European Medicines Agency
`
`June 2001
`CPMP/ICH/539/00
`
`ICH Topic S 7 A
`Safety Pharmacology Studies for Human Pharmaceuticals
`
`Step 5
`
`NOTE FOR GUIDANCE ON SAFETY PHARMACOLOGY STUDIES
`FOR HUMAN PHARMACEUTICALS
`(CPMP/ICH/539/00)
`
`TRANSMISSION TO CPMP
`
`TRANSMISSION TO INTERESTED PARTIES
`
`DEADLINE FOR COMMENTS
`
`APPROVAL BY CPMP
`
`DATE FOR COMING INTO OPERATION
`
`March 2000
`
`March 2000
`
`November 2000
`
`November 2000
`
`June 2001
`
`7 Westferry Circus, Canary Wharf, London, E14 4HB, UK
`Tel. (44-20) 74 18 85 75 Fax (44-20) 75 23 70 40
`E-mail: mail@emea.eu.int http://www.emea.eu.int
`EMEA 2006 Reproduction and/or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged
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`NOTE FOR GUIDANCE ON SAFETY PHARMACOLOGY STUDIES FOR HUMAN
`PHARMACEUTICALS
`
`
`INTRODUCTION
`1.
`Objectives Of The Guideline
`1.1
`This guideline was developed to help protect clinical trial participants and patients receiving
`marketed products from potential adverse effects of pharmaceuticals, while avoiding
`unnecessary use of animals and other resources.
`This guideline provides a definition, general principles and recommendations for safety
`pharmacology studies.
`
`Background
`1.2
`Pharmacology studies have been performed worldwide for many years as part of the non-
`clinical evaluation of pharmaceuticals for human use. There have been, however, no
`internationally accepted definitions, objectives or recommendations on the design and conduct
`of safety pharmacology studies. (Note 1)
`The term “safety pharmacology studies” first appeared in the ICH topics, “Timing of Non-
`Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals (M3)”
`and “Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (S6)” as
`studies that should be conducted to support use of therapeutics in humans (1, 2). Details of
`the safety pharmacology studies, including their definition and objectives, were left for future
`discussion.
`
`Scope Of The Guideline
`1.3
`This guideline generally applies to new chemical entities and biotechnology-derived products
`for human use. This guideline can be applied to marketed pharmaceuticals when appropriate
`(e.g. when adverse clinical events, a new patient population, or a new route of administration
`raises concerns not previously addressed).
`
`1.4 General Principle
`It is important to adopt a rational approach when selecting and conducting safety
`pharmacology studies. The specific studies that should be conducted and their design will vary
`based on the individual properties and intended uses of the pharmaceuticals. Scientifically
`valid methods should be used, and when there are internationally recognized methods that are
`applicable to pharmaceuticals, these are preferable. Moreover, the use of new technologies
`and methodologies in accordance with sound scientific principles is encouraged.
`Some safety pharmacology endpoints can be incorporated in the design of toxicology, kinetic,
`clinical studies, etc., while in other cases these endpoints should be evaluated in specific
`safety pharmacology studies. Although adverse effects of a substance may be detectable at
`exposures that fall within the therapeutic range in appropriately designed safety pharmacology
`studies, they may not be evident from observations and measurements used to detect toxicity
`in conventional animal toxicity studies.
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`Definition Of Safety Pharmacology
`1.5
`Pharmacology studies can be divided into three categories: primary pharmacodynamic,
`secondary pharmacodynamic and safety pharmacology studies.
`For the purpose of this document, safety pharmacology studies are defined as those studies
`that investigate the potential undesirable pharmacodynamic effects of a substance on
`physiological functions in relation to exposure in the therapeutic range and above. (See Note 2
`for definitions of primary pharmacodynamic and secondary pharmacodynamic studies.)
`In some cases, information on the primary and secondary pharmacodynamic properties of the
`substance may contribute to the safety evaluation for potential adverse effect(s) in humans and
`should be considered along with the findings of safety pharmacology studies.
