GUIDELINE ON THE NEED FOR STUDIES OF PHARMACEUTICALS

CARCINOGENICITY

The objectives of carcinogenicity studies are to identify a tumorogenic potential in animals and to assess the relevant risk in humans. Any cause for concern derived from laboratory investigations, animal toxicology studies, and data in humans may lead to a need for carcinogenicity studies. The practice of requiring carcinogenicity studies in rodents was instituted for pharmaceuticals that were expected to be administered regularly over a substantial part of a patient's lifetime. The design and interpretation of the results from these studies preceded much of the available current technology to test for genotoxic potential and the more recent advances in technologies to assess systemic exposure. These studies also preceded our current understanding of tumorigenesis with non-genotoxic agents. Results from genotoxicity studies, toxicokinetics, and mechanistic studies can now be routinely applied in preclinical safety assessment. These additional data are important not only in considering whether to perform carcinogenicity studies but for interpreting study outcomes with respect to relevance for human safety. Since carcinogenicity studies are time consuming and resource intensive they should only be performed when human exposure warrants the need for information from life-time studies in animals in order to assess carcinogenic potential. FACTORS 4.1 Duration and Exposure Carcinogenicity studies should be performed for any pharmaceutical whose expected clinical use is continuous for at least 6 months

Certain classes of compounds may not be used continuously over a minimum of 6 months but may be expected to be used repeatedly in an intermittent manner. It is difficult to determine and to justify scientifically what time represents a clinically relevant treatment periods for frequent use with regard to carcinogenic potential, especially for discontinuous treatment periods. For pharmaceuticals used frequently in an intermittent manner in the treatment of chronic or recurrent conditions, carcinogenicity studies are generally needed. Examples of such conditions include allergic rhinitis, depression, and anxiety. Carcinogenicity studies may also need to be considered for certain delivery systems which may result in prolonged exposures. Pharmaceuticals administered infrequently or for short duration of exposure (e.g., anaesthetics and radiolabelled imaging agents) do not need carcinogenicity studies unless there is cause for concern. 4.2 Cause for Concern Carcinogenicity studies may be recommended for some pharmaceuticals if there is concern about their carcinogenic potential. Several factors which could be considered may include: (1) previous demonstration of carcinogenic potential in the product class that is considered relevant to humans; (2) structure-activity relationship suggesting carcinogenic risk; (3) evidence of preneoplastic lesions in repeated dose toxicity studies; (4) long-term tissue retention of parent compound or metabolite(s) resulting in local tissue reactions or other pathophysiological responses. 4.3 Genotoxicity Unequivocally genotoxic compounds, in the absence of other data, are presumed to be trans-species carcinogens, implying a hazard to humans. Such compounds need not be subjected to long-term carcinogenicity

studies. However, if such a drug is intended to be administered chronically to humans a chronic toxicity study (up to one year) may be necessary to detect early tumorigenic effects. Assessment of the genotoxic potential of a compound should take into account the totality of the findings and acknowledge the intrinsic value and limitations of both in vitro and in vivo tests. The test battery approach of in vitro and in vivo tests is designed to reduce the risk of false negative results for compounds with genotoxic potential. A single positive result in any assay for genotoxicity does not necessarily mean that the test compound poses a genotoxic hazard to humans (ICH Guidance on Specific Aspects of Regulatory Genotoxicity Tests).

TESTING FOR CARCINOGENICITY OF PHARMACEUTICALS 2. BACKGROUND Historically, the regulatory requirements for the assessment of the carcinogenic potential of pharmaceuticals in the three regions (E.U., Japan, U.S.) provided for the conduct of long-term carcinogenicity studies in two rodent species, usually the rat and the mouse This guideline should be read in conjunction with other guidelines S1.A: Guideline on the Need for Carcinogenicity Studies of Pharmaceuticals. S1.C: Dose Selection for Carcinogenicity Studies of Pharmaceuticals. Long-term rodent carcinogenicity studies for assessing the carcinogenic potential of chemicals (including pharmaceuticals) to humans are currently receiving critical examination. Since the early 1970's, many investigations have shown that it is possible to provoke a carcinogenic response in rodents by a diversity of experimental procedures, some of which are now considered to have

little or no relevance for human risk assessment. This guideline outlines experimental approaches to the evaluation of carcinogenic potential that may obviate the necessity for the routine conduct of two long-term rodent carcinogenicity studies for those pharmaceuticals that need such evaluation. The relative individual contribution of rat and mouse carcinogenicity studies and whether the use of rats or mice alone would result in a significant loss of information on carcinogenicity relevant to human risk assessment has been addressed by six surveys of the data for human pharmaceuticals. The surveys were those of the International Agency for Research on Cancer (IARC), the U.S. Food and Drug Administration (FDA), the U.S. Physicians Desk Reference (PDR), the Japanese Pharmaceutical Manufacturers Association (JPMA), the EU Committee for Proprietary Medicinal Products (CPMP), and the UK Centre for Medicines Research (CMR). Positive results in long-term carcinogenicity studies that are not relevant to the therapeutic use of a pharmaceutical present a dilemma to all parties: regulatory reviewers, companies developing drugs and the public at large. The conduct of one long-term carcinogenicity study (rather than two long term studies) would, in part, allow resources to be diverted to other approaches to uncover potential carcinogenicity relevant to humans. A weight of evidence approach, that is use of scientific judgment in evaluation of the totality of the data derived from one long-term carcinogenicity study along with other appropriate experimental investigations, enhances the assessment of carcinogenic risk to humans. Experimental approaches to testing for carcinogenic potential. The basic principle: The basic scheme comprises one long-term rodent carcinogenicity study, plus one other study that supplements the long term carcinogenicity study and provides additional information that is not readily available from the long term assay.

Choice of species for a long-term carcinogenicity study. The species selected should be appropriate, based on considerations that include the following: (a) Pharmacology. (b) Repeated-dose toxicology. (c) Metabolism (see also Guidelines S1C and S3A). (d) Toxicokinetics (see also Guidelines S1C, S3A, and S3B). (e) Route of administration (e.g., less common routes such as dermal and inhalation).

A long-term carcinogenicity study in a second rodent species is still considered acceptable 4.2.3 Considerations in the choice of short or medium term tests for carcinogenicity. Emphasis should be placed on selection of a test method that can contribute information valuable to the overall weight of evidence for the assessment of carcinogenic potential. The rationale for this choice should be documented and based on information available at the time of method selection This rationale should include a scientific discussion of the strengths and weaknesses of the method 5. MECHANISTIC STUDIES 5.1 Cellular changes. Relevant tissues may be examined for changes at the cellular level using morphological, histochemical, or functional criteria. As appropriate, attention may be directed to such changes as the dose-relationships for apoptosis, cell proliferation, liver foci of cellular alteration, or changes in intercellular communication. 5.2. Biochemical measurements. Depending on the putative mode of tumorigenic action, investigations could involve measurements of: plasma hormone levels, e.g. T3/T4, TSH, prolactin growth factors binding to proteins such as 2-globulin tissue enzyme activity, etc. 5.3. Considerations for additional genotoxicity testing Additional genotoxicity testing in appropriate models may be invoked for compounds that were negative in the standard test battery but which have shown effects in a carcinogenicity test with no clear evidence for an epigenetic mechanism. Additional testing can include modified

conditions for metabolic activation in in vitro tests or can include in vivo tests measuring genotoxic damage in target organs of tumor induction

7. EVALUATION OF CARCINOGENIC POTENTIAL. Evidence of tumorigenic effects of the drug in rodent models should be evaluated in light of the tumor incidence and latency, the pharmacokinetics of the drug in the rodent models as compared to humans, and data from any mechanistic studies that are informative with respect to the relevance of the observed effects to humans. The results from any tests cited above should be considered as part of the overall weight of evidence taking into account the scientific status of the test systems.

DOSE SELECTION OF PHARMACEUTICALS FOR CARCINOGENICITY STUDIES 1. INTRODUCTION Traditionally, carcinogenicity studies for chemical agents have relied upon the maximally tolerated dose (MTD) as the standard method for high dose selection The MTD is generally chosen based on data derived from toxicity studies of 3 months' duration. In the past, the criteria for high dose selection for carcinogenicity studies of human pharmaceuticals have not been uniform among international regulatory agencies. In Europe and Japan, dose selection based on toxicity endpoints or attaining high multiples of the maximum recommended human daily dose (>100x on a mg/kg basis) has been accepted. However, in the United States, dose selection based on the MTD has traditionally been

considered the only appropriate practice. All regions have used a maximum feasible dose as an appropriate endpoint. For pharmaceuticals with low rodent toxicity, use of the MTD can result in the administration of very large doses in carcinogenicity studies, often representing high multiples of the clinical dose. This has led to the concern that exposures in rodents greatly in excess of the intended human exposures might not be relevant to human risk; because they so greatly alter the physiology of the test species, the findings might not reflect what would occur following human exposure. Ideally, the doses selected for rodent bioassays for pharmaceuticals should provide an exposure to the agent that (1) allows an adequate margin of safety over the human therapeutic exposure, (2) is tolerated without significant chronic physiological dysfunction and is compatible with good survival, (3) is guided by a comprehensive set of animal and human data that focus broadly on the properties of the agent and the suitability of the animal, and (4) permits data interpretation in the context of clinical use. In order to achieve international harmonisation of requirements for high dose selection for carcinogenicity studies of pharmaceuticals, and to establish a rational basis for high dose selection, the ICH Expert Working Group on Safety initiated a process to arrive at common, scientifically based criteria for high dose selection. This document proposes that any one of several approaches could be useful for dose selection, and should provide for a more rational approach to dose selection for carcinogenicity studies for pharmaceuticals. These include: 1) toxicity-based endpoints; 2) pharmacokinetic endpoints; 3) saturation of absorption; 4) pharmacodynamic endpoints; 5) maximum feasible dose; 6) limit dose; 7) additional endpoints.

1.1 General Considerations for the Conduct of Dose-Ranging Studies 1. In practice, carcinogenicity studies are carried out in a limited number of rat and mouse strains for which there is reasonable information on spontaneous tumour incidence. Ideally, rodent species/strains with metabolic profiles as similar as possible to humans should be studied 2. Dose-ranging studies should be conducted for both males and females for all strains and species to be tested in the carcinogenicity bioassay; 3. Dose selection is generally determined from 90-day studies using the route and method of administration that will be used in the bioassay; 4. Selection of an appropriate dosing schedule and regimen should be based on clinical use and exposure patterns, pharmacokinetics, and practical considerations; 5. Ideally, both the toxicity profile and any dose-limiting toxicity should be characterised 6. Changes in metabolite profile or alterations in metabolising enzyme activities (induction or inhibition) over time should be understood 1.2 Toxicity Endpoints in High Dose Selection ICH 1 agreed to evaluate endpoints other than the MTD for the selection of the high dose in carcinogenicity studies. These were to be based on the pharmacological properties and toxicological profile of the test compound. There is no scientific consensus on the use of toxicity endpoints other than the MTD. Therefore, the ICH Expert Working Group on Safety has agreed to continue use of the MTD as a useful toxicity-based endpoint for high dose selection for carcinogenicity studies. 1.3 Pharmacokinetic Endpoints in High Dose Selection A systemic exposure representing a large multiple of the human area under the exposure curve (AUC) can be an appropriate endpoint for dose selection for carcinogenicity studies for pharmaceuticals which have similar metabolic profiles in humans and rodents and low organ toxicity in rodents The level of animal systemic exposure should be sufficiently

great compared to exposure to provide reassurance of an adequate test of carcinogenicity. It is recognised that the doses administered to different species might not correspond to tissue concentrations because of different metabolic and excretory patterns. Comparability of systemic exposure is better assessed by blood concentrations of parent drug and metabolites than by administered dose. The unbound drug in plasma is thought to be the most relevant indirect measure of tissue concentrations of unbound drug. The AUC is considered the most comprehensive pharmacokinetic endpoint

1.4 Criteria for Comparisons of AUC in Animals and Man for use in High Dose Selection The following criteria are especially applicable for use in determining a pharmacokinetically-defined exposure for high dose selection. 1. Rodent pharmacokinetic data are derived from the strains used for the carcinogenicity studies using the route of compound administration and dose ranges planned for the carcinogenicity study 2. Pharmacokinetic data are derived from studies of sufficient duration to take into account potential time-dependent changes in pharmacokinetic parameters which might occur during the dose ranging studies; 3. Documentation is provided on the similarity of metabolism between rodents and humans 4. In assessing exposure, scientific judgement is used to determine whether the AUC comparison is based on data for the parent, parent and metabolite(s), 5. Interspecies differences in protein binding are taken into consideration when estimating relative exposure (Note 8); 6. Human pharmacokinetic data are derived from studies encompassing the maximum recommended human daily dose 1.5 Saturation of Absorption in High Dose Selection

High dose selection based on saturation of absorption measured by systemic availability of drug-related substances can be considered. The mid and low doses selected for the carcinogenicity study should take into account saturation of metabolic and elimination pathways. 1.6 Pharmacodynamic Endpoints in High Dose Selection The utility and safety of many pharmaceuticals depend on their pharmacodynamic receptor selectivity. Pharmacodynamic endpoints for high dose selection will be highly compound-specific and can be considered for individual study designs based on scientific merits. The high dose selected should produce a pharmacodynamic response in dosed animals of such magnitude as would preclude further dose escalation. 1.7 Maximum Feasible Dose Currently, the maximum feasible dose by dietary administration is considered to be 5% of diet. 1.8 Limit Dose In determining the high dose for carcinogenicity studies using the approaches outlined in this guideline it is appropriate to limit this dose to 1500 mg/kg/day This limit dose applies where the maximum recommended human dose does not exceed 500 mg/day 1.9 Additional Endpoints in High Dose Selection It is recognised that there might be merit in the use of alternative endpoints not specifically defined in this guidance on high dose selection for rodent carcinogenicity studies. Use of these additional endpoints in individual study designs should be based on scientific rationale.

