Guidance for Industry
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`S9 Nonclinical Evaluation
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`for
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`Anticancer Pharmaceuticals
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`U.S. Department of Health and Human Services
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`Food and Drug Administration
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`Center for Drug Evaluation and Research (CDER)
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`Center for Biologics Evaluation and Research (CBER)
`
`March 2010
`ICH
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`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1027, p. 1 of 12
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`
`
`Guidance for Industry
`
`
`S9 Nonclinical Evaluation
`
`for
`
`Anticancer Pharmaceuticals
`
`
`
`
`
`
`Additional copies are available from:
`
`
`Office of Communications
`
`
`Division of Drug Information, WO51, Room 2201
`
`
`
`
`10903 New Hampshire Ave.
`
`Silver Spring, MD 20993
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`
`Phone: 301-796-3400; Fax: 301-847-8714
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`
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`druginfo@fda.hhs.gov
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`
`http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
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`
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`
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`Office of Communication, Outreach and Development, HFM-40
`
`Center for Biologics Evaluation and Research
`
`
`
`Food and Drug Administration
`
`
`1401 Rockville Pike, Rockville, MD 20852-1448
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`
`
`(Tel) 800-835-4709 or 301-827-1800
`
`
`http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
`
`
`
`
`U.S. Department of Health and Human Services
`
`Food and Drug Administration
`
`Center for Drug Evaluation and Research (CDER)
`
`Center for Biologics Evaluation and Research (CBER)
`
`
`March 2010
`
`ICH
`
`
`
`
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`
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`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1027, p. 2 of 12
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` I.
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`TABLE OF CONTENTS
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`
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`INTRODUCTION (1, 1.1)................................................................................................ 1
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`A. Background (1.2)............................................................................................................................1
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`B. Scope (1.3).......................................................................................................................................2
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`C. General Principles (1.4).................................................................................................................3
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`STUDIES TO SUPPORT NONCLINICAL EVALUATION (2) ................................. 3
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` II.
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`A. Pharmacology (2.1) ........................................................................................................................3
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`B. Safety Pharmacology (2.2).............................................................................................................3
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`C Pharmacokinetics (2.3) ..................................................................................................................4
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`D. General Toxicology (2.4) ...............................................................................................................4
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`E. Reproduction Toxicology (2.5)......................................................................................................4
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`F. Genotoxicity (2.6) ...........................................................................................................................5
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`G. Carcinogenicity (2.7)......................................................................................................................5
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`
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`H.
`Immunotoxicity (2.8)......................................................................................................................5
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`
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`Photosafety testing (2.9).................................................................................................................5
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`I.
`III. NONCLINICAL DATA TO SUPPORT CLINICAL TRIAL DESIGN AND
`
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`MARKETING (3) ............................................................................................................. 6
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`
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`A. Start Dose for First Administration in Humans (3.1).................................................................6
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`
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`B. Dose Escalation and the Highest Dose in a Clinical Trial (3.2)..................................................6
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`C. Duration and Schedule of Toxicology Studies to Support Initial Clinical Trials (3.3) ............6
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`D. Duration of Toxicology Studies to Support Continued Clinical Development
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`and Marketing (3.4) .......................................................................................................................7
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`E. Combination of Pharmaceuticals (3.5).........................................................................................7
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`F. Nonclinical Studies to Support Trials in Pediatric Populations (3.6)........................................7
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`IV. OTHER CONSIDERATIONS (4)................................................................................... 8
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`A. Conjugated Products (4.1).............................................................................................................8
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`B. Liposomal Products (4.2)...............................................................................................................8
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`C. Evaluation of Drug Metabolites (4.3) ...........................................................................................8
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`D. Evaluation of Impurities (4.4).......................................................................................................8
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`NOTES (5) ......................................................................................................................... 9
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` V.
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`Guidance for Industry1
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`
`
`S9 Nonclinical Evaluation for Anticancer Pharmaceuticals
`
`
`
`
`
`This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It
`
`does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
`You can use an alternative approach if the approach satisfies the requirements of the applicable statutes
`and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for
`implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate
`number listed on the title page of this guidance.
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`I.
`
`INTRODUCTION (1, 1.1)
`
`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 guidance 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 guidances 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.
`A.
`Background (1.2)
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`
`
` 1 This guidance was developed within the Expert Working Group (Safety) of the International Conference on
`
`
`
`
` Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been
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` subject to consultation by the regulatory parties, in accordance with the ICH process. This guidance has been
` endorsed by the ICH Steering Committee at Step 4 of the ICH process, October 2009. At Step 4 of the process, the
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` final draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United
`States.
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`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.
`B.
`Scope (1.3)
`
`
`This guidance provides information for pharmaceuticals that are intended to treat cancer in
`patients with serious and life threatening malignancies. For the purpose of this guidance, this
`patient population is referred to as patients with advanced cancer. The guidance applies to both
`small molecule and biotechnology-derived pharmaceuticals (biopharmaceuticals), regardless of
`the route of administration. This guidance 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 1 and the clinical Phase 1 data would normally be sufficient for
`moving to Phase 2 and into second or first line therapy in patients with advanced cancer. The
`guidance also describes further nonclinical 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 guidance 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
`guidance should be followed. Radiopharmaceuticals are not covered in this guidance, but some
`
`of the principles could be adapted.