`
`GUIDELINE
`2.
`2.1 Objectives Of Studies
`identify undesirable
`to
`The objectives of safety pharmacology studies are: 1)
`pharmacodynamic properties of a substance that may have relevance to its human safety; 2) to
`evaluate adverse pharmacodynamic and/or pathophysiological effects of a substance observed
`in toxicology and/or clinical studies; and 3) to investigate the mechanism of the adverse
`pharmacodynamic effects observed and/or suspected. The investigational plan to meet these
`objectives should be clearly identified and delineated.
`
`General Considerations In Selection And Design Of Safety Pharmacology
`
`2.2
`Studies
`Since pharmacological effects vary depending on the specific properties of each test
`substance, the studies should be selected and designed accordingly. The following factors
`should be considered (the list is not comprehensive):
`(1) Effects related to the therapeutic class of the test substance, since the mechanism of
`action may suggest specific adverse effects (e.g., proarrhythmia is a common feature of
`antiarrhythmic agents);
`(2) Adverse effects associated with members of the chemical or therapeutic class, but
`independent of the primary pharmacodynamic effects (e.g., anti-psychotics and QT
`prolongation);
`(3) Ligand binding or enzyme assay data suggesting a potential for adverse effects;
`(4) Results from previous safety pharmacology studies, from secondary pharmacodynamic
`studies, from toxicology studies, or from human use that warrant further investigation to
`establish and characterize the relevance of these findings to potential adverse effects in
`humans.
`During early development, sufficient information (e.g., comparative metabolism) may not
`always be available to rationally select or design the studies in accordance with the points
`stated above; in such circumstances, a more general approach in safety pharmacology
`investigations can be applied.
`A hierarchy of organ systems can be developed according to their importance with respect to
`life-supporting functions. Vital organs or systems, the functions of which are acutely critical
`for life, such as the cardiovascular, respiratory and central nervous systems, are considered to
`be the most important ones to assess in safety pharmacology studies. Other organ systems,
`such as the renal or gastrointestinal system, the functions of which can be transiently disrupted
`by adverse pharmacodynamic effects without causing irreversible harm, are of less immediate
`investigative concern. Safety pharmacology evaluation of effects on these other systems may
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`be of particular importance when considering factors such as the likely clinical trial or patient
`population (e.g. gastrointestinal tract in Crohn’s disease, renal function in primary renal
`hypertension, immune system in immunocompromised patients.).
`
`Test Systems
`2.3
`2.3.1 General Considerations On Test Systems
`Consideration should be given to the selection of relevant animal models or other test systems
`so that scientifically valid information can be derived. Selection factors can include the
`pharmacodynamic responsiveness of the model, pharmacokinetic profile, species, strain,
`gender and age of the experimental animals, the susceptibility, sensitivity, and reproducibility
`of the test system and available background data on the substance. Data from humans (e.g., in
`vitro metabolism), when available, should also be considered in the test system selection. The
`time points for the measurements should be based on pharmacodynamic and pharmacokinetic
`considerations. Justification should be provided for the selection of the particular animal
`model or test system.
`2.3.2 Use Of In Vivo And In Vitro Studies
`Animal models as well as ex vivo and in vitro preparations can be used as test systems. Ex
`vivo and in vitro systems can include, but are not limited to: isolated organs and tissues, cell
`cultures, cellular fragments, subcellular organelles, receptors, ion channels, transporters and
`enzymes. In vitro systems can be used in supportive studies (e.g., to obtain a profile of the
`activity of the substance or to investigate the mechanism of effects observed in vivo).
`In conducting in vivo studies, it is preferable to use unanesthetized animals. Data from
`unrestrained animals that may be chronically instrumented for telemetry, other suitable
`instrumentation methods for conscious animals, or animals conditioned to the laboratory
`environment are preferable to data from restrained or unconditioned animals. In the use of
`unanesthetized animals, the avoidance of discomfort or pain is a foremost consideration.