GUIDANCE ON GENOTOXICITY TESTING AND DATA INTERPRETATION FOR PHARMACEUTICALS INTENDED FOR HUMAN USE
1.1 Objectives of the Guideline This guidance replaces and combines the ICH S2A and S2B guidelines. The purposeof the revision is to optimize the standard genetic toxicology battery for prediction of potential human risks, and to provide guidance on interpretation of results, with the ultimate goal of improving risk characterization for carcinogenic effects that have their basis in changes in the genetic material. The revised guidance describes internationally agreed upon standards for follow-up testing and interpretation of positive results in vitro and in vivo in the standard genetic toxicology battery 1.2 Background the recommendations from the latest OECD guidelines and the reports from the International Workshops on Genotoxicity Testing (IWGT) have been considered where relevant. . 1.4 General Principles Genotoxicity tests can be defined as in vitro and in vivo tests designed to detect compounds that induce genetic damage by various mechanisms. These tests enable hazard identification with respect to damage to DNA and its fixation. Fixation of damage to DNA in the form of gene mutations, larger scale chromosomal damage or recombination is generally considered to be essential for heritable effects a complex process in which genetic

changes may play only a part. Numerical chromosome changes have also been associated with tumorigenesis and can indicate a potential for aneuploidy in germ cells. Compounds that are positive in tests that detect such kinds of damage have the potential to be human carcinogens and/or mutagens. Because the relationship between exposure to particular chemicals and carcinogenesis is established for humans, whilst a similar relationship has been difficult to prove for heritable diseases, genotoxicity tests have been used mainly for the prediction of carcinogenicity. 2. THE STANDARD TEST BATTERY FOR GENOTOXICITY 2.1 Rationale Registration of pharmaceuticals requires a comprehensive assessment of their genotoxic potential. Extensive reviews have shown that many compounds that are mutagenic in the bacterial reverse mutation (Ames) test are rodent carcinogens. Nevertheless, a battery approach is still reasonable because no single test is capable of detecting all genotoxic mechanisms relevant in tumorigenesis. The general features of a standard test battery are as follows: i. Assessment of mutagenicity in a bacterial reverse mutation test. This test has been shown to detect relevant genetic changes and the majority of genotoxic rodent and human carcinogens; ii. Genotoxicity should also be evaluated in mammalian cells in vitro and/or in vivo. Several in vitro mammalian cell systems are widely used and can be considered sufficiently validated: The in vitro metaphase chromosome aberration assay, the in vitro micronucleus assay (Note 1) and the mouse lymphoma L5178Y cell tk gene mutation assay. These three assays are currently considered equally appropriate and therefore interchangeable when used together with other genotoxicity tests in a standard battery for testing of pharmaceuticals,

In vivo test(s) for genetic damage should usually be a part of the test
battery to provide additional relevant factors (absorption, distribution metabolism, excretion) that can influence the genotoxic activity of a compound and permit the detection of some additional genotoxic agents An in vivo test for chromosomal damage in rodent cells largely fulfills this need, either an analysis of micronuclei in erythrocytes in blood or bone marrow, or of chromosomal aberrations at metaphase in bone marrow cells Lymphocytes cultured from treated animals can also be used for cytogenetic analysis, although experience with such analyses is less widespread. In vitro and in vivo tests that measure chromosomal aberrations in metaphase cells can detect a wide spectrum of changes in chromosomal integrity. Breakage of chromatids or chromosomes can result in micronucleus formation if an acentric fragment is produced; therefore assays that detect either chromosomal aberrations or micronuclei are appropriate for detecting clastogens. The mouse lymphoma cell mutation assay detects mutations in the tk gene that result from both gene mutations and changes in chromosome integrity. There is some evidence that the mouse lymphoma assay can also detect chromosome loss. 2.2 Description of the Two Options for the Standard Battery The following two options for the standard battery are considered equally suitable: Option 1 i. A test for gene mutation in bacteria; ii. A cytogenetic test for chromosomal damage iii. An in vivo test for genotoxicity, generally a test for chromosomal damage using rodent hematopoietic cells,

Option 2 i. A test for gene mutation in bacteria; ii. An in vivo assessment of genotoxicity with two tissues, usually an assay using rodent hematopoietic cells and a second in vivo assay. Under both standard battery options, the in vivo genotoxicity assays can often be integrated into repeat-dose toxicity studies when the doses are sufficient Under Option 2, if dose/exposure is not appropriate, an acute in vivo study (incorporating two genotoxicity assays in one study where possible) should be performed to optimize dose selection based on exposure/toxicity or Option 1, including an in vitro mammalian cell assay, should be followed. For compounds that give negative results, the completion of either test battery, performed and evaluated in accordance with current recommendations, Compounds that give positive results in the standard test battery may, depending on their therapeutic use, need to be tested more extensively The preferred in vivo cytogenetic test under Option 2 is the micronucleus assay, not a chromosome aberration assay, to include more direct capability for detection of chromosome loss (potential for aneuploidy). There are several in vivo assays that may be used as the second part of the in vivo assessment under Option 2 The liver is typically the preferred tissue because of exposure and metabolizing capacity, but choice of in vivo tissue and assay should be based on factors such as any knowledge of the potential mechanism, of the metabolism in vivo, and of the exposed tissues thought to be relevant. In vivo genotoxicity assays may be integrated into existing (repeat dose) toxicity studies when the dose levels are justifiable and the protocols are compatible. The suggested standard set of tests does not imply that other genotoxicity tests are generally considered inadequate or inappropriate.

Additional tests can be used for further investigation of genotoxicity test results obtained in the standard battery Alternative species, including non-rodents, can also be used if indicated, and if sufficiently validated. Under extreme conditions in which one or more tests in the standard battery cannot be employed for technical reasons, alternative validated tests can serve as substitutes provided sufficient scientific justification is given to support the argument that a given standard battery test is not appropriate. 2.3 Modifications to the Test Battery situations where modification of the standard test battery advisable. 2.3.1 Compounds from Well Characterized Classes For compounds from well characterized classes where genotoxicity is expected, e.g., some quinolone antibiotics and some nucleoside analogues, 2.3.2 Testing Compounds that are Toxic to Bacteria In cases where compounds are highly toxic to bacteria (e.g., some antibiotics), the bacterial reverse mutation (Ames) test should still be carried out, because mutagenicity can occur at lower, less toxic concentrations. In such cases, any one of the in vitro mammalian cell assays should be done, i.e., Option 1 is followed. 2.3.3 Compounds Bearing Structural Alerts for Genotoxic Activity Structurally alerting compounds are usually detectable in the standard test battery since the majority of structural alerts are defined in relation to bacterial mutagenicity. A few chemical classes are known to be more easily detected in mammalian cell chromosome damage assays than bacterial mutation assays. Thus negative results in either test battery with a compound that has a structural alert isusually sufficient assurance of a lack of genotoxicity.

THE STANDARD TEST BATTERY FOR GENOTOXICITY The general features of a standard test battery can be outlined as follows: i) It is appropriate to assess genotoxicity in a bacterial reverse mutation test. This test has been shown to detect relevant genetic changes and the majority of genotoxic rodent carcinogens. ii) DNA damage considered to be relevant for mammalian cells and not adequately measured in bacteria should be evaluated in mammalian cells. Several mammalian cell systems are in use: systems that detect gross chromosomal damage (in vitro tests for structural and numerical chromosomal aberrations), systems that detect primarily gene mutations and a system that detects gene mutations and clastogenic effects (mouse lymphoma tk assay).

The following standard test battery is recommended i) A test for gene mutation in bacteria. ii) An in vitro test with cytogenetic evaluation of chromosomal damage with mammalian cells or an in vitro mouse lymphoma tk assay. iii) An in vivo test for chromosomal damage using rodent hematopoietic cells. For compounds giving negative results, the completion of this 3-test battery, performed and evaluated in accordance with current recommendations, will usually provide a sufficient level of safety to demonstrate the absence of genotoxic activity Compounds giving positive results in the standard test battery may, depending on their therapeutic use, need to be tested more extensively The suggested standard set of tests does not imply that other genotoxicity tests are generally considered as inadequate or inappropriate (e.g. tests for measurement of DNA adducts, DNA strand breaks, DNA repair or recombination). Such tests serve as options in addition to the standard battery for further investigation of genotoxicity test results obtained in the standard battery. Furthermore, molecular techniques to study mechanisms of genotoxicity in the standard battery systems may be useful for risk assessment. Only under extreme conditions in which one or more tests comprising the standard battery cannot be employed for technical reasons, alternative validated tests can serve as substitutes. For this to occur, sufficient scientific justification should be provided to support the argument that a given standard battery test is not appropriate. 5. STANDARD PROCEDURES FOR IN VITRO TESTS Reproducibility of experimental results is an essential component of research involving novel methods or unexpected findings; however, the

routine testing of chemicals with standard, widely used genotoxicity tests need not always be completely replicated. These tests are sufficiently well characterized and have sufficient internal controls that repetition can usually be avoided if protocols with built-in confirmatory elements, such as those outlined below, are used. For both bacterial and mammalian cell gene mutation tests, the results of a range-finding test can be used to guide the selection of concentrations to be used in the definitive mutagenicity test. By these means, a rangefinding test may supply sufficient data to provide reassurance that the reported result is the correct one. In bacterial mutagenicity tests, preliminary range-finding tests performed on all bacterial strains, with and without metabolic activation, with appropriate positive and negative controls, and with quantification of mutants, may be considered a sufficient replication of a subsequent complete test. Similarly, a range-finding test may also be a satisfactory substitute for a complete repeat of a test in gene mutation tests with mammalian cells other than the mouse lymphoma tk assay (see below) if the range-finding test is performed with and without metabolic activation, with appropriate positive and negative controls, and with quantification of mutants For the cytogenetic evaluation of chromosomal damage in vitro, the test protocol includes the conduct of tests with and without metabolic activation, with appropriate positive and negative controls, where the exposure to the test articles is 3 to 6 hours and a sampling time of approximately 1.5 normal cell cycles from the beginning of the treatment. A continuous treatment without metabolic activation up to the sampling time of approximately 1.5 normal cell cycles is needed in case of a negative result for the short treatment period without metabolic activation. Certain chemicals may be more readily detected by longer treatment or delayed sampling times, e.g. some nucleoside analogues or some nitrosamines.

Negative results in the presence of a metabolic activation system may need confirmation on a case by case basis In any case information on the ploidy status should be obtained by recording the incidence of polyploid cells as a percentage of the number of metaphase cells. An elevated mitotic index or an increased incidence of polyploid cells may give an indication of the potential of a compound to induce aneuploidy. In such cases, further testing may be needed. For the mouse lymphoma tk assay, the test protocol includes the conduct of tests with and without metabolic activation, with appropriate positive and negative controls, where the exposure to the test articles is 3 to 4 hours. A continuous treatment without metabolic activation for approximately 24 hours is needed in case of a negative result for the short treatment without metabolic activation. Negative results in the presence of a metabolic activation system may need confirmation on a case by case basis In any case, an acceptable mouse lymphoma tk assay includes (i)

the incorporation of positive controls which induces mainly small colonies, (ii) colony sizing for positive controls, solvent controls and at least one positive test compound dose (should any exist), including the culture that gave the greatest mutant frequency. Following such testing, further confirmatory testing in the case of clearly negative or positive test results is not usually needed. Ideally it should be possible to declare test results as clearly negative or clearly positive. However, test results sometimes do not fit the predetermined criteria for a positive or negative call and therefore are declared equivocal.

