INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL

REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE

ICH HARMONISED TRIPARTITE GUIDELINE

NONCLINICAL EVALUATION FOR

ANTICANCER PHARMACEUTICALS

S9

Current Step 4 version

dated 29 October 2009

This Guideline has been developed by the appropriate ICH Expert Working Group and
has been subject to consultation by the regulatory parties, in accordance with the ICH
Process. At Step 4 of the Process the final draft is recommended for adoption to the
regulatory bodies of the European Union, Japan and USA.
 S9
Document History

First
History Date
Codification

13
Approval by the Steering Committee under Step 2
S9 November
and release for public consultation.
2009

Current Step 4 version

Approval by the Steering Committee under Step 4 and 29

S9 recommendation for adoption to the three ICH October
regulatory bodies. 2009
 NONCLINICAL EVALUATION FOR ANTICANCER PHARMACEUTICALS
ICH Harmonised Tripartite Guideline
Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting on
October 29, 2009, this guideline is recommended for adoption to the three regulatory
parties to ICH.

TABLE OF CONTENTS
1. INTRODUCTION .................................................................................................. 1
1.1 Objectives of the Guideline ................................................................................ 1
1.2 Background......................................................................................................... 1
1.3 Scope ................................................................................................................... 1
1.4 General Principles .............................................................................................. 2
2. STUDIES TO SUPPORT NONCLINICAL EVALUATION .......................................... 2
2.1 Pharmacology ..................................................................................................... 2
2.2 Safety Pharmacology .......................................................................................... 3
2.3 Pharmacokinetics ............................................................................................... 3
2.4 General Toxicology ............................................................................................. 3
2.5 Reproduction Toxicology .................................................................................... 4
2.6 Genotoxicity ........................................................................................................ 4
2.7 Carcinogenicity ................................................................................................... 5
2.8 Immunotoxicity .................................................................................................. 5
2.9 Photosafety testing ............................................................................................. 5
3. NONCLINICAL DATA TO SUPPORT CLINICAL TRIAL DESIGN AND MARKETING 5
3.1 Start Dose for First Administration in Humans ............................................... 5
3.2 Dose Escalation and the Highest Dose in a Clinical Trial ................................ 5
3.3 Duration and Schedule of Toxicology Studies to Support Initial Clinical Trials
............................................................................................................................ 6
3.4 Duration of Toxicology Studies to Support Continued Clinical Development
and Marketing .................................................................................................... 6
3.5 Combination of Pharmaceuticals ....................................................................... 6
3.6 Nonclinical Studies to Support Trials in Pediatric Populations ....................... 7
4. OTHER CONSIDERATIONS ................................................................................. 7
4.1 Conjugated Products .......................................................................................... 7
4.2 Liposomal Products ............................................................................................ 7
4.3 Evaluation of Drug Metabolites ......................................................................... 7
4.4 Evaluation of Impurities .................................................................................... 7
5. NOTES ................................................................................................................. 9

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1. INTRODUCTION

1.1 Objectives of the Guideline

The purpose of this guidance is to provide information to assist in the design of an

appropriate program of nonclinical studies for the development of anticancer
pharmaceuticals. The guidance provides recommendations for nonclinical evaluations
to support the development of anticancer pharmaceuticals in clinical trials for the
treatment of patients with advanced disease and limited therapeutic options.

This guideline aims to facilitate and accelerate the development of anticancer

pharmaceuticals and to protect patients from unnecessary adverse effects, while
avoiding unnecessary use of animals, in accordance with the 3R principles
(reduce/refine/replace), and other resources.

As appropriate, the principles described in other ICH guidelines should be considered

in the development of anticancer pharmaceuticals. Specific situations where
recommendations for nonclinical testing deviate from other guidance are described in
this document.

1.2 Background

Because malignant tumors are life-threatening, the death rate from these diseases is
high, and existing therapies have limited effectiveness, it is desirable to provide new,
effective anticancer drugs to patients more expeditiously.

There have been no internationally accepted objectives or recommendations on the

design and conduct of nonclinical studies to support the development of anticancer
pharmaceuticals in clinical trials for the treatment of patients with advanced disease
and limited therapeutic options. Nonclinical evaluations are conducted to:

1) identify the pharmacologic properties of a pharmaceutical;

2) establish a safe initial dose level for the first human exposure; and

3) understand the toxicological profile of a pharmaceutical (e.g., identification of

target organs, exposure-response relationships, and reversibility).