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`C.
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`General Principles (1.4)
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`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.
`
`II.
`
`STUDIES TO SUPPORT NONCLINICAL EVALUATION (2)
`
`A.
`
`Pharmacology (2.1)
`
`
`Prior to Phase 1 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.
`These studies can:
`● provide nonclinical proof of principle;
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`● guide schedules and dose-escalation schemes;
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`● provide information for selection of test species;
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`● aid in start dose selection and selection of investigational biomarkers, where appropriate;
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`and,
`●
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`if relevant, justify pharmaceutical combinations.
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`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.
`B.
`Safety Pharmacology (2.2)
`
`
`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 nonrodents
`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
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`considered. In the absence of a specific risk, such studies will not be called for to support
`clinical trials or for marketing.
`
`
`C
`
`Pharmacokinetics (2.3)
`
`
`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 1 studies. Further information on
`absorption, distribution, metabolism, and excretion of the pharmaceutical in animals should
`normally be generated in parallel with clinical development.
`D.
`General Toxicology (2.4)
`
`
`The primary objective of Phase 1 clinical trials in patients with advanced cancer is to assess the
`safety of the pharmaceutical. Phase 1 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 sections III.C and III.D (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 nondosing
`period is called for if there is severe toxicity 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 nonrodents. 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.
`E.
`Reproduction Toxicology (2.5)
`
`
`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.
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`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.
`F.
`Genotoxicity (2.6)
`
`
`Genotoxicity studies are not considered essential to support clinical trials for therapeutics
`intended to treat patients with advanced cancer. Genotoxicity studies 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.
`
`
`G.
`
`Carcinogenicity (2.7)
`
`
`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.
`
`
`H.
`
`Immunotoxicity (2.8)
`
`
`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.
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`
`
`I.
`
`Photosafety testing (2.9)
`
`
`An initial assessment of phototoxic potential should be conducted prior to Phase 1, 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
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`nonclinical data or clinical experience, a photosafety assessment consistent with the principles
`described in ICH M3 should be provided prior to marketing.
`
`
`III. NONCLINICAL DATA TO SUPPORT CLINICAL TRIAL DESIGN AND
`MARKETING (3)
`
`
`
`A.
`
`Start Dose for First Administration in Humans (3.1)
`
`
`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.
`Dose Escalation and the Highest Dose in a Clinical Trial (3.2)
`B.
`
`
`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 toxicity is available, smaller than usual dose
`increments (fractional increments rather than dose doubling) should be considered.
`Duration and Schedule of Toxicology Studies to Support Initial Clinical
`C.
`Trials (3.3)
`
`
`
`In Phase 1 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.
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`D.
`
`Duration of Toxicology Studies to Support Continued Clinical Development
`and Marketing (3.4)
`
`
`The nonclinical data to support Phase 1 and the clinical Phase 1 data would normally be
`sufficient for moving to Phase 2 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 3 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 III.C (3.3) above should be considered.
`
`
`E.
`
`Combination of Pharmaceuticals (3.5)
`
`
`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 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.
`F.
`Nonclinical Studies to Support Trials in Pediatric Populations (3.6)
`
`
`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.
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`IV. OTHER CONSIDERATIONS (4)
`
`A.
`
`Conjugated Products (4.1)
`
`
`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.
`B.
`Liposomal Products (4.2)
`
`
`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.
`C.
`Evaluation of Drug Metabolites (4.3)
`
`
`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.
`D.
`Evaluation of Impurities (4.4)
`
`
`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 guidances
`could be appropriate for anticancer 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.
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`Table 1: Examples of Treatment Schedules for Anticancer Pharmaceuticals to Support
`Initial Clinical Trials
`
`
`
`Examples of Nonclinical Treatment Schedule1,2,3,4
`Single dose
`Daily for 5 days
`Daily for 5-7 days, alternating weeks (2-dose cycles)
`
`Once a week for 3 weeks
`
`Clinical Schedule
`Once every 3-4 weeks
`Daily for 5 days every 3 weeks
`Daily for 5-7 days, alternating
`weeks
`Once a week for 3 weeks,
`1 week off
`Two or three times a week for 4 weeks
`Two or three times a week
`Daily for 4 weeks
`Daily
`
`Once a week for 4-5 doses
`Weekly
`1 Table 1 describes the dosing phase. The timing of the toxicity assessment(s) in the nonclinical 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 nonclinical
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`toxicity studies, see section III.C (3.3).
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`3 The treatment schedules described in the table do not specify recovery periods (see section II.D (2.4) and
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`Note 1 regarding recovery).
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`4 The treatment schedules described in this table should be modified as appropriate for molecules with
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`extended pharmacodynamic effects, long half-lives or potential for anaphylactic reactions. In addition, the
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`potential effects of immunogenicity should be considered (see ICH S6).
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`NOTES (5)
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`V.
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`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 II.D (2.4)). Both sexes should
`generally be used, or justification should be given for specific omissions.
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` 2. A common approach for many small molecules is to set a start dose at 1/10 the severely toxic
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`dose in 10% of the animals (STD 10) in rodents. If the nonrodent 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.
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`9
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`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1027, p. 12 of 12
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