`2.3.3 Experimental Design
`2.3.3.1 Sample Size And Use Of Controls
`The size of the groups should be sufficient to allow meaningful scientific interpretation of the
`data generated. Thus, the number of animals or isolated preparations should be adequate to
`demonstrate or rule out the presence of a biologically significant effect of the test substance.
`This should take into consideration the size of the biological effect that is of concern for
`humans. Appropriate negative and positive control groups should be included in the
`experimental design. In well-characterized in vivo test systems, positive controls may not be
`necessary. The exclusion of controls from studies should be justified.
`2.3.3.2 Route Of Administration
`In general, the expected clinical route of administration should be used when feasible.
`Regardless of the route of administration, exposure to the parent substance and its major
`metabolites should be similar to or greater than that achieved in humans when such
`information is available. Assessment of effects by more than one route may be appropriate if
`the test substance is intended for clinical use by more than one route of administration (e.g.
`oral and parenteral), or where there are observed or anticipated significant qualitative and
`quantitative differences in systemic or local exposure.
`
`2.4
`2.4.1
`
`Dose Levels Or Concentrations Of Test Substance
`In Vivo Studies
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`Safety pharmacology studies should be designed to define the dose-response relationship of
`the adverse effect observed. The time course (e.g., onset and duration of response) of the
`adverse effect should be investigated, when feasible. Generally, the doses eliciting the adverse
`effect should be compared to the doses eliciting the primary pharmacodynamic effect in the
`test species or the proposed therapeutic effect in humans, if feasible. It is recognized that there
`are species differences in pharmacodynamic sensitivity. Therefore, doses should include and
`exceed the primary pharmacodynamic or therapeutic range. In the absence of an adverse
`effect on the safety pharmacology parameter(s) evaluated in the study, the highest tested dose
`should be a dose that produces moderate adverse effects in this or in other studies of similar
`route and duration. These adverse effects can include dose-limiting pharmacodynamic effects
`or other toxicity. In practice, some effects in the toxic range (e.g., tremors or fasciculation
`during ECG recording) may confound the interpretation of the results and may also limit dose
`levels. Testing of a single group at the limiting dose as described above may be sufficient in
`the absence of an adverse effect on safety pharmacology endpoints in the test species.
`2.4.2
`In Vitro Studies
`In vitro studies should be designed to establish a concentration-effect relationship. The range
`of concentrations used should be selected to increase the likelihood of detecting an effect on
`the test system. The upper limit of this range may be influenced by physico-chemical
`properties of the test substance and other assay specific factors. In the absence of an effect, the
`range of concentrations selected should be justified.
`
`Duration Of Studies
`2.5
`Safety pharmacology studies are generally performed by single dose administration. When
`pharmacodynamic effects occur only after a certain duration of treatment, or when results
`from repeat dose non-clinical studies or results from use in humans give rise to concerns about
`safety pharmacological effects, the duration of the safety pharmacology studies to address
`these effects should be rationally based.
`
`Studies On Metabolites, Isomers And Finished Products
`2.6
`Generally, any parent compound and its major metabolite(s) that achieve, or are expected to
`achieve, systemic exposure in humans should be evaluated in safety pharmacology studies.
`Evaluation of major metabolites is often accomplished through studies of the parent
`compound in animals. If the major human metabolite(s) is (are) found to be absent or present
`only at relatively low concentrations in animals, assessment of the effects of such
`metabolite(s) on safety pharmacology endpoints should be considered. Additionally, if
`metabolites from humans are known to substantially contribute to the pharmacological actions
`of the therapeutic agent, it may be important to test such active metabolites. When the in vivo
`studies on the parent compound have not adequately assessed metabolites, as discussed above,
`the tests of metabolites can use in vitro systems based on practical considerations.
`In vitro or in vivo testing of the individual isomers should also be considered when the
`product contains an isomeric mixture.