In the development of anticancer drugs, clinical studies often involve cancer patients
whose disease condition is progressive and fatal. In addition, the dose levels in these
clinical studies often are close to or at the adverse effect dose levels. For these
reasons, the type, timing and flexibility called for in the design of nonclinical studies
of anticancer pharmaceuticals can differ from those elements in nonclinical studies for
other pharmaceuticals.

1.3 Scope

This guideline provides information for pharmaceuticals that are intended to treat
cancer in patients with serious and life threatening malignancies. For the purpose of
this guideline, this patient population is referred to as patients with advanced cancer.

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Nonclinical Evaluation for Anticancer Pharmaceuticals

The guideline applies to both small molecule and biotechnology-derived

pharmaceuticals (biopharmaceuticals), regardless of the route of administration. This
guideline describes the type and timing of nonclinical studies in relation to the
development of anticancer pharmaceuticals in patients with advanced cancer and
references other guidance as appropriate. It describes the minimal considerations for initial
clinical trials in patients with advanced cancer whose disease is refractory or resistant to
available therapy, or where current therapy is not considered to be providing benefit. The
nonclinical data to support Phase I and the clinical Phase I data would normally be
sufficient for moving to Phase II and into second or first line therapy in patients with
advanced cancer. The guideline also describes further non-clinical data to be collected
during continued clinical development in patients with advanced cancer. When an
anticancer pharmaceutical is further investigated in cancer patient populations with long
expected survival (e.g., those administered pharmaceuticals on a chronic basis to reduce
the risk of recurrence of cancer), the recommendations for and timing of additional
nonclinical studies depend upon the available nonclinical and clinical data and the nature
of the toxicities observed.
This guideline does not apply to pharmaceuticals intended for cancer prevention,
treatment of symptoms or side effects of chemotherapeutics, studies in healthy
volunteers, vaccines, or cellular or gene therapy. If healthy volunteers are included in
clinical trials, the ICH M3 guideline should be followed. Radiopharmaceuticals are not
covered in this guideline, but some of the principles could be adapted.

1.4 General Principles

The development of each new pharmaceutical calls for studies designed to
characterize its pharmacological and toxicological properties according to its intended
use in humans. Modification of "standard" nonclinical testing protocols generally is
warranted to address novel characteristics associated with the pharmaceutical or with
the manner in which it is to be used in humans.

The manufacturing process can change during the course of development. However,
the active pharmaceutical substance used in nonclinical studies should be well
characterized and should adequately represent the active substance to be used in the
clinical trials.

In general, nonclinical safety studies that are used to support the development of a
pharmaceutical should be conducted in accordance with Good Laboratory Practices.

2. STUDIES TO SUPPORT NONCLINICAL EVALUATION

2.1 Pharmacology

Prior to Phase I studies, preliminary characterization of the mechanism(s) of action

and schedule dependencies as well as anti-tumor activity of the pharmaceutical
should have been made. Appropriate models should be selected based on the target
and mechanism of action, but the pharmaceutical need not be studied using the same
tumor types intended for clinical evaluation.

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These studies can:

● provide nonclinical proof of principle;

● guide schedules and dose-escalation schemes;

● provide information for selection of test species;

● aid in start dose selection and selection of investigational biomarkers, where

appropriate; and

● if relevant, justify pharmaceutical combinations.

Understanding the secondary pharmacodynamic properties of a pharmaceutical could

contribute to the assessment of safety for humans, and those properties might be
investigated as appropriate.

2.2 Safety Pharmacology

An assessment of the pharmaceutical’s effect on vital organ functions (including
cardiovascular, respiratory and central nervous systems) should be available before
the initiation of clinical studies; such parameters could be included in general
toxicology studies. Detailed clinical observations following dosing and appropriate
electrocardiographic measurements in non-rodents are generally considered sufficient.
Conducting stand-alone safety pharmacology studies to support studies in patients
with advanced cancer is not called for. In cases where specific concerns have been
identified that could put patients at significant additional risks in clinical trials,
appropriate safety pharmacology studies described in ICH S7A and/or S7B should be
considered. In the absence of a specific risk, such studies will not be called for to
support clinical trials or for marketing.

2.3 Pharmacokinetics
The evaluation of limited pharmacokinetic parameters (e.g., peak plasma/serum
levels, area under the curve (AUC), and half-life) in the animal species used for
nonclinical studies can facilitate dose selection, schedule and escalation during Phase
I studies. Further information on absorption, distribution, metabolism and excretion
of the pharmaceutical in animals should normally be generated in parallel with
clinical development.