IMMUNOTOXICITY STUDIES FOR HUMAN PHARMACEUTICALS

1.1 Objectives of the Guideline The objectives of this guideline are to provide (1) recommendations on nonclinical testing approaches to identify compounds which have the potential to be immunotoxic, (2) guidance on a weight-of-evidence decision making approach for immunotoxicity testing. Immunotoxicity is, for the purpose of this guideline, defined as unintended immunosuppression or enhancement. Drug-induced hypersensitivity and autoimmunity are excluded. 1.2 Background . Toxicity to the immune system encompasses a variety of adverse effects. These include suppression or enhancement of the immune response. Suppression of the immune response can lead to decreased host resistance to infectious agents or tumor cells. Enhancing the immune response can exaggerate autoimmune diseases or hypersensitivity. Subsequent exposures to the drug can lead to hypersensitivity (allergic) reactions. Much of the science and method development and validation efforts in the past have been focused on evaluating drug development candidates for their potential for either immunosuppression or contact sensitization. Immunosuppression or enhancement can be associated with two distinct groups: 1) Drugs intended to modulate immune function for therapeutic purposes (e.g., to prevent organ transplant rejection) 2) Drugs not intended to affect immune function but cause immunotoxicity due, for instance, to necrosis or apoptosis of immune cells 1.3 Scope of the Guideline This guideline is focused on providing recommendations on nonclinical testing for immunotoxicity induced by human pharmaceuticals This guideline applies to new pharmaceuticals intended for use in humans, as well as to marketed pharmaceuticals proposed for different indications or other variations on the current product label in which the change could result in unaddressed and relevant immunotoxicity issues. In addition, the guideline might

also apply to drugs for which clinical signs of immunotoxicity are observed during clinical trials and following approval to market. The guideline does not apply to biotechnology-derived pharmaceutical products covered by ICH S6 Guideline1 and other biologicals. 1.4 Overview The general principles that apply to this guideline are: 1) All new human pharmaceuticals should be evaluated for the potential to produce immunotoxicity; 2) Methods include standard toxicity studies (STS) and additional immunotoxicity studies conducted as appropriate. 2. GUIDELINE 2.1 Factors to Consider in the Evaluation of Potential Immunotoxicity : (1) findings from STS; (2) the pharmacological properties of the drug; (3) the intended patient population; (4) structural similarities to known immunomodulators; (5) the disposition of the drug; and (6) clinical information. 2.1.1 Standard Toxicity Studies Data from STS should be evaluated for signs of immunotoxic potential. Signs that should be taken into consideration are the following: 1) Hematological changes such as leukocytopenia/leukocytosis, granulocytopenia/granulocytosis, or lymphopenia/lymphocytosis; 2) Alterations in immune system organ weights and/or histology (e.g., changes in thymus, spleen, lymph nodes, and/or bone marrow); 3) Changes in serum globulins that occur without a plausible explanation, such as effects on the liver or kidney, can be an indication that there are changes in serum immunoglobulins; 4) Increased incidence of infections; 5) Increased occurrence of tumors can be viewed as a sign of immunosuppression in the absence of other plausible causes such as genotoxicity, 2.1.2 Pharmacological Properties If the pharmacological properties of a test compound indicate it has the potential to affect immune function (e.g., anti-inflammatory drugs), additional immunotoxicity testing should be considered. Information obtained from the nonclinical pharmacology studies on the ability of the compound to affect the immune system

could be used in a weight of evidence approach to decide if additional immunotoxicity studies are needed. 2.1.3 Intended Patient Population Additional immunotoxicity studies might be warranted if the majority of the patient population for whom the drug is intended is immunocompromised by a disease state or concurrent therapy. 2.1.4 Structural Similarity Compounds structurally similar to compounds with known immunosuppressive properties should also be considered for additional immunotoxicity testing. 2.1.5 Disposition of the Drug If the compound and/or its metabolites are retained at high concentrations in cells of the immune system, additional immunotoxicity testing should be considered. 2.1.6 Signs Observed in Clinical Trials or Clinical Use Clinical findings suggestive of immunotoxicity in patients exposed to the drug could call for additional nonclinical immunotoxicity testing. 3. SELECTION AND DESIGN OF ADDITIONAL IMMUNOTOXICITY STUDIES 3.1 Objectives If a cause for concern is identified, additional immunotoxicity studies should be performed to verify the immunotoxic potential of the compound. These studies can also help determine the cell type affected reversibility, and the mechanism of action. This type of information can also provide more insight into potential risk and possibly lead to biomarker selection for clinical studies. 3.2 Selection of assays . If there are changes instandard toxicity testing data suggesting immunotoxicity, the type of additional immunotoxicity testing that is considered appropriate will depend on the nature of the immunological changes observed and the concerns raised by the class of compound. It is recommended that an immune function study be conducted, such as a T-cell dependent antibody response (TDAR). If specific cell types that are affected in STS are not known to participate in a TDAR, assays that measure function of that specific affected cell type might be conducted Where a specific target is not identified, an immune function study such as the TDAR is recommended. In addition, immunophenotyping of leukocyte populations, a non-functional assay, can be conducted to identify the specific cell populations affected and might provide useful clinical biomarkers.

T-cell Dependent Antibody Response (TDAR) The TDAR should be performed using a recognized T-cell dependent antigen (e.g., sheep red blood cells (SRBC) or keyhole limpet hemocyanin (KLH)) that results in a robust antibody response. The endpoint selected should be justified as the most appropriate for the chosen assay and the selected species. Antigens for immunization should not be used with adjuvants without justification. Alum might be considered acceptable for use only in non-human primate studies. The relative TDAR response can be strain-dependent, especially in mice. With outbred rats, there can be significant variability among rats within the same group. Inbred rat strains could be used with provision of sufficient exposure data to bridge to the strain used in the STS. Antibody can be measured by using an ELISA or other immunoassay methods. One advantage of this method over the antibody forming cell response is that samples can be collected serially during the study. In monkeys, serial blood collection can be important due to the high inter-animal variability in the kinetics of the response. Immunophenotyping Immunophenotyping is the identification and/or enumeration of leukocyte subsets using antibodies. Immunophenotyping is usually conducted by flow cytometric analysis or by immunohistochemistry. Flow cytometry, when employed to enumerate specific cell populations, is not a functional assay. However, flow cytometry can be used to measure antigenspecific immune responses of lymphocytes. Data obtained from peripheral blood can be useful as a bridge for clinical studies in which peripheral blood leukocytes are also evaluated. It is recommended that absolute numbers of lymphocyte subsets as well as percentages be used in evaluating treatment-related changes. One of the advantages of immunohistochemistry over flow cytometry is that tissues from standard toxicity studies can be analyzed retrospectively if signs of immunotoxicity are observed Natural Killer Cell Activity Assays Natural killer (NK) cell activity assays can be conducted if immunophenotyping studies demonstrate a change in number, or if STS studies demonstrate increased viral infection rates, or in response to other factors. In general, all NK cell assays are ex vivo assays in which tissues (e.g., spleen) or blood are obtained from animals that have been treated with the test compound. Cell preparations are coincubated with target cells that have been labeled with 51Cr. New methods that involve nonradioactive labels can be used if adequately validated. Different effector to target cell ratios should be evaluated for each assay to obtain a sufficient level of cytotoxicity and generate a curve.

Host Resistance Studies Host resistance studies involve challenging groups of mice or rats treated with the different doses of test compound with varying concentrations of a pathogen (bacteria, fungal, viral, parasitic) or tumor cells. . Models have been developed to evaluate a wide range of pathogens such as Listeria monocytogenes, Streptococcus pneumoniae, Candida albicans, influenza virus, cytomegalovirus, Plasmodium yoelii and Trichinella spiralis. Tumor host resistance models in mice have used the B16F10 melanoma and PYB6 sarcoma tumor cell lines. Host resistance assays can provide information on the susceptibility to particular classes of infectious agents

QUALITY
STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS
1. INTRODUCTION

1.1. Objectives of the Guideline The following guideline is a revised version of the ICH Q1A guideline and defines the stability data package for a new drug substance or drug product that is sufficient for a registration application within the three regions of the EC, Japan, and the United States The guideline seeks to exemplify the core stability data package for new drug substances and products, but leaves sufficient flexibility to encompass the variety of different practical situations that may be encountered due to specific scientific considerations and characteristics of the materials being evaluated. Alternative approaches can be used when there are scientifically justifiable reasons.

1.2. Scope of the Guideline The guideline addresses the information to be submitted in registration applications for new molecular entities and associated drug products. This guideline does not currently seek to cover the information to be submitted for abbreviated or abridged applications, variations, clinical trial applications, etc. Specific details of the sampling and testing for particular dosage forms in their proposed container closures are not covered in this guideline. Further guidance on new dosage forms and on biotechnological/biological products can be found in ICH guidelines Q1C and Q5C, respectively. 1.3. General Principles The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light, and to establish a re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions. The choice of test conditions defined in this guideline is based on an analysis of the effects of climatic conditions in the three regions of the EC, Japan and the United States. The mean kinetic temperature in any part of the world can be derived from climatic data, and the world can be divided into four climatic zones, I-IV. This guideline addresses climatic zones I and II. The principle has been established that stability information generated in any one of the three regions of the EC, Japan and the United States would be mutually acceptable to the other two regions, provided the information is consistent with this guideline and the labeling is in accord with national/regional requirements. 2. GUIDELINES 2.1. Drug Substance 2.1.1. General Information on the stability of the drug substance is an integral part of the systematic approach to stability evaluation. 2.1.2. Stress Testing Stability Testing of New Drug Substances and Products 2

Stress testing of the drug substance can help identify the likely degradation products, which can in turn help establish the degradation pathways and the intrinsic stability of the molecule and validate the stability indicating power of the analytical procedures used. The nature of the stress testing will depend on the individual drug substance and the type of drug product involved. Stress testing is likely to be carried out on a single batch of the drug substance. It should include the effect of temperatures (in 10C increments (e.g., 50C, 60C, etc.) above that for accelerated testing), humidity (e.g., 75% RH or greater) where appropriate, oxidation, and photolysis on the drug substance. The testing should also evaluate the susceptibility of the drug substance to hydrolysis across a wide range of pH values when in solution or suspension. Photostability testing should be an integral part of stress testing. The standard conditions for photostability testing are described in ICH Q1B. Examining degradation products under stress conditions is useful in establishing degradation pathways and developing and validating suitable analytical procedures. However, it may not be necessary to examine specifically for certain degradation products if it has been demonstrated that they are not formed under accelerated or long term storage conditions. Results from these studies will form an integral part of the information provided to regulatory authorities. 2.1.3. Selection of Batches Data from formal stability studies should be provided on at least three primary batches of the drug substance. The batches should be manufactured to a minimum of pilot scale by the same synthetic route as, and using a method of manufacture and procedure that simulates the final process to be used for, production batches. The overall quality of the batches of drug substance placed on formal stability studies should be representative of the quality of the material to be made on a production scale. 2.1.4. Container Closure System The stability studies should be conducted on the drug substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution. 2.1.5. Specification Specification, which is a list of tests, reference to analytical procedures, and proposed acceptance criteria, is addressed in ICH Q6A and Q6B.

In addition, specification for degradation products in a drug substance is discussed in Q3A. Stability studies should include testing of those attributes of the drug substance that are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy. The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes. Validated stability-indicating analytical procedures should be applied. Whether and to what extent replication should be performed will depend on the results from validation studies. Stability Testing of New Drug Substances and Products 3

2.1.6. Testing Frequency For long term studies, frequency of testing should be sufficient to establish the stability profile of the drug substance. For drug substances with a proposed re-test period of at least 12 months, the frequency of testing at the long term storage condition should normally be every 3 months over the first year, every 6 months over the second year, and annually thereafter through the proposed re-test period. At the accelerated storage condition, a minimum of three time points, including the initial and final time points (e.g., 0, 3, and 6 months), from a 6-month study is recommended. Where an expectation (based on development experience) exists that results from accelerated studies are likely to approach significant change criteria, increased testing should be conducted either by adding samples at the final time point or by including a fourth time point in the study design. When testing at the intermediate storage condition is called for as a result of significant change at the accelerated storage condition, a minimum of four time points, including the initial and final time points (e.g., 0, 6, 9, 12 months), from a 12-month study is recommended. 2.1.7. Storage Conditions In general, a drug substance should be evaluated under storage conditions (with appropriate tolerances) that test its thermal stability and, if applicable, its sensitivity to moisture. The storage conditions and the lengths of studies chosen should be sufficient to cover storage, shipment, and subsequent use. The long term testing should cover a minimum of 12 months duration on at least three primary batches at the time of submission and should be continued for a period of time sufficient to cover the proposed re-test period Long term, accelerated, and, where appropriate, intermediate storage conditions for drug substances are detailed in the sections below.

