressed in ICH S9 and ICH S9 Q&A.
TABLE 3.5 Options to evaluate carcinogenic potential.
Endpoint/Assay Comments
Addition of cell
proliferation markers
Might show that cell proliferation is not increased but is duration sufficiently long to
negate a potential carcinogenic effect?
Addition of biomarkers May show that pathway is not affected or if it is affected, does this necessarily reflect
carcinogenic potential?
Two-year rodent bioassay Although standard for small molecules, even if feasible, question is whether the data
will be definitive for the label
Standard transgenic mouse
bioassay
Could be useful for answering a specific question but unlikely to be useful for general
purpose due to lack of validation of these models
Studies using homologs May be situations in which a very well-validated model may be useful to answer a
specific question. The use of homologs for 2-year bioassay is discouraged by ICH S6(R1)
In vitro cell proliferation
assays
May be useful for initial evaluation and as part of weight of evidence but literature
examples seem to question relevance to human and lack of impact on the label
information
Xenograft models Similar to the in vitro cell proliferation assays regarding relevance to human
3. Regulatory guidelines and their application in the nonclinical evaluation of biological medicines84
I. Development of biopharmaceuticals
For the nonclinical assessment of anticancer drugs the objectives are the same as for drugs
in other therapeutic areas. These include understanding the pharmacological properties of the
drug in the intended indication, establishing a safe starting dose for the first clinical trial, and
understanding the toxicity profile of the drug, including the identification of target organs
and the reversibility and/or ability to monitor any observed adverse effects. So why, then,
is there a different guideline for anticancer drugs? One key difference for anticancer drugs
versus pharmaceuticals for other indications is that the clinically efficacious exposure level
in patients is often close to or at an observed adverse effect level in the nonclinical toxicity
studies. More safety risk is tolerated for anticancer drugs because patients with advanced
cancer often have limited time and treatment options for their disease. The possible benefit
to these patients outweighs the potentially greater risk that these drugs may pose. Because
of the increased safety risk and opportunity for increased benefit, most of the initial clinical
trials conducted with anticancer drugs occur in pat ients with advanced cancer rather than in
healthy volunteers. For all these reasons, there is a greater sense of urgency which requires a
more flexible and somewhat less conservative approach to the development of anticancer bio-
pharmaceuticals. This does not mean that patient safety is compromised but that physicians
and patients are willing to assume some greater amount of risk because of the severity and
seriousness of their disease.
Since a different level of safety risk is acceptable for anticancer agents, different terminol-
ogy is used to define toxic dose levels and subsequent safety margins for these drugs. The
two most used terms are the STD10 and the HNSTD. The STD10 is the dose level that is
severely toxic to approximately 10% of animals. Severely toxic is usually defined as mortality,
life-threatening toxicity or observation of toxicities that are not reversible during a recovery
period and would substantially diminish organ function. The STD10 is typically used in ro-
dent toxicology studies. The HNSTD is defined as the highest nonseverely toxic dose and is
typically used in nonrodent toxicology studies with severe toxicity, including mortality and
the other parameters mentioned above. Both are defined in the ICH S9 guideline and can be
used to aid in the calculation of safety margins and selection of starting dose for first in pa-
tient clinical trials.
Identifying a no-observable-adverse-effect level (NOAEL) or no-observable-effect level
(NOEL) is not required to support clinical use of an anticancer agent (either small molecules
or biopharmaceuticals) and this should be taken into consideration when selecting doses for
nonclinical toxicity studies. In general, the highest dose/exposure tested in the repeat-dose
toxicity studies does not limit the dose escalation or highest dose that can be investigated
in the clinical trials. Clinical trials can continue beyond the highest dose and duration of
completed toxicity studies based on individual patient responses. The dosing intervals
selected for the toxicity studies are generally chosen to allow for flexibility of dosing sched-
ules in the clinic. It is not expected that the exact clinical schedule be used in the toxicity
studies, but that the information from the toxicity studies (Cmax and cumulative expos ure)
be sufficient to support the clinical dose/exposure and schedule and to identify potential clin-
ically important toxicities. The nonclinical data used to support Phase 1 clinical trials in
conjunction with Phase 1 clinical data are generally sufficient to support entry into Phase 2
clinical trials. Chronic toxicity studies will need to be conducted to support Phase 3 clinical
trials. In accordance with ICH S9, chronic toxicity studies of 3 months duration are
Special considerations for anticancer drugs 85
I. Development of biopharmaceuticals
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