2.4 General Toxicology

The primary objective of Phase I clinical trials in patients with advanced cancer is to
assess the safety of the pharmaceutical. Phase I assessments can include dosing to a
maximum tolerated dose (MTD) and dose limiting toxicity (DLT). Toxicology studies
to determine a no observed adverse effect level (NOAEL) or no effect level (NOEL) are
not considered essential to support clinical use of an anticancer pharmaceutical. As
the toxicity of the pharmaceutical can be greatly influenced by its schedule of
administration, an approximation of its clinical schedule should be evaluated in
toxicology studies. This is further discussed in Section 3.3 and 3.4.

Assessment of the potential to recover from toxicity should be provided to

understand whether serious adverse effects are reversible or irreversible. A
study that includes a terminal non-dosing period is called for if there is severe toxicity
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at approximate clinical exposure and recovery cannot be predicted by scientific

assessment. This scientific assessment can include the extent and severity of the
pathologic lesion and the regenerative capacity of the organ system showing the effect.
If a study of recovery is called for, it should be available to support clinical
development. The demonstration of complete recovery is not considered essential.

For small molecules, the general toxicology testing usually includes rodents and non-
rodents. In certain circumstances, determined case-by-case, alternative approaches
can be appropriate (e.g., for genotoxic drugs targeting rapidly dividing cells, a repeat-
dose toxicity study in one rodent species might be considered sufficient, provided the
rodent is a relevant species). For biopharmaceuticals, see ICH S6 for the number of
species to be studied.

Toxicokinetic evaluation should be conducted as appropriate.

2.5 Reproduction Toxicology

An embryofetal toxicology assessment is conducted to communicate potential risk for
the developing embryo or fetus to patients who are or might become pregnant.
Embryofetal toxicity studies of anticancer pharmaceuticals should be available when
the marketing application is submitted, but these studies are not considered essential
to support clinical trials intended for the treatment of patients with advanced cancer.
These studies are also not considered essential for the purpose of marketing
applications for pharmaceuticals that are genotoxic and target rapidly dividing cells
(e.g., crypt cells, bone marrow) in general toxicity studies or belong to a class that has
been well characterized as causing developmental toxicity.

For small molecules, embryofetal toxicology studies are typically conducted in two
species as described by ICH S5(R2). In cases where an embryofetal developmental
toxicity study is positive for embryofetal lethality or teratogenicity, a confirmatory
study in a second species is usually not warranted.

For biopharmaceuticals, an assessment in one pharmacologically relevant species

should usually be sufficient. This assessment might be done by evaluating the toxicity
during the period of organogenesis or study designs as described by ICH S6.
Alternative approaches might be considered appropriate if scientifically justified. The
alternative approaches might include a literature assessment, assessment of placental
transfer, the direct or indirect effects of the biopharmaceutical, or other factors.

A study of fertility and early embryonic development is not warranted to support

clinical trials or for marketing of pharmaceuticals intended for the treatment of
patients with advanced cancer. Information available from general toxicology studies
on the pharmaceutical’s effect on reproductive organs should be used as the basis of
the assessment of impairment of fertility.

A pre- and postnatal toxicology study is generally not warranted to support clinical
trials or for marketing of pharmaceuticals for the treatment of patients with advanced
cancer.

2.6 Genotoxicity
Genotoxicity studies are not considered essential to support clinical trials for
therapeutics intended to treat patients with advanced cancer. Genotoxicity studies

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 Nonclinical Evaluation for Anticancer Pharmaceuticals

should be performed to support marketing (see ICH S2). The principles outlined in
ICH S6 should be followed for biopharmaceuticals. If the in vitro assays are positive,
an in vivo assay might not be warranted.

2.7 Carcinogenicity

The appropriateness of a carcinogenicity assessment for anticancer pharmaceuticals is

described in ICH S1A. Carcinogenicity studies are not warranted to support
marketing for therapeutics intended to treat patients with advanced cancer.

2.8 Immunotoxicity

For most anticancer pharmaceuticals, the design components of the general toxicology
studies are considered sufficient to evaluate immunotoxic potential and support
marketing. For immunomodulatory pharmaceuticals, additional endpoints (such as
immunophenotyping by flow cytometry) might be included in the study design.