2.1.7.1. General case Study

Storage condition

Minimum time period covered by data at submission

Long term*

25C 2C/60% RH 12 months 5% RH or 30C 2C/65% RH 5% RH 30C 2C/65% RH 6 months 5% RH 40C 2C/75% RH 6 months 5% RH

Intermediate** Accelerated

STABILITY TESTING: PHOTOSTABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS 1. GENERAL The ICH Harmonized Tripartite Guideline covering the Stability Testing of New Drug Substances and Products (hereafter referred to as the Parent Guideline) notes that light testing should be an integral part of stress testing. A. Preamble The intrinsic photostability characteristics of new drug substances and products should be evaluated to demonstrate that, as appropriate, light exposure does not result in unacceptable change. Normally, photostability testing is carried out on a single batch of material selected as described under Selection of Batches in the Parent Guideline. Under some circumstances these studies should be repeated if certain variations and changes are made to the product (e.g., formulation, packaging). Whether these studies should be repeated depends on the photostability characteristics determined at the time of initial filing and the type of variation and/or change made. A systematic approach to photostability testing is recommended covering, as appropriate, studies such as:

i) Tests on the drug substance; ii) Tests on the exposed drug product outside of the immediate pack; and if necessary ; iii) Tests on the drug product in the immediate pack; and if necessary ; iv) Tests on the drug product in the marketing pack.

B. Light Sources The light sources described below may be used for photostability testing. Option 1 Any light source that is designed to produce an output similar to the D65/ID65 emission standard such as an artificial daylight fluorescent lamp combining visible and ultraviolet (UV) outputs, xenon, or metal halide lamp. D65 is the internationally recognized standard for outdoor daylight as defined in ISO 10977 (1993). ID65 is the equivalent indoor indirect daylight standard. For a light source emitting significant radiation below 320 nm, an appropriate filter(s) may be fitted to eliminate such radiation. Option 2 For option 2 the same sample should be exposed to both the cool white fluorescent and near ultraviolet lamp. 1. A cool white fluorescent lamp designed to produce an output similar to that specified in ISO 10977(1993) ; and 2. A near UV fluorescent lamp having a spectral distribution from 320 nm to 400 nm with a maximum energy emission between 350 nm and 370 nm; a significant proportion of UV should be in both bands of 320 to 360 nm and 360 to 400 nm. C. Procedure For confirmatory studies, samples should be exposed to light providing an overall illumination of not less than 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200 watt hours/square meter to allow direct comparisons to be made between the drug substance and drug product. Samples may be exposed side-by-side with a validated chemical actinometric system to ensure the specified light exposure is obtained, or for the appropriate duration of time when conditions have been monitored using calibrated radiometers/lux meters.. If protected samples (e.g., wrapped in aluminum foil) are used as dark controls to evaluate the contribution of thermally induced change to the total observed change, these should be placed alongside the authentic sample.

Photostability Testing of New Drug Substances and Products DRUG SUBSTANCE For drug substances, photostability testing should consist of two parts: forced degradation testing and confirmatory testing. The purpose of forced degradation testing studies is to evaluate the overall photosensitivity of the material for method development purposes and/or degradation pathway elucidation. This testing may involve the drug substance alone and/or in simple solutions/suspensions to validate the analytical procedures. In these studies, the samples should be in chemically inert and transparent containers. In these forced degradation studies, a variety of exposure conditions may be used, depending on the photosensitivity of the drug substance involved and the intensity of the light sources used. For development and validation purposes it is appropriate to limit exposure and end the studies if extensive decomposition occurs. For photostable materials, studies may be terminated after an appropriate exposure level has been used. Under forcing conditions, decomposition products may be observed that are unlikely to be formed under the conditions used for confirmatory studies. This information may be useful in developing and validating suitable analytical methods. If in practice it has been demonstrated they are not formed in the confirmatory studies, these degradation products need not be further examined.

Confirmatory studies

should then be undertaken to provide the information necessary for handling, packaging, and labeling Normally, only one batch of drug substance is tested during the development phase, and then the photostability characteristics should be confirmed on a single batch selected as described in the Parent Guideline if the drug is clearly photostable or photolabile A. Presentation of Samples Care should be taken to ensure that the physical characteristics of the samples under test are taken into account and efforts should be made, such as cooling and/or placing the samples in sealed containers, to ensure that the effects of the changes in physical states such as sublimation, evaporation or melting are

minimized. All such precautions should be chosen to provide minimal interference with the exposure of samples under test. As a direct challenge for samples of solid drug substances, an appropriate amount of sample should be taken and placed in a suitable glass or plastic dish and protected with a suitable transparent cover if considered necessary. Solid drug substances should be spread across the container to give a thickness of typically not more than 3 millimeters. Drug substances that are liquids should be exposed in chemically inert and transparent containers.

B. Analysis of Samples At the end of the exposure period, the samples should be examined for any changes in physical properties (e.g., appearance, clarity, or color of solution) and for assay and degradants by a method suitably validated for products likely to arise from photochemical degradation processes. Where solid drug substance samples are involved, sampling should ensure that a representative portion is used in individual tests. Similar sampling considerations, such as homogenization of the entire sample, apply to other materials that may not be homogeneous after exposure. The analysis of the exposed sample should be performed concomitantly with that of any protected samples used as dark controls if these are used in the test. C. Judgement of Results The forced degradation studies should be designed to provide suitable information to develop and validate test methods for the confirmatory studies. These test methods should be capable of resolving and detecting photolytic degradants that appear during the confirmatory studies. The confirmatory studies should identify precautionary measures needed in manufacturing or in formulation of the drug product, and if light resistant packaging is needed. When evaluating the results of confirmatory studies to determine whether change due to exposure to light is acceptable, it is important to consider the results from other formal stability studies in order to assure that the drug will be within justified limits at time of use. DRUG PRODUCT Normally, the studies on drug products should be carried out in a sequential manner starting with testing the fully exposed product then progressing as necessary to the product in the immediate pack and then in the marketing pack. Testing should progress until the results demonstrate that the drug product is adequately protected from exposure to light. The drug product should be exposed to the light conditions described under the procedure in section I.C. Normally, only one batch of drug product is tested during the development phase, and then the photostability characteristics should be confirmed on a single batch selected as described in the Parent Guideline if the product is clearly photostable or photolabile. If the results of the confirmatory study are equivocal, testing of up to two additional batches should be conducted.

For some products where it has been demonstrated that the immediate pack is completely impenetrable to light, such as aluminium tubes or cans, testing should normally only be conducted on directly exposed drug product. It may be appropriate to test certain products such as infusion liquids, dermal creams, etc., to support their photostability in-use. The extent of this testing should depend on and relate to the directions for use, and is left to the applicants discretion. The analytical procedures used should be suitably validated.

A. Presentation of Samples Care should be taken to ensure that the physical characteristics of the samples under test are taken into account and efforts, such as cooling and/or placing the samples in sealed containers, should be made to ensure that the effects of the changes in physical states are minimized, such as sublimation, evaporation, or melting. All such precautions should be chosen to provide a minimal interference with the irradiation of samples under test. Possible interactions between the samples and any material used for containers or for general protection of the sample should also be considered and eliminated wherever not relevant to the test being carried out. Where practicable when testing samples of the drug product outside of the primary pack, these should be presented in a way similar to the conditions mentioned for the drug substance. The samples should be positioned to provide maximum area of exposure to the light source. For example, tablets, capsules, etc., should be spread in a single layer. If direct exposure is not practical (e.g., due to oxidation of a product), the sample should be placed in a suitable protective inert transparent container (e.g., quartz). If testing of the drug product in the immediate container or as marketed is needed, the samples should be placed horizontally or transversely with respect to the light source, whichever provides for the most uniform exposure of the samples. Some adjustment of testing conditions may have to be made when testing large volume containers (e.g., dispensing packs). B. Analysis of Samples At the end of the exposure period, the samples should be examined for any changes in physical properties (e.g., appearance, clarity or color of solution, dissolution/disintegration for dosage forms such as capsules, etc.) and for assay and degradants by a method suitably validated for products likely to arise from photochemical degradation processes. When powder samples are involved, sampling should ensure that a representative portion is used in individual tests. For solid oral dosage form products, testing should be conducted on an appropriately sized composite of, for example, 20 tablets or capsules. Similar sampling considerations, such as homogenization or solubilization of the entire sample, apply to other materials that may not be homogeneous after exposure (e.g., creams, ointments, suspensions, etc.). The analysis of the exposed sample should be performed concomitantly with that of any protected samples used as dark controls if these are used in the test. C. Judgement of Results

Depending on the extent of change special labeling or packaging may be needed to mitigate exposure to light. When evaluating the results of photostability studies to determine whether change due to exposure to light is acceptable, it is important to consider the results obtained from other formal stability studies in order to assure that the product will be within proposed specifications during the shelf life

PHARMACOPOEIAL HARMONISATION
EVALUATION AND RECOMMENDATION OF PHARMACOPOEIAL TEXTS FOR USE IN THE ICH REGIONS 1. INTRODUCTION 1.1 Objective(s) of the Guideline This document describes a process for the evaluation and recommendation by the Q4B Expert Working Group (EWG) of selected pharmacopoeial texts to facilitate their recognition by regulatory authorities for use as interchangeable in the ICH regions. 1.2 Background When issuing Q6A: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances, and Test Procedures and Acceptance Criteria for Biotechnological/Biological Products, ICH recognized that full use and value of both ICH Guidelines would depend on the successful harmonisation of pharmacopoeial procedures and encouraged the work of the Pharmacopoeial Discussion Group (PDG). 1.2.1 The Pharmacopoeial Discussion Group (PDG) The PDG, founded in 1990, consists of representatives from the European Directorate for the Quality of Medicines (EDQM) in the Council of Europe; the Ministry of Health, Labour and Welfare (MHLW) of Japan; and the United States Pharmacopoeial Convention, Inc (USP). The PDG produces harmonised pharmacopoeial texts through independent public comment and consultation. The PDG reports on the status of its harmonisation efforts at ICH meetings as appropriate.

Q6B: Specifications:

1.2.2 The Q4B Expert Working Group (EWG) In November 2003, ICH established the Q4B EWG to evaluate and recommend pharmacopoeial texts that are proposed for use in the three ICH regions. The Q4B EWG anticipates that the PDG will be the principal source of pharmacopoeial text proposals. There might be an occasion where not all three parties of the PDG participate in a harmonisation effort for a specific pharmacopoeial text. In such a case, the Q4B EWG can accept proposals from one or two PDG pharmacopoeias. 1.3 Scope of the Guideline Initially, the Q4B process will focus on evaluating the 11 General Test Chapters discussed during the development of ICH Q6A . Many other pharmacopoeial harmonisation proposals are being developed and could also be considered for Q4B evaluation. 1.4 General Principles The EWG will evaluate pharmacopoeial text proposals and assess the regulatory impact of the proposals. The Q4B EWG will continue its dialogue with the PDG as necessary during the Q4B process. Following its evaluation, the Q4B EWG will reach a conclusion and make a recommendation on the use of the text in the ICH regions which will be conveyed to the ICH Steering Committee. For each proposal that is Evaluation and Recommendation of Pharmacopoeial Texts for Use in ICH Regions To preserve transparency, the Q4B EWG should be notified of any revisions to a pharmacopoeial text that has been submitted to the Q4B evaluation process. Any change to pharmacopoeial text that has been proposed to, or recommended through, the Q4B evaluation process will prompt a Q4B EWG review to assess both the merit of the change and the appropriateness of any subsequent Q4B activity related to that text. 2. GUIDELINES 2.1 Q4B Evaluation Process The process begins with a document submission to the Q4B EWG The document submission should outline any issues for resolution and should contain any appropriate supporting data.