`Safety pharmacology studies with the finished product formulation(s) should be conducted
`only for formulations that substantially alter the pharmacokinetics and/or pharmacodynamics
`of the active substance in comparison to formulations previously tested (i.e. through active
`excipients such as penetration enhancers,
`liposomes, and other changes such as
`polymorphism).
`
`2.7
`
`Safety Pharmacology Core Battery
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`The purpose of the safety pharmacology core battery is to investigate the effects of the test
`substance on vital functions. In this regard, the cardiovascular, respiratory and central nervous
`systems are usually considered the vital organ systems that should be studied in the core
`battery. In some instances, based on scientific rationale, the core battery should be
`supplemented (see section 2.8) or need not be implemented (see also section 2.9).
`The exclusion of certain test(s) or exploration(s) of certain organs, systems or functions
`should be scientifically justified.
`2.7.1 Central Nervous System
`Effects of the test substance on the central nervous system should be assessed appropriately.
`Motor activity, behavioral changes, coordination, sensory/motor reflex responses and body
`temperature should be evaluated. For example, a functional observation battery (FOB) (3),
`modified Irwin’s (4), or other appropriate test (5) can be used.
`2.7.2 Cardiovascular System
`Effects of the test substance on the cardiovascular system should be assessed appropriately.
`Blood pressure, heart rate, and the electrocardiogram should be evaluated. In vivo, in vitro
`and/or ex vivo evaluations,
`including methods for repolarization and conductance
`abnormalities, should also be considered. (Note 3)
`2.7.3 Respiratory System
`Effects of the test substance on the respiratory system should be assessed appropriately.
`Respiratory rate and other measures of respiratory function (e.g., tidal volume (6) or
`hemoglobin oxygen saturation) should be evaluated. Clinical observation of animals is
`generally not adequate to assess respiratory function, and thus these parameters should be
`quantified by using appropriate methodologies.
`
`Follow-up and Supplemental Safety Pharmacology Studies
`2.8
`Adverse effects may be suspected based on the pharmacological properties or chemical class
`of the test substance. Additionally, concerns may arise from the safety pharmacology core
`battery, clinical trials, pharmacovigilance, experimental in vitro or in vivo studies, or from
`literature reports. When such potential adverse effects raise concern for human safety, these
`should be explored in follow-up or supplemental safety pharmacology studies, as appropriate.
`
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`2.8.1 Follow-up Studies For Safety Pharmacology Core Battery
`Follow-up studies are meant to provide a greater depth of understanding than, or additional
`knowledge to, that provided by the core battery on vital functions. The following subsections
`provide lists of studies to further evaluate these organ systems for potential adverse
`pharmacodynamic effects. These lists are not meant to be comprehensive or prescriptive, and
`the studies should be selected on a case-by-case basis after considering factors such as
`existing non-clinical or human data. In some cases, it may be more appropriate to address
`these effects during the conduct of other non-clinical and/or clinical studies.
`2.8.1.1 Central Nervous System
`Behavioral pharmacology, learning and memory, ligand-specific binding, neurochemistry,
`visual, auditory and/or electrophysiology examinations, etc.
`2.8.1.2 Cardiovascular System
`Cardiac output, ventricular contractility, vascular resistance, the effects of endogenous and/or
`exogenous substances on the cardiovascular responses, etc.
`2.8.1.3 Respiratory System
`Airway resistance, compliance, pulmonary arterial pressure, blood gases, blood pH, etc.
`2.8.2 Supplemental Safety Pharmacology Studies
`Supplemental studies are meant to evaluate potential adverse pharmacodynamic effects on
`organ system functions not addressed by the core battery or repeated dose toxicity studies
`when there is a cause for concern.
`2.8.2.1 Renal/Urinary System
`Effects of the test substance on renal parameters should be assessed. For example, urinary
`volume, specific gravity, osmolality, pH, fluid/electrolyte balance, proteins, cytology, and
`blood chemistry determinations such as blood urea nitrogen, creatinine and plasma proteins
`can be used.