2.9 Photosafety testing

An initial assessment of phototoxic potential should be conducted prior to Phase I, based

on photochemical properties of the drug and information on other members in the class. If
assessment of these data indicates a potential risk, appropriate protective measures should
be taken during outpatient trials. If the photosafety risk cannot be adequately evaluated
based on nonclinical data or clinical experience, a photosafety assessment consistent with
the principles described in ICH M3 should be provided prior to marketing.

3. NONCLINICAL DATA TO SUPPORT CLINICAL TRIAL DESIGN AND MARKETING

3.1 Start Dose for First Administration in Humans

The goal of selecting the start dose is to identify a dose that is expected to have
pharmacologic effects and is reasonably safe to use. The start dose should be
scientifically justified using all available nonclinical data (e.g., pharmacokinetics,
pharmacodynamics, toxicity), and its selection based on various approaches (see Note
2). For most systemically administered small molecules, interspecies scaling of the
animal doses to an equivalent human dose is usually based on normalization to body
surface area. For both small molecules and biopharmaceuticals, interspecies scaling
based on body weight, AUC, or other exposure parameters might be appropriate.

For biopharmaceuticals with immune agonistic properties, selection of the start dose
using a minimally anticipated biologic effect level (MABEL) should be considered.

3.2 Dose Escalation and the Highest Dose in a Clinical Trial

In general, the highest dose or exposure tested in the nonclinical studies does not
limit the dose-escalation or highest dose investigated in a clinical trial in patients
with cancer. When a steep dose- or exposure-response curve for severe toxicity is
observed in nonclinical toxicology studies, or when no preceding marker of severe

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toxicity is available, smaller than usual dose increments (fractional increments rather
than dose doubling) should be considered.

3.3 Duration and Schedule of Toxicology Studies to Support Initial

Clinical Trials

In Phase I clinical trials, treatment can continue according to the patient’s response,
and in this case, a new toxicology study is not called for to support continued
treatment beyond the duration of the completed toxicology studies.

The design of nonclinical studies should be appropriately chosen to accommodate

different dosing schedules that might be utilized in initial clinical trials. It is not
expected that the exact clinical schedule always will be followed in the toxicological
study, but the information provided from the toxicity studies should be sufficient to
support the clinical dose and schedule and to identify potential toxicity. For example,
one factor that can be considered is the half-life in the test species and the projected
(or known) half-life in humans. Other factors could include exposure assessment,
toxicity profile, saturation of receptors, etc. Table 1 provides examples of nonclinical
treatment schedules that are commonly used in anticancer pharmaceutical
development and can be used for small molecules or biopharmaceuticals. In cases
where the available toxicology information does not support a change in clinical
schedules, an additional toxicology study in a single species is usually sufficient.

3.4 Duration of Toxicology Studies to Support Continued Clinical

Development and Marketing

The nonclinical data to support Phase I and the clinical Phase I data would normally be
sufficient for moving to Phase II and into second or first line therapy in patients with
advanced cancer. In support of continued development of an anticancer pharmaceutical
for patients with advanced cancer, results from repeat dose studies of 3 months’
duration following the intended clinical schedule should be provided prior to initiating
Phase III studies. For most pharmaceuticals intended for the treatment of patients
with advanced cancer, nonclinical studies of 3 months duration are considered
sufficient to support marketing.

When considering a change in the clinical schedule, an evaluation of the existing

clinical data should be conducted to justify such change. If the clinical data alone are
inadequate to support the change in schedule, the factors discussed in Section 3.3
above should be considered.

3.5 Combination of Pharmaceuticals

Pharmaceuticals planned for use in combination should be well studied individually in

toxicology evaluations. Data to support a rationale for the combination should be
provided prior to starting the clinical study. In general, toxicology studies
investigating the safety of combinations of pharmaceuticals intended to treat patients
with advanced cancer are not warranted. If the human toxicity profile of the
pharmaceuticals has been characterized, a nonclinical study evaluating the
combination is not usually warranted. For studies in which at least one of these
compounds is in early stage development (i.e., the human toxicity profile has not been
characterized), a pharmacology study to support the rationale for the combination
should be provided. This study should provide evidence of increased activity in the
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absence of a substantial increase in toxicity on the basis of limited safety endpoints,

such as mortality, clinical signs, and body weight. Based on available information, a
determination should be made whether or not a dedicated toxicology study of the
combination is warranted.