When the Q4B evaluation process results in a conclusion and recommendation that the pharmacopoeial text can be used as interchangeable in the ICH regions, a topicspecific Q4B annex will be issued following the steps in the ICH process as detailed below. 2.1.1 Step 1 Each Q4B party independently evaluates the documents for regulatory impact. Additional discussion within the Q4B EWG, and/or communication/dialogue with the submitting party (e.g., the PDG), might be warranted to resolve any issues that surfaced during the evaluation When the Q4B evaluation process results in a recommendation that the pharmacopoeial text can be used as interchangeable in the ICH regions, the Q4B EWG prepares and signs off on a draft Q4B annex, which is submitted to the Steering Committee for adoption at Step 2.

2.1.2 Step 2 The Steering Committee agrees, based on the report of the Q4B EWG, that there is sufficient scientific consensus on the technical issues for the draft annex to proceed to Step 3 regulatory consultation and discussion. 2.1.3 Step 3 The draft Q4B annex is made available for regulatory consultation in the three regions (generally for 3 months). The regulatory consultation and discussion should focus on the Q4B Outcome in the annex. The Q4B EWG can revise the annex based on comments received and submits a final draft of the annex to the ICH Steering Committee. 2.1.4 Step 4 The ICH Steering Committee adopts the annex and issues it as a stand-alone companion document to the ICH Q4B guideline. 2.1.5 Step 5 The annex moves to the regional regulatory implementation step. 2.2 Annex Contents The Q4B annexes will contain the following information at a minimum. Topic title; Introduction; Q4B Outcome; As appropriate, statements that will assist in the use of the referenced pharmacopoeial text by stakeholders; Implementation timelines indicating regulators' advice on when stakeholders can begin using the pharmacopoeial text as interchangeable; References to methods and acceptance criteria, as appropriate. 2.3 Use of the Pharmacopoeial Text After a regulatory ICH region has implemented the Q4B annex, the official pharmacopoeial texts referenced in the annex can be used as interchangeable in that region.

In addition to these general considerations, specific information for each regulatory region can assist the implementation in that region. Each regulatory region will provide such notification to its stakeholders in conjunction with regional implementation of the annex.

FDA consideration:
Based on the recommendation above, and in accordance with the conditions set forth in the annex, the pharmacopoeial texts as referenced in Section 2 of the annex can be considered interchangeable. However, FDA might request that a company demonstrate that the chosen method is acceptable and suitable for a specific material or product, irrespective of the origin of the method.

EU consideration:
For the European Union, the monographs of the Ph. Eur. have mandatory applicability. Regulatory authorities can accept the reference in a marketing authorisation application, renewal or variation application citing the use of the corresponding text from another pharmacopoeia as referenced in Section 2 of the annex

MHLW consideration:
The pharmacopoeial texts as referenced in Section 2 of the annex can be used as interchangeable in accordance with the conditions set out in the annex. Details of implementation requirements will be provided in the notification by MHLW when the specific annex is implemented

3. GLOSSARY Document Submission The working documents received from the PDG or one or more pharmacopoeial sources (USP, Ph. Eur., or JP) that contain the proposed pharmacopoeial text and any other support documents provided for Q4B evaluation. Interchangeable Where such status is indicated, any of the official texts from JP, EP, or USP can be substituted one for the other (appropriately referenced) in the ICH regions for purposes of the pharmaceutical registration/approval process PDG The three-party Pharmacopoeial Discussion Group consisting of representatives from the European Directorate for the Quality of Medicines (EDQM) in the Council of Europe; the Ministry of Health, Labour and Welfare (MHLW) of Japan, and the United States Pharmacopoeial Convention, Inc (USP). Pharmacopoeial text The pharmacopoeial monographs, general test chapters, and analytical methods emanating from the three regional pharmacopoeias. Q4B Outcome Produced by the Q4B evaluation process; information concerning how the evaluated pharmacopoeial text can be used. The Q4B Outcome is included as part of the topic-specific Q4B annex developed as a result of each favourable evaluation.

1) EVALUATION AND RECOMMENDATION OF PHARMACOPOEIAL TEXTS FOR USE IN THE ICH REGIONS ON RESIDUE ON IGNITION/SULPHATED ASH GENERAL CHAPTER
1. INTRODUCTION This annex is the result of the Q4B process for Residue on Ignition/Sulphated Ash. The proposed texts were submitted by the Pharmacopoeial Discussion Group (PDG).

2. Q4B OUTCOME 2.1 Analytical Procedures The ICH Steering Committee, based on the evaluation by the Q4B Expert Working Group (EWG), recommends that the official pharmacopoeial texts, Ph.Eur. 20414 Sulphated Ash, JP 2.44 Residue on Ignition Test, and USP <281> Residue on Ignition can be used as interchangeable in the ICH regions given the following: 2.1.1 Unless otherwise specified in a monograph, an appropriate sample weight is chosen, typically 1-2 g, to result in a level of residue sufficient to be accurately measurable by weight (typically 1 mg). If not specified in the monograph, the appropriate sample weight should be justified, and the sample weight and the acceptance criteria should be specified in the application dossier. 2.1.2 The muffle furnace should be appropriately calibrated to ensure compliance with regional GMP requirements. 2.2 Acceptance Criteria The proposed texts evaluated did not contain acceptance criteria. 3. TIMING OF ANNEX IMPLEMENTATION When this annex is implemented (incorporated into the regulatory process at ICH Step 5) in a region, it can be used in that region. Timing may differ for each region. 4. CONSIDERATIONS FOR IMPLEMENTATION 4.1 General consideration: When sponsors or manufacturers change their existing methods to the implemented Q4B-evaluated pharmacopoeial texts that are referenced in Section 2.1 of this annex, any change notification, variation, and/or prior approval procedures should be handled in accordance with established regional regulatory mechanisms pertaining to compendial changes. 4.2US ,4.3 EU ,4.4 MHLW consideration are similar as mentioned above

2 ) ON TEST FOR PARTICULATE CONTAMINATION: SUB-VISIBLE PARTICLES GENERAL CHAPTER 1. INTRODUCTION This annex is the result of the Q4B process for Test for Particulate Contamination: Sub-Visible Particles. The proposed texts were submitted by the Pharmacopoeial Discussion Group (PDG). 2. Q4B OUTCOME 2.1 Analytical Procedures The ICH Steering Committee, based on the evaluation by the Q4B Expert Working Group (EWG), recommends that the official pharmacopoeial texts, Ph.Eur. 2.9.19. Particulate Contamination: Sub-visible Particles, JP 6.07 Insoluble Particulate Matter Test for Injections, and USP <788> Particulate Matter in Injections can be used as interchangeable in the ICH regions subject to the following condition: 2.1.1 Instrument calibration and system suitability measurements should follow regional good manufacturing practice (GMP) requirements. 2.2 Acceptance Criteria Except for nominal 100-milliliter (mL) parenteral products, the acceptance criteria are interchangeable. At the 100-mL nominal volume, the criteria specified in JP are more stringent than those in the other two pharmacopoeias; therefore, the criteria are not interchangeable in all three regions at that volume. 3. TIMING OF ANNEX IMPLEMENTATION When this annex is implemented (incorporated into the regulatory process at ICH Step 5) in a region, it can be used in that region. Timing might differ for each region.

3)

ON MICROBIOLOGICAL EXAMINATION OF NON-STERILE PRODUCTS: TEST FOR SPECIFIED MICRO-ORGANISMS GENERAL CHAPTER

1. INTRODUCTION

This annex is the result of the Q4B process for Microbiological Examination of Non-Sterile Products: Tests for Specified Micro-organisms. The proposed texts were submitted by the Pharmacopoeial Discussion Group (PDG). 2. Q4B OUTCOME 2.1 Analytical Procedures The ICH Steering Committee, based on the evaluation by the Q4B Expert Working Group (EWG), recommends that the official pharmacopoeial texts, Ph.Eur. 2.6.13. Microbiological Examination of Non-Sterile Products: Tests for Specified Microorganisms, JP 4.05 Microbiological Examination of Non-Sterile Products: II. Microbiological Examination of Non-Sterile Products: Tests for Specified Microorganisms, and USP <62> Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms can be used as interchangeable in the ICH regions. 2.2 Acceptance Criteria The proposed texts evaluated did not contain acceptance criteria. 3. TIMING OF ANNEX IMPLEMENTATION When this annex is implemented (incorporated into the regulatory process at ICH Step 5) in a region, it can be used in that region. Timing might differ for each region. 4. CONSIDERATIONS FOR IMPLEMENTATION 4.1 General Consideration When sponsors or manufacturers change their existing methods to the implemented Q4B-evaluated pharmacopoeial texts that are referenced in Section 2.1 of this annex, any change notification, variation, and/or prior approval procedures should be handled in accordance with established regional regulatory mechanisms pertaining to compendial changes. 4.2 FDA Consideration

Based on the recommendation above, and with reference to the conditions set forth in this annex, the pharmacopoeial texts referenced in Section 2.1 of this annex can be considered interchangeable. However, FDA might request that a company demonstrate that the chosen method is acceptable and suitable for a specific material or product, irrespective of the origin of the method. Microbiological Examination of Non-Sterile Products: Tests for Specified Micro-Organisms General Chapter 4.3 EU Consideration For the European Union, the monographs of the Ph. Eur. have mandatory applicability. Regulatory authorities can accept the reference in a marketing authorisation application, renewal or variation application citing the use of the corresponding text from another pharmacopoeia as referenced in Section 2.1, in accordance with the conditions set out in this annex, as fulfilling the requirements for compliance with the Ph. Eur. Chapter 2.6.13. on the basis of the declaration of interchangeability made above. 4.4 MHLW Consideration The pharmacopoeial texts referenced in Section 2.1 of this annex can be used as interchangeable in accordance with the conditions set out in this annex. Details of implementation requirements will be provided in the notification by MHLW when this annex is implemented. 4.5 Health Canada Consideration In Canada, any of the texts cited in section 2.1 of this annex and used in accordance with the conditions set out in this annex can be considered interchangeable.
4) ON DISINTEGRATION TEST GENERAL CHAPTER Q4B ANNEX

5(R1) 1. INTRODUCTION

This annex is the result of the Q4B process for Disintegration Test General Chapter. The proposed texts were submitted by the Pharmacopoeial Discussion Group (PDG). 2. Q4B OUTCOME 2.1 Analytical Procedures The ICH Steering Committee, based on the evaluation by the Q4B Expert Working Group (EWG), recommends that for tablets and capsules, the official pharmacopoeial texts, Ph. Eur. 2.9.1. Disintegration of Tablets and Capsules, JP 6.09 Disintegration Test, and USP <701> Disintegration, can be used as interchangeable in the ICH regions subject to the conditions detailed below. Testing conditions for specific dosage forms are outside the scope of the harmonization of this chapter. 2.1.1 For tablets and capsules larger than 18 millimeters (mm) long for which a different apparatus is used, the Disintegration Test is not considered to be interchangeable in the three regions. 2.1.2 The Disintegration Test is not considered to be interchangeable in the three regions for dosage forms referred to in the regional compendia as delayed-release, gastro-resistant, or enteric-coated. 2.1.3 Product-specific parameters such as media and the use of discs should be specified in the application dossier. 2.2 Acceptance Criteria Acceptance criteria are outside the scope of the harmonization of this chapter and should be specified in the application dossier. 1. TIMING OF ANNEX IMPLEMENTATION When this annex is implemented (incorporated into the regulatory process at ICH Step 5) in a region, it can be used in that region. Timing might differ for each region. 4. CONSIDERATIONS FOR IMPLEMENTATION 4.1 General Consideration When sponsors or manufacturers change their existing methods to the implemented Q4B-evaluated pharmacopoeial texts that are referenced in Section 2.1 of this

annex, any change notification, variation, and/or prior approval procedures should be handled in accordance with established regional regulatory mechanisms pertaining to compendial changes. Disintegration Test General Chapter 2