`2.8.2.2 Autonomic Nervous System
`Effects of the test substance on the autonomic nervous system should be assessed. For
`example, binding to receptors relevant for the autonomic nervous system, functional responses
`to agonists or antagonists in vivo or in vitro, direct stimulation of autonomic nerves and
`measurement of cardiovascular responses, baroreflex testing, and heart rate variability can be
`used.
`2.8.2.3 Gastrointestinal System
`Effects of the test substance on the gastrointestinal system should be assessed. For example,
`gastric secretion, gastrointestinal injury potential, bile secretion, transit time in vivo, ileal
`contraction in vitro, gastric pH measurement and pooling can be used.
`2.8.2.4 Other Organ Systems
`Effects of the test substance on organ systems not investigated elsewhere should be assessed
`when there is a reason for concern. For example, dependency potential or skeletal muscle,
`immune and endocrine functions can be investigated.
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`Conditions Under Which Studies Are Not Necessary
`2.9
`Safety pharmacology studies may not be needed for locally applied agents (e.g., dermal or
`ocular) where the pharmacology of the test substance is well characterized, and where
`systemic exposure or distribution to other organs or tissues is demonstrated to be low.
`Safety pharmacology studies prior to the first administration in humans may not be needed for
`cytotoxic agents for treatment of end-stage cancer patients. However, for cytotoxic agents
`with novel mechanisms of action, there may be value in conducting safety pharmacology
`studies.
`For biotechnology-derived products that achieve highly specific receptor targeting, it is often
`sufficient to evaluate safety pharmacology endpoints as a part of toxicology and/or
`pharmacodynamic studies, and therefore safety pharmacology studies can be reduced or
`eliminated for these products.
`For biotechnology-derived products that represent a novel therapeutic class and/or those
`products that do not achieve highly specific receptor targeting, a more extensive evaluation by
`safety pharmacology studies should be considered.
`There may be additional exceptions where safety pharmacology testing is not needed, for
`example, in the case of a new salt having similar pharmacokinetics and pharmacodynamics.
`
`2.10 Timing Of Safety Pharmacology Studies In Relation To Clinical Development
`When planning a safety pharmacology program, section 2.9 should be reviewed to determine
`whether or not specific studies are recommended.
`2.10.1 Studies Prior To First Administration In Humans
`The effects of a test substance on the functions listed in the safety pharmacology core battery
`should be investigated prior to first administration in humans. Any follow-up or supplemental
`studies identified as appropriate, based on a cause for concern, should also be conducted.
`Information from toxicology studies adequately designed and conducted to address safety
`pharmacology endpoints can result
`in reduction or elimination of separate safety
`pharmacology studies.
`2.10.2 Studies During Clinical Development
`Additional studies may be warranted to clarify observed or suspected adverse effects in
`animals and humans during clinical development.
`2.10.3 Studies Before Approval
`Safety pharmacology effects on systems listed in section 2.8 should be assessed prior to
`product approval, unless not warranted, in which case this should be justified. Available
`information from toxicology studies adequately designed and conducted to address safety
`pharmacology endpoints, or information from clinical studies, can support this assessment and
`replace safety pharmacology studies.
`
`2.11 Application Of Good Laboratory Practice (GLP)
`It is important to ensure the quality and reliability of non-clinical safety studies. This is
`normally accomplished through the conduct of the studies in compliance with GLP. Due to
`the unique design of, and practical considerations for, some safety pharmacology studies, it
`may not be feasible to conduct these in compliance with GLP. It has to be emphasized that
`data quality and integrity in safety pharmacology studies should be ensured even in the
`absence of formal adherence to the principles of GLP. When studies are not conducted in
`compliance with GLP, study reconstruction should be
` ensured
`through adequate
`documentation of study conduct and archiving of data. Any study or study component not
`
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`conducted in compliance with GLP should be adequately justified, and the potential impact
`on evaluation of the safety pharmacology endpoints should be explained.