3.6 Nonclinical Studies to Support Trials in Pediatric Populations

The general paradigm for investigating most anticancer pharmaceuticals in pediatric

patients is first to define a relatively safe dose in adult populations and then to assess
some fraction of that dose in initial pediatric clinical studies. The recommendations
for nonclinical testing outlined elsewhere in this document also apply for this
population. Studies in juvenile animals are not usually conducted in order to support
inclusion of pediatric populations for the treatment of cancer. Conduct of studies in
juvenile animals should be considered only when human safety data and previous
animal studies are considered insufficient for a safety evaluation in the intended
pediatric age group.

4. OTHER CONSIDERATIONS

4.1 Conjugated Products

Conjugated products are pharmaceuticals covalently bound to carrier molecules, such

as proteins, lipids, or sugars. The safety of the conjugated material is the primary
concern. The safety of the unconjugated material, including the linker used, can have
a more limited evaluation. Stability of the conjugate in the test species and human
plasma should be provided. A toxicokinetic evaluation should assess both the
conjugated and the unconjugated compound after administration of the conjugated
material.

4.2 Liposomal Products

A complete evaluation of the liposomal product is not warranted if the unencapsulated

material has been well characterized. As appropriate, the safety assessment should
include a toxicological evaluation of the liposomal product and a limited evaluation of
the unencapsulated pharmaceutical and carrier (e.g., a single arm in a toxicology
study). The principle described here might also apply to other similar carriers. A
toxicokinetic evaluation should be conducted as appropriate. If possible, such an evaluation
should assess both the liposomal product and the free compound after administration of the
liposomal product.

4.3 Evaluation of Drug Metabolites

In some cases, metabolites that have been identified in humans have not been
qualified in nonclinical studies. For these metabolites, a separate evaluation is
generally not warranted for patients with advanced cancer.

4.4 Evaluation of Impurities

It is recognized that impurity standards have been based on a negligible risk, as

discussed in ICH Q3A and Q3B. Exceeding the established limits for impurities
identified in these ICH guidelines could be appropriate for anticancer
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pharmaceuticals, and a justification should be provided in the marketing application.

The justification could include the disease being treated and the patient population,
the nature of the parent pharmaceutical (pharmacologic properties, genotoxicity and
carcinogenic potential, etc.), duration of treatment, and the impact of impurity
reduction on manufacturing. Further, the qualification assessment could include
consideration of either the dose or concentration tested in nonclinical study relative to
clinical levels. For genotoxic impurities, several approaches have been used to set
limits based on increase in lifetime risk of cancer. Such limits are not appropriate for
pharmaceuticals intended to treat patients with advanced cancer, and justifications
described above should be considered to set higher limits. Impurities that are also
metabolites present in animal and/or human studies are generally considered
qualified.

Table 1: Examples of Treatment Schedules for Anticancer Pharmaceuticals

to Support Initial Clinical Trials
Clinical Schedule Examples of Nonclinical Treatment
Schedule1,2,3,4
Once every 3-4 weeks Single dose
Daily for 5 days every 3 weeks Daily for 5 days
Daily for 5-7 days, alternating Daily for 5-7 days, alternating weeks (2-dose cycles)
weeks
Once a week for 3 weeks, Once a week for 3 weeks
1 week off
Two or three times a week Two or three times a week for 4 weeks
Daily Daily for 4 weeks
Weekly Once a week for 4-5 doses

1Table 1 describes the dosing Phase. The timing of the toxicity assessment(s) in the
non-clinical studies should be scientifically justified based on the anticipated toxicity
profile and the clinical schedule. For example, both a sacrifice shortly after the dosing
Phase to examine early toxicity and a later sacrifice to examine late onset of toxicity
should be considered.
2 For further discussion regarding flexibility in the relationship of the clinical
schedule and the non-clinical toxicity studies, see Section 3.3.
3The treatment schedules described in the table do not specify recovery periods (see
Section 2.4 and Note 1 regarding recovery).
4 The treatment schedules described in this table should be modified as appropriate
for molecules with extended pharmacodynamic effects, long half-lives or potential for
anaphylactic reactions. In addition, the potential effects of immunogenicity should be
considered (see ICH S6).

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5. NOTES

1. For nonrodent studies, dose groups usually consist of at least 3 animals/sex/group,

with an additional 2/sex/group for recovery, if appropriate (see Section 2.4). Both sexes
should generally be used, or justification should be given for specific omissions.
2. A common approach for many small molecules is to set a start dose at 1/10 the
Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is
the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD)
is considered an appropriate starting dose. The HNSTD is defined as the highest dose
level that does not produce evidence of lethality, life-threatening toxicities or
irreversible findings.