4.2 FDA Consideration Based on the recommendation above, and with reference to the conditions set forth in this annex, the pharmacopoeial texts referenced in Section 2.1 of this annex can be considered interchangeable. However, FDA might request that a company demonstrate that the chosen method is acceptable and suitable for a specific material or product, irrespective of the origin of the method. 4.3 EU Consideration For the European Union, the monographs of the Ph. Eur. have mandatory applicability. Regulatory authorities can accept the reference in a marketing authorisation application, renewal or variation application citing the use of the corresponding text from another pharmacopoeia as referenced in Section 2.1, in accordance with the conditions set out in this annex, as fulfilling the requirements for compliance with the Ph. Eur. Chapter 2.9.1. on the basis of the declaration of interchangeability made above. 4.4 MHLW Consideration The pharmacopoeial texts referenced in Section 2.1 of this annex can be used as interchangeable in accordance with the conditions set out in this annex. Details of implementation requirements will be provided in the notification by MHLW when this annex is implemented. 4.5 Health Canada Consideration In Canada, any of the pharmacopoeial texts cited in section 2.1 of this annex and used in accordance with the conditions set out in this annex can be considered interchangeable. ON UNIFORMITY OF DOSAGE UNITS 1. INTRODUCTION This annex is the result of the Q4B process for Uniformity of Dosage Units.
5)

The proposed texts were submitted by the Pharmacopoeial Discussion Group (PDG). 2. Q4B OUTCOME 2.1 Analytical Procedures

The ICH Steering Committee, based on the evaluation by the Q4B Expert Working Group (EWG), recommends that the official pharmacopoeial texts, Ph.Eur. 2.9.40. Uniformity of Dosage Units, JP 6.02 Uniformity of Dosage Units, and USP General Chapter <905> Uniformity of Dosage Units, can be used as interchangeable in the ICH regions subject to the following conditions: 2.1.2 Unless the 25 milligrams (mg)/25% threshold limit is met, the use of the Mass/Weight Variation test as an alternative test for Content Uniformity is not considered interchangeable in all ICH regions; 2.1.3 For specific dosage forms which have been indicated in local text in the pharmacopoeias by enclosing the text within the black diamond symbols, application of the Uniformity of Dosage Units test is not considered interchangeable in all ICH regions; 2.1.4 For Mass/Weight Variation, the PDG-harmonised definition for W Bar should be used; 2.1.5 If a correction factor is called for when different procedures are used for assay of the preparation and for the Content Uniformity Test, the correction factor should be specified and justified in the application dossier. 2.2 Acceptance Criteria The acceptance criteria are harmonized between the three pharmacopoeias. Uniformity of Dosage Units General Chapter 2

3. TIMING OF ANNEX IMPLEMENTATION When this annex is implemented (incorporated into the regulatory process at ICH Step 5) in a region, it can be used in that region. Timing might differ for each region. 4. CONSIDERATIONS FOR IMPLEMENTATION

Similar as previous
6)

ON DISSOLUTION TEST GENERAL CHAPTER

1. INTRODUCTION This annex is the result of the Q4B process for Dissolution Test. 2. Q4B OUTCOME 2.1. Analytical Procedures The ICH Steering Committee, based on the evaluation by the Q4B Expert Working Group (EWG), recommends that the official pharmacopoeial texts, Ph.Eur. 2.9.3. Dissolution Test for Solid Dosage Forms, JP 6.10 Dissolution Test, and USP <711> Dissolution can be used as interchangeable in the ICH regions subject to the following conditions: 2.1.1 The declaration of interchangeability applies to the Basket Apparatus (Apparatus 1), the Paddle Apparatus (Apparatus 2), and the Flow-Through Cell. 2.1.2 The Dissolution Test is not considered to be interchangeable in the ICH regions when enzymes are used in the media. 2.1.3 The dissolution apparatus should be appropriately calibrated to ensure compliance with regional good manufacturing practice (GMP) requirements. 2.1.4 The Dissolution Test is not considered to be interchangeable in the three ICH regions for dosage forms referred to in the regional compendia as

delayed-release, gastro-resistant, or enteric-coated. 2.1.5 Validation studies should be conducted to demonstrate that the test results are not adversely affected if the thermometer is to remain in the dissolution vessel per regional good manufacturing practice (GMP). 2.1.6 The Dissolution Test is not considered to be interchangeable in the ICH regions for JP Interpretation 2. 2.1.7 The Dissolution Test is not considered to be interchangeable in the ICH regions for use of large vessels (greater than 1 liter). 2.1.8 Product-specific parameters such as media, stirring rate, sampling time, and the use and type of sinkers should be specified and justified in the application dossier. 2.2. Acceptance Criteria Acceptance criteria should be specified in the application dossier. 3. TIMING OF ANNEX IMPLEMENTATION When this annex is implemented (incorporated into the regulatory process at ICH Step 5) in a region, it can be used in that region. Timing might differ for each region. 4. CONSIDERATIONS FOR IMPLEMENTATION 4.1. General Consideration When sponsors or manufacturers change their existing methods to the implemented Q4Bevaluated pharmacopoeial texts that are referenced in Section 2.1 of this annex, any change notification, variation, and/or prior approval procedures should be handled in accordance with established regional regulatory mechanisms pertaining to compendial changes.

EFFICAY
THE EXTENT OF POPULATION EXPOSURE TO ASSESS CLINICAL SAFETY FOR DRUGS INTENDED FOR LONG-TERM TREATMENT OF NON-LIFE-THREATENING CONDITIONS ICH Harmonised Tripartite Guideline The objective of this guideline is to present an accepted set of principles for the safety evaluation of drugs intended for the long-term treatment (chronic or repeated intermittent use for longer than 6 months) of non-life-threatening diseases. The safety evaluation during clinical drug development is expected to characterise and Quantify the safety profile of a drug over a reasonable duration of time consistent with the intended long-term use of the drug. Thus, duration of drug exposure and its relationship to both time and magnitude of occurrence of adverse events are important considerations in determining the size of the data base necessary to achieve such goals.

For the purpose of this guideline, it is useful to distinguish between clinical data on adverse drug events (ADEs) derived from studies of shorter duration of exposure and data from studies of longer duration, It is expected that short-term event rates (cumulative 3-month incidence of about 1%) will be well characterised. Events where the rate of occurrence changes over a longer period of time may need to be characterised depending on their severity and importance to the risk-benefit assessment of the drug. The safety evaluation during clinical drug development is not expected to characterise rare adverse events, for example, those occurring in less than 1 in 1000 patients.
There was general agreement on the following: 1. A harmonised regulatory standard is of value for the extent and duration of treatment needed to provide the safety data base for drugs intended for long-term treatment of non-life-threatening conditions. .2. Regulatory standards for the safety evaluation of drugs should be based on previous experience with the occurrence and detection of adverse drug events (ADEs), statistical considerations of the probability of detecting specified frequencies of ADEs, and practical considerations. 3 Available information suggests that most ADEs first occur, and are most frequent, within the first few months of drug treatment. The number of patients treated for 6 months at dosage levels intended for clinical use, should be adequate to characterise the pattern of ADEs over time. 4. There is concern that, although they are likely to be uncommon, some ADEs may increase in frequency or severity with time or that some serious ADEs may occur

only after drug treatment for more than 6 months. Therefore, some patients should be treated with the drug for 12 months. 100 patients exposed for a minimum of one-year is considered to be acceptable to include as part of the safety data base. 5. It is anticipated that the total number of individuals treated with the investigational drug, including short-term exposure, will be about 1500. Japan currently accepts 500-1500 patients: the potential for a smaller number of patients is due to the post-marketing surveillance requirement, the actual number for a specific drug being determined by the information available on the drug and drug class. 7. There are a number of circumstances where the harmonised general standards for the clinical safety evaluation may not be applicable. E.g

Exceptions:
a. Instances where there is concern that the drug will cause late developing ADEs, or cause ADEs that increase in severity or frequency over time, would require a larger and/or longer-term safety data base. b. Situations in which there is a need to quantitate the occurrence rate of an expected specific low-frequency ADE will require a greater long-term data c. Larger safety data bases may be needed to make risk/benefit decisions in situations where the benefit from the drug is either (1) small or (2) will be experienced by only a fraction of the treated patients Or (3) is of uncertain magnitude d. In situations where there is concern that a drug may add to an already significant background rate of morbidity or mortality, clinical trials may need

to be designed with a sufficient number of patients to provide adequate statistical power to detect prespecified increases over the baseline morbidity or mortality. e. In some cases, a smaller number of patients may be acceptable, for example, where the intended treatment population is small. 8. Filing for approval will usually be possible based on the data from patients treated through 6 months. Data on patients treated through 12 months must be submitted as soon as available and prior to approval in the United States and Japan but may be submitted after approval in the E.C

PHARMACOVIGILANCE PLANNING
This guideline is intended to aid in planning pharmacovigilance activities, especially in preparation for the early postmarketing period of a new drug (in this guideline, the term drug denotes chemical entities, biotechnology-derived products, and vaccines). The main focus of this guideline is on a Safety Specification and Pharmacovigilance Plan that might be submitted at the time of licence application. The guideline can be used by sponsors to develop a stand-alone document for regions that prefer this approach or to provide guidance on incorporation of elements of the Safety Specification and Pharmacovigilance Plan into the Common Technical Document (CTD). The guideline describes a method for summarising the important identified risks of a drug, important potential risks, and important missing information, including the potentially at-risk populations and situations where the product is likely to be used that have not been studied pre-approval. It proposes a structure for a Pharmacovigilance Plan and sets out principles of good practice for the design and conduct of observational studies. It does not describe other methods to reduce risks from drugs, such as risk

communication. The guideline takes into consideration ongoing work in the three regions and beyond on these issues. This guideline does not cover the entire scope of pharmacovigilance. It uses the WHO definition of the term pharmacovigilance as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug related problems. This definition encompasses the use of pharmacoepidemiological studies. 1.2 Background The decision to approve a drug is based on its having a satisfactory balance of benefits and risks within the conditions specified in the product labeling. This decision is based on the information available at the time of approval. The knowledge related to the safety profile of the product can change over time through expanded use in terms of patient characteristics and the number of patients exposed. In particular, during the early postmarketing period the product might be used in settings different from clinical trials and a much larger population might be exposed in a relatively short timeframe. Once a product is marketed, new information will be generated, which can have an impact on the benefits or risks of the product; evaluation of this information should be a continuing process, in consultation with regulatory authorities. Detailed evaluation of the information generated through pharmacovigilance activities is important for all products to ensure their safe use. The benefit-risk balance can be improved by reducing risks to patients through effective pharmacovigilance that can enable information feedback to the users of medicines in a timely manner. Industry and regulators have identified the need for better and earlier planning of pharmacovigilance activities before a product is approved or a license is granted. This ICH guideline has been developed to encourage harmonisation and consistency, to

prevent duplication of effort, and could be of benefit to public health programs throughout the world as they consider new drugs in their countries. Pharmacovigilance Planning 2 1.3 Scope The guideline could be most useful for new chemical entities, biotechnology-derived products, and vaccines, as well as for significant changes in established products (e.g., new dosage form, new route of administration, or new manufacturing process for a biotechnologically-derived product) and for established products that are to be introduced to new populations or in significant new indications or where a new major safety concern has arisen. The purpose of this guideline is to propose a structure for a Pharmacovigilance Plan, and a Safety Specification that summarises the identified and potential risks of the product to be addressed in the Plan. The guideline is divided into the following sections: Safety Specification; Pharmacovigilance Plan; Annex Pharmacovigilance Methods. It is recommended that company pharmacovigilance experts get involved early in product development. Planning and dialogue with regulators should also start long before license application. A Safety Specification and Pharmacovigilance Plan can also be developed for products already on the market (e.g., new indication or major new safety concern). The Plan could be used as the basis for discussion of pharmacovigilance activities with regulators in the different ICH regions and beyond. For products with important identified risks, important potential risks or important missing information, the Pharmacovigilance Plan should include additional actions designed to address these concerns. For products for which no special concerns have

arisen, routine pharmacovigilance as described in section 3.1.2 should be sufficient for post-approval safety monitoring, without the need for additional actions (e.g., safety studies). During the course of implementing the various components of the Plan, any important emerging benefit or risk information should be discussed and used to revise the Plan. The following principles underpin this guideline: Planning of pharmacovigilance activities throughout the product life-cycle; Science-based approach to risk documentation; Effective collaboration between regulators and industry; Applicability of the Pharmacovigilance Plan across the three ICH regions. 2. SAFETY SPECIFICATION The Safety Specification should be a summary of the important identified risks of a drug, important potential risks, and important missing information. It should also address the populations potentially at-risk (where the product is likely to be used), and outstanding safety questions which warrant further investigation to refine understanding of the benefit-risk profile during the post-approval period. This Safety Specification is intended to help industry and regulators identify any need for specific data collection and also to facilitate the construction of the Pharmacovigilance Plan. The Safety Specification can be built initially during the pre-marketing phase and, at the time Pharmacovigilance Planning 3 approval is sought, it should reflect the status of issues that were being followed during development. The Common Technical Document (CTD), especially the Overview of Safety [2.5.5], Benefits and Risks Conclusions [2.5.6], and the Summary of Clinical Safety [2.7.4]

sections, includes information relating to the safety of the product, and should be the basis of the safety issues identified in the Safety Specification. Sponsors should support the Safety Specification with references to specific pages of the CTD or other relevant documents. The Safety Specification can be a stand-alone document, usually in conjunction with the Pharmacovigilance Plan, but elements can also be incorporated into the CTD. The length of the document will generally depend on the product and its development program. Appendices can be added if it is considered important to provide a more detailed explanation of important risks or analyses. 2.1 Elements of the Specification It is recommended that sponsors follow the structure of elements provided below when compiling the Safety Specification. The elements of the Safety Specification that are included are only a guide. The Safety Specification can include additional elements, depending on the nature of the product and its development program. Conversely, for products already on the market with emerging new safety concerns, only a subset of the elements might be relevant. The focus of the Safety Specification should be on the identified risks, important potential risks, and important missing information. The following elements should be considered for inclusion. 2.1.1 Non-Clinical Within the Specification, this section should present non-clinical safety findings that have not been adequately addressed by clinical data, for example: Toxicity (including repeat-dose toxicity, reproductive/developmental toxicity, nephrotoxicity, hepatotoxicity, genotoxicity, carcinogenicity etc.); General pharmacology (cardiovascular, including QT interval prolongation; nervous system; etc.);