`The safety pharmacology core battery should ordinarily be conducted in compliance with
`GLP. Follow-up and supplemental studies should be conducted in compliance with GLP to
`the greatest extent feasible. Safety pharmacology investigations can be part of toxicology
`studies; in such cases, these studies would be conducted in compliance with GLP.
`Primary pharmacodynamic studies do not need to be conducted in compliance with GLP.
`Generally, secondary pharmacodynamic studies do not need to be conducted in compliance
`with GLP. Results from secondary pharmacodynamic studies conducted during the compound
`selection process may contribute to the safety pharmacology evaluation; when there is no
`cause for concern (e.g., there are no findings for the safety pharmacological endpoint or the
`chemical or therapeutic class), these studies need not be repeated in compliance with GLP. In
`some circumstances, results of secondary pharmacodynamic studies may make a pivotal
`contribution to the safety evaluation for potential adverse effects in humans, and these are
`normally conducted in compliance with GLP.
`
`2.
`
`NOTES
`3.
`1. General pharmacology studies have been considered an important component in drug
`safety assessment. General pharmacology studies were originally referred to as those
`designed to examine effects other than the primary therapeutic effect of a drug
`candidate. Safety pharmacology studies were focused on identifying adverse effects on
`physiological functions. All
`three regions have accepted data from general
`pharmacology studies (Japan and EC) or safety pharmacology studies (USA) in the
`assessment of a marketing application. The Japanese Ministry of Health and Welfare
`(MHW) issued the “Guideline for General Pharmacology “ in 1991. In this MHW
`guideline, general pharmacology studies include those designed to identify unexpected
`effects on organ system function, and to broaden pharmacological characterization
`(pharmacological profiling). However, there has been no internationally accepted
`definition of the terms “primary pharmacodynamics”, “secondary pharmacodynamics”
`and “safety pharmacology.” The need for
`international harmonization of
`the
`nomenclature and
`the development of an
`international guideline for safety
`pharmacology has been recognized.
`Studies on the mode of action and/or effects of a substance in relation to its desired
`therapeutic target are primary pharmacodynamic studies. Studies on the mode of action
`and/or effects of a substance not related to its desired therapeutic target are secondary
`pharmacodynamic studies (these have sometimes been referred to as part of general
`pharmacology studies).
`3. There is no scientific consensus on the preferred approach to, or internationally
`recognized guidance on, addressing risks for repolarization-associated ventricular
`tachyarrhythmia (e.g., Torsade de Pointes). A guideline (S7B) will be prepared to
`present some currently available methods and discuss
`their advantages and
`disadvantages. Submission of data to regulatory authorities to support the use of these
`methods is encouraged.
`REFERENCES
`ICH Harmonized Tripartite Guideline (M3) “Timing of Non-clinical Safety Studies for
`the Conduct of Human Clinical Trials for Pharmaceuticals” (1997)
`ICH Harmonized Tripartite Guideline (S6) “Preclinical Safety Evaluation of
`Biotechnology-derived Pharmaceuticals” (1997)
`
`4.
`1)
`
`2)
`
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`4)
`
`3) Mattsson, J. L., Spencer, P. J. and Albee, R. R.: A performance standard for clinical
`and Functional Observational Battery examinations of rats. J. Am. Coll. Toxicol. 15,
`239 (1996).
`Irwin, S.: Comprehensive observational assessment: 1a. A systematic, quantitative
`procedure for assessing the behavioural and physiologic state of the mouse.
`Psychopharmacologia (Berl.) 13, 222-257(1968).
`5) Haggerty, G.C.: Strategies for and experience with neurotoxicity testing of new
`pharmaceuticals. J. Am. Coll. Toxicol. 10:677-687 (1991).
`6) Murphy, D.J.: Safety Pharmacology of the Respiratory System: Techniques and Study
`Design. Drug Dev. Res. 32: 237-246 (1994).
`
`
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