 Drug interactions; Other toxicity-related information or data. If the product is intended for use in special populations, consideration should be given to whether specific non-clinical data needs exist. 2.1.2 Clinical a. Limitations of the Human Safety Database Limitations of the safety database (e.g., related to the size of the study population, study inclusion/exclusion criteria) should be considered, and the implications of such limitations with respect to predicting the safety of the product in the marketplace should be explicitly discussed. Particular reference should be made to populations likely to be exposed during the intended or expected use of the product in medical practice. Pharmacovigilance Planning 4 The world-wide experience should be briefly discussed, including: The extent of the world-wide exposure; Any new or different safety issues identified; Any regulatory actions related to safety. b. Populations not Studied in the Pre-Approval Phase The Specification should discuss which populations have not been studied or have only been studied to a limited degree in the pre-approval phase. The implications of this with respect to predicting the safety of the product in the marketplace should be explicitly discussed (CTD 2.5.5). Populations to be considered should include (but might not be limited to): Children; The elderly;

 Pregnant or lactating women; Patients with relevant co-morbidity such as hepatic or renal disorders; Patients with disease severity different from that studied in clinical trials; Sub-populations carrying known and relevant genetic polymorphism; Patients of different racial and/or ethnic origins. c. Adverse Events (AEs) / Adverse Drug Reactions (ADRs) This section should list the important identified and potential risks that require further characterisation or evaluation. Specific references should be made to guide a reviewer to where clinical safety data are presented (e.g., relevant sections of the CTD 2.5.5 and 2.7.4). Discussion of risk factors and potential mechanisms that apply to identified AEs/ADRs should draw on information from any part of the CTD (non-clinical and clinical) and other relevant information, such as other drug labels, scientific literature, and postmarketing experience. Identified risks that require further evaluation More detailed information should be included on the most important identified AEs/ADRs, which would include those that are serious or frequent and that also might have an impact on the balance of benefits and risks of the product. This information should include evidence bearing on a causal relationship, severity, seriousness, frequency, reversibility and at-risk groups, if available. Risk factors and potential mechanisms should be discussed. These AEs/ADRs should usually call for further evaluation as part of the Pharmacovigilance Plan (e.g., frequency in normal conditions of use, severity, outcome, at-risk groups, etc.). Potential risks that require further evaluation Important potential risks should be described in this section. The evidence that led to

the conclusion that there was a potential risk should be presented. It is anticipated that for any important potential risk, there should be further evaluation to characterise the association. Pharmacovigilance Planning 5 d. Identified and Potential Interactions, Including Food-Drug and DrugDrug Interactions Identified and potential pharmacokinetic and pharmacodynamic interactions should be discussed. For each, the evidence supporting the interaction and possible mechanism should be summarised, and the potential health risks posed for the different indications and in the different populations should be discussed. e. Epidemiology The epidemiology of the indication(s) should be discussed. This discussion should include incidence, prevalence, mortality and relevant co-morbidity, and should take into account whenever possible stratification by age, sex, and racial and/or ethnic origin. Differences in the epidemiology in the different regions should be discussed (because the epidemiology of the indication(s) may vary across regions), if this information is available. In addition, for important adverse events that may require further investigation, it is useful to review the incidence rates of these events among patients in whom the drug is indicated (i.e., the background incidence rates). For example, if condition X is an important adverse event in patients who are treated with drug Y for disease Z, then it is useful to review the incidence of condition X in patients with disease Z who are not treated with drug Y; this is the background rate of condition X among patients with disease Z. Information on risk factors for an adverse event (condition X) would also be useful to include, if available. f. Pharmacological Class Effects

The Safety Specification should identify risks believed to be common to the pharmacological class. 2.2 Summary At the end of the Safety Specification a summary should be provided of the: Important identified risks; Important potential risks; Important missing information. Sponsors are encouraged to summarise specific ongoing safety issues on an issue-byissue basis, including both non-clinical and clinical data that are pertinent to the problem. 3. PHARMACOVIGILANCE PLAN This section gives guidance on the structure of a Pharmacovigilance Plan. The Pharmacovigilance Plan should be based on the Safety Specification. The Specification and Plan can be written as two parts of the same document. The Plan would normally be developed by the sponsor and can be discussed with regulators during product development, prior to approval (i.e., when the marketing application is submitted) of a new product, or when a safety concern arises post-marketing. It can be a stand-alone document but elements could also be incorporated into the CTD. For products for which no special concerns have arisen, routine pharmacovigilance as described in section 3.1.2 should be sufficient for post-approval safety monitoring, Pharmacovigilance Planning 6 without the need for additional actions (e.g., safety studies). However, for products with important identified risks, important potential risks, or important missing information, additional actions designed to address these concerns should be considered. The length of the document will likely depend on the product and its development

program. The Pharmacovigilance Plan should be updated as important information on safety becomes available and milestones are reached. 3.1 Structure of the Pharmacovigilance Plan Outlined below is a suggested structure for the Pharmacovigilance Plan. The structure can be varied depending on the product in question and the issues identified in the Safety Specification. 3.1.1 Summary of Ongoing Safety Issues At the beginning of the Pharmacovigilance Plan a summary should be provided of the: Important identified risks; Important potential risks; Important missing information. This is important if the Pharmacovigilance Plan is a separate document from the Safety Specification. 3.1.2 Routine Pharmacovigilance Practices Routine pharmacovigilance should be conducted for all medicinal products, regardless of whether or not additional actions are appropriate as part of a Pharmacovigilance Plan. This routine pharmacovigilance should include the following: Systems and processes that ensure that information about all suspected adverse reactions that are reported to the personnel of the company are collected and collated in an accessible manner; The preparation of reports for regulatory authorities: o Expedited adverse drug reaction (ADR) reports; o Periodic Safety Update Reports (PSURs). Continuous monitoring of the safety profile of approved products including signal detection, issue evaluation, updating of labeling, and liaison with regulatory

authorities; Other requirements, as defined by local regulations. In some ICH regions, there might be a regulatory requirement to present within the Pharmacovigilance Plan an overview of the companys organisation and practices for conducting pharmacovigilance. In the absence of such a requirement, a statement that the companys routine pharmacovigilance practices include the elements outlined in the bulleted list above should be sufficient. Pharmacovigilance Planning 7 3.1.3 Action Plan for Safety Issues The Plan for each important safety issue should be presented and justified according to the following structure: Safety issue; Objective of proposed action(s); Action(s) proposed; Rationale for proposed action(s); Monitoring by the sponsor for safety issue and proposed action(s); Milestones for evaluation and reporting. Any protocols for specific studies can be provided in the CTD section 5.3.5.4 Other Clinical Study Reports or other sections as appropriate (e.g., Module 4 if the study is a non-clinical study). 3.1.4 Summary of Actions to be Completed, Including Milestones An overall Pharmacovigilance Plan for the product bringing together the actions for all individual safety issues should be presented. Whereas section 3.1.3 suggests presenting an action plan by ongoing safety issue, for this section the Pharmacovigilance Plan for the product should be organised in terms of the actions to be undertaken and their

milestones. The reason for this is that one proposed action (e.g., a prospective safety cohort study) could address more than one of the identified issues. It is recommended that milestones for completion of studies and other evaluations, and for submission of safety results, be included in the Pharmacovigilance Plan. In developing these milestones one should consider when: Exposure to the product will have reached a level sufficient to allow potential identification/characterisation of the AEs/ADRs of concern or resolution of a particular concern; and/or The results of ongoing or proposed safety studies are expected to be available. These milestones might be aligned with regulatory milestones (e.g., PSURs, annual reassessment and license renewals) and used to revise the Pharmacovigilance Plan. 3.2 Pharmacovigilance Methods The best method to address a specific situation can vary depending on the product, the indication, the population being treated and the issue to be addressed. The method chosen can also depend on whether an identified risk, potential risk or missing information is the issue and whether signal detection, evaluation or safety demonstration is the main objective of further study. When choosing a method to address a safety concern, sponsors should employ the most appropriate design. The Annex provides a summary of the key methods used in pharmacovigilance. This is provided to aid sponsors considering possible methods to address specific issues identified by the Safety Specification. This list is not all-inclusive, and sponsors should use the most up-to-date methods that are relevant and applicable. Pharmacovigilance Planning 8 3.2.1 Design and Conduct of Observational Studies Carefully designed and conducted pharmacoepidemiological studies, specifically

observational (non-interventional, non-experimental) studies, are important tools in pharmacovigilance. In observational studies, the investigator observes and evaluates results of ongoing medical care without 'controlling' the therapy beyond normal medical practice.1 Before the observational study that is part of a Pharmacovigilance Plan commences, a protocol should be finalised. Experts from relevant disciplines (e.g., pharmacovigilance experts, pharmacoepidemiologists and biostatisticians) should be consulted. It is recommended that the protocol be discussed with the regulatory authorities before the study starts. It is also suggested that the circumstances in which a study should be terminated early be discussed with regulatory authorities and documented in advance. A study report after completion, and interim reports if appropriate, should be submitted to the authorities according to the milestones within the Pharmacovigilance Plan. Study protocols should, as a minimum, include the study aims and objectives, the methods to be used, and the plan for analysis. The final study report should accurately and completely present the study objectives, methods, results, and the principal investigators interpretation of the findings. It is recommended that the sponsor follow good epidemiological practice for observational studies and also internationally accepted guidelines, such as the guidelines endorsed by the International Society for Pharmacoepidemiology.2 In some of the ICH regions, local laws and guidelines also apply to the design and conduct of observational studies and should be followed. The highest possible standards of professional conduct and confidentiality should always be maintained and any relevant national legislation on data protection followed. 1. Passive Surveillance

 Spontaneous Reports A spontaneous report is an unsolicited communication by healthcare professionals or consumers to a company, regulatory authority or other organisation (e.g., WHO, Regional Centres, Poison Control Centre) that describes one or more adverse drug reactions in a patient who was given one or more medicinal products and that does not derive from a study or any organised data collection scheme.1 Spontaneous reports play a major role in the identification of safety signals once a drug is marketed. In many instances, a company can be alerted to rare adverse events that were not detected in earlier clinical trials or other pre-marketing studies. Spontaneous reports can also provide important information on at-risk groups, risk factors, and clinical features of known serious adverse drug reactions. Caution should be exercised in evaluating spontaneous reports, especially when comparing drugs. The data accompanying spontaneous reports are often incomplete, and the rate at which cases are reported is dependent on many factors including the time since launch, pharmacovigilance-related regulatory activity, media attention, and the indication for use of the drug.2 3, , ,4 5 Systematic Methods for the Evaluation of Spontaneous Reports More recently, systematic methods for the detection of safety signals from spontaneous reports have been used. Many of these techniques are still in development and their usefulness for identifying safety signals is being evaluated. These methods include the calculation of the proportional reporting ratio, as well as the use of Bayesian and other techniques for signal detection6, ,7 8 . Data mining techniques have also been used to examine drug-drug interactions9

. Data mining techniques should always be used in conjunction with, and not in place of, analyses of single case reports. Data mining techniques facilitate the evaluation of spontaneous reports by using statistical methods to detect potential signals for further evaluation. This tool does not quantify the magnitude of risk, and caution should be exercised when comparing drugs. Further, when using data mining techniques, consideration should be given to the threshold established for detecting signals, since this will have implications for the sensitivity and specificity of the method (a high threshold is associated with high specificity and low sensitivity). Confounding factors that influence spontaneous adverse event reporting are not removed by data mining. Results of data mining should be interpreted with the knowledge of the weaknesses of the spontaneous reporting system and, more specifically, the large differences in the ADR reporting rate among different drugs and the many potential biases inherent in spontaneous reporting. All signals should be evaluated recognising the possibility of false positives. In addition, the absence of a signal does not mean that a problem does not exist. Case Series Series of case reports can provide evidence of an association between a drug and an adverse event, but they are generally more useful for generating hypotheses than for verifying an association between drug exposure and outcome. There are Pharmacovigilance Planning 10 certain distinct adverse events known to be associated more frequently with drug therapy, such as anaphylaxis, aplastic anemia, toxic epidermal necrolysis and

Stevens-Johnson Syndrome10,11 Therefore, when events such as these are . spontaneously reported, sponsors should place more emphasis on these reports for detailed and rapid follow-up. 2. Stimulated Reporting Several methods have been used to encourage and facilitate reporting by health professionals in specific situations (e.g., in-hospital settings) for new products or for limited time periods12 Such methods include on-line reporting of adverse events and . systematic stimulation of reporting of adverse events based on a pre-designed method. Although these methods have been shown to improve reporting, they are not devoid of the limitations of passive surveillance, especially selective reporting and incomplete information. During the early post-marketing phase, companies might actively provide health professionals with safety information, and at the same time encourage cautious use of new products and the submission of spontaneous reports when an adverse event is identified. A plan can be developed before the product is launched (e.g., through site visits by company representatives, by direct mailings or faxes, etc.). Stimulated adverse event reporting in the early post-marketing phase can lead companies to notify healthcare professionals of new therapies and provide safety information early in use by the general population (e.g., Early Post-marketing Phase Vigilance, EPPV in Japan). This should be regarded as a form of spontaneous event reporting, and thus data obtained from stimulated reporting cannot be used to generate accurate incidence rates, but reporting rates can be estimated. 3. Active Surveillance

Active surveillance, in contrast to passive surveillance, seeks to ascertain completely the number of adverse events via a continuous pre-organised process. An example of active surveillance is the follow-up of patients treated with a particular drug through a risk management program. Patients who fill a prescription for this drug may be asked to complete a brief survey form and give permission for later contact13 In general, it is . more feasible to get comprehensive data on individual adverse event reports through an active surveillance system than through a passive reporting system. Sentinel Sites Active surveillance can be achieved by reviewing medical records or interviewing patients and/or physicians in a sample of sentinel sites to ensure complete and accurate data on reported adverse events from these sites. The selected sites can provide information, such as data from specific patient subgroups, that would not be available in a passive spontaneous reporting system. Further, information on the use of a drug, such as abuse, can be targeted at selected sentinel sites14 Some . of the major weaknesses of sentinel sites are problems with selection bias, small numbers of patients, and increased costs. Active surveillance with sentinel sites is most efficient for those drugs used mainly in institutional settings such as hospitals, nursing homes, haemodialysis centres, etc. Institutional settings can have a greater frequency of use for certain drug products and can provide an infrastructure for dedicated reporting. In addition, automatic detection of abnormal laboratory values from computerized laboratory reports in certain Pharmacovigilance Planning 11

clinical settings can provide an efficient active surveillance system. Intensive monitoring of sentinel sites can also be helpful in identifying risks among patients taking orphan drugs. Drug Event Monitoring Drug event monitoring is a method of active pharmacovigilance surveillance. In drug event monitoring, patients might be identified from electronic prescription data or automated health insurance claims. A follow-up questionnaire can then be sent to each prescribing physician or patient at pre-specified intervals to obtain outcome information. Information on patient demographics, indication for treatment, duration of therapy (including start dates), dosage, clinical events, and reasons for discontinuation can be included in the questionnaire12 15 , , , 16 17 . Limitations of drug event monitoring can include poor physician and patient response rates and the unfocused nature of data collection, which can obscure important signals. In addition, maintenance of patient confidentiality might be a concern. On the other hand, more detailed information on adverse events from a large number of physicians and/or patients might be collected. Registries A registry is a list of patients presenting with the same characteristic(s). This characteristic can be a disease (disease registry) or a specific exposure (drug registry). Both types of registries, which only differ by the type of patient data of interest, can collect a battery of information using standardised questionnaires in a prospective fashion. Disease registries, such as registries for blood dyscrasias, severe cutaneous reactions, or congenital malformations can help collect data on drug exposure and other factors associated with a clinical condition. A disease

registry might also be used as a base for a case-control study comparing the drug exposure of cases identified from the registry and controls selected from either patients with another condition within the registry, or patients outside the registry. Exposure (drug) registries address populations exposed to drugs of interest (e.g., registry of rheumatoid arthritis patients exposed to biological therapies) to determine if a drug has a special impact on this group of patients. Some exposure (drug) registries address drug exposures in specific populations, such as pregnant women. Patients can be followed over time and included in a cohort study to collect data on adverse events using standardised questionnaires. Single cohort studies can measure incidence, but, without a comparison group, cannot provide proof of association. However, they can be useful for signal amplification, particularly for rare outcomes. This type of registry can be very valuable when examining the safety of an orphan drug indicated for a specific condition. Pharmacovigilance Planning 12 4. Comparative Observational Studies Traditional epidemiologic methods are a key component in the evaluation of adverse events. There are a number of observational study designs that are useful in validating signals from spontaneous reports or case series. Major types of these designs are crosssectional studies, case-control studies, and cohort studies (both retrospective and prospective)12,15 . Cross-Sectional Study (Survey) Data collected on a population of patients at a single point in time (or interval of time) regardless of exposure or disease status constitute a cross-sectional study.

These types of studies are primarily used to gather data for surveys or for ecological analyses. The major drawback of cross-sectional studies is that the temporal relationship between exposure and outcome cannot be directly addressed. These studies are best used to examine the prevalence of a disease at one time point or to examine trends over time, when data for serial time points can be captured. These studies can also be used to examine the crude association between exposure and outcome in ecologic analyses. Cross-sectional studies are best utilised when exposures do not change over time. Case-Control Study In a case-control study, cases of disease (or events) are identified. Controls, or patients without the disease or event of interest, are then selected from the source population that gave rise to the cases. The controls should be selected in such a way that the prevalence of exposure among the controls represents the prevalence of exposure in the source population. The exposure status of the two groups is then compared using the odds ratio, which is an estimate of the relative risk of disease in the two groups. Patients can be identified from an existing database or using data collected specifically for the purpose of the study of interest. If safety information is sought for special populations, the cases and controls can be stratified according to the population of interest (the elderly, children, pregnant women, etc.). For rare adverse events, existing large population-based databases are a useful and efficient means of providing needed drug exposure and medical outcome data in a relatively short period of time. Case-control studies are particularly useful when the goal is to investigate whether there is an association between a drug (or drugs) and one specific rare adverse event, as well as to identify risk factors for adverse events. Risk factors

can include conditions such as renal and hepatic dysfunction, that might modify the relationship between the drug exposure and the adverse event. Under specific conditions, a case-control study can provide the absolute incidence rate of the event. If all cases of interest (or a well-defined fraction of cases) in the catchment area are captured and the fraction of controls from the source population is known, an incidence rate can be calculated. Cohort Study In a cohort study, a population-at-risk for the disease (or event) is followed over time for the occurrence of the disease (or event). Information on exposure status is known throughout the follow-up period for each patient. A patient might be exposed to a drug at one time during follow-up, but non-exposed at another time point. Since the population exposure during follow-up is known, incidence rates Pharmacovigilance Planning 13 can be calculated. In many cohort studies involving drug exposure, comparison cohorts of interest are selected on the basis of drug use and followed over time. Cohort studies are useful when there is a need to know the incidence rates of adverse events in addition to the relative risks of adverse events. Multiple adverse events can also be investigated using the same data source in a cohort study. However, it can be difficult to recruit sufficient numbers of patients who are exposed to a drug of interest (such as an orphan drug) or to study very rare outcomes. Like case-control studies, the identification of patients for cohort studies can come from large automated databases or from data collected specifically for the study at hand. In addition, cohort studies can be used to examine safety issues in special populations (the elderly, children, patients with

co-morbid conditions, pregnant women) through over-sampling of these patients or by stratifying the cohort if sufficient numbers of patients exist. There are several automated databases available for pharmacoepidemiologic studies12, , 15 18 They include databases which contain automated medical records . or automated accounting/billing systems. Databases that are created from accounting/billing systems might be linked to pharmacy claims and medical claims databases. These datasets might include millions of patients. Since they are created for administrative or billing purposes, they might not have the detailed and accurate information needed for some research, such as validated diagnostic information or laboratory data. Although medical records can be used to ascertain and validate test results and medical diagnoses, one should be cognizant of the privacy and confidentiality regulations that apply to patient medical records. 5. Targeted Clinical Investigations When significant risks are identified from pre-approval clinical trials, further clinical studies might be called for to evaluate the mechanism of action for the adverse reaction. In some instances, pharmacodynamic and pharmacokinetic studies might be conducted to determine whether a particular dosing instruction can put patients at an increased risk of adverse events. Genetic testing can also provide clues about which group of patients might be at an increased risk of adverse reactions. Furthermore, based on the pharmacological properties and the expected use of the drug in general practice, conducting specific studies to investigate potential drug-drug interactions and food-drug interactions might be called for. These studies can include population pharmacokinetic studies and drug concentration monitoring in patients and normal volunteers.

Sometimes, potential risks or unforeseen benefits in special populations might be identified from pre-approval clinical trials, but cannot be fully quantified due to small sample sizes or the exclusion of subpopulations of patients from these clinical studies. These populations might include the elderly, children, or patients with renal or hepatic disorder. Children, the elderly, and patients with co-morbid conditions might metabolise drugs differently than patients typically enrolled in clinical trials. Further clinical trials might be used to determine and to quantify the magnitude of the risk (or benefit) in such populations. To elucidate the benefit-risk profile of a drug outside of the formal/traditional clinical trial setting and/or to fully quantify the risk of a critical but relatively rare adverse event, a large simplified trial might be conducted. Patients enrolled in a large simplified trial are usually randomized to avoid selection bias. In this type of trial, though, the Pharmacovigilance Planning 14 event of interest will be focused to ensure a convenient and practical study. One limitation of this method is that the outcome measure might be too simplified and this might have an impact on the quality and ultimate usefulness of the trial. Large, simplified trials are also resource-intensive. 6. Descriptive Studies Descriptive studies are an important component of pharmacovigilance, although not for the detection or verification of adverse events associated with drug exposures. These studies are primarily used to obtain the background rate of outcome events and/or establish the prevalence of the use of drugs in specified populations. Natural History of Disease The science of epidemiology originally focused on the natural history of disease,

including the characteristics of diseased patients and the distribution of disease in selected populations, as well as estimating the incidence and prevalence of potential outcomes of interest. These outcomes of interest now include a description of disease treatment patterns and adverse events. Studies that examine specific aspects of adverse events, such as the background incidence rate of or risk factors for the adverse event of interest, can be used to assist in putting spontaneous reports into perspective15 For example, an epidemiologic study can . be conducted using a disease registry to understand the frequency at which the event of interest might occur in specific subgroups, such as patients with concomitant illnesses. Drug Utilisation Study Drug utilisation studies (DUS) describe how a drug is marketed, prescribed, and used in a population, and how these factors influence outcomes, including clinical, social, and economic outcomes12 These studies provide data on specific . populations, such as the elderly, children, or patients with hepatic or renal dysfunction, often stratified by age, gender, concomitant medication, and other characteristics. DUS can be used to determine if a product is being used in these populations. From these studies denominator data can be developed for use in determining rates of adverse drug reactions. DUS have been used to describe the effect of regulatory actions and media attention on the use of drugs, as well as to develop estimates of the economic burden of the cost of drugs. DUS can be used to examine the relationship between recommended and actual clinical practice. These studies can help to determine whether a drug has the potential for drug

abuse by examining whether patients are taking escalating dose regimens or whether there is evidence of inappropriate repeat prescribing. Important limitations of these studies can include a lack of clinical outcome data or information of the indication for use of a product.