1. ByMd gayasuddinM.Pharm (pharmacology)MNR college of pharmacy

2. Contents introduction ICH objectives ICH Organizational structure ICH Harmonisation process ICH Work Product ICH Guidelines 3. introduction 4. What does ICH stands for? The complete name of ICH is the "International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use". 5. What is ICH ? ICH is a joint initiative involving both regulators andresearch-based industry representatives of theEuropean Union, Japan and the USA in scientific andtechnical discussions of the testing proceduresrequired to assess and ensure the safety, quality andefficacy of medicines. 6. What is the goal of ICH ? The goal of ICH is to promote international harmonizationby bringing together representatives from the three ICHregions (EU, Japan and USA) to discuss and establishcommon guidelines. Another goal of ICH is to make information available onICH, ICH activities and ICH guidelines to any country orcompany that requests the information, and to promote amutual understanding of regional initiatives in order tofacilitate harmonisation processes related to ICHguidelines regionally and globally, and to strengthen thecapacity of drug regulatory authorities and industry toutilise them. The ICH Global Cooperation Group (GCG) was formed in1999 and is charged with this task. 7. ICH objectives The objective of ICH is to increase international harmonisation of technical requirements to ensure that safe, effective, and high quality medicines are developed and registered in the most efficient and cost-effective manner. These activities have been undertaken to promote public health, prevent unnecessary duplication of clinical trials in humans, and minimize the use of animal testing without compromising safety and effectiveness. 8. ICH Organisational StructureThe ICH structure consists of the ICH Steering Committee, ICH Coordinators, ICH Secretariat and ICH Working Groups. The ICH Global Cooperation Group (GCG) and theICH MedDRA Management Board are sub-committeesof the ICH Steering Committee. 9. Steering committee The Steering Committee is the body that governs the ICH, determines the policies and procedures for ICH, selects topics for harmonisation and monitors the progress of harmonisation initiatives. Each of the six ICH parties has two seats on the ICH Steering Committee. Each of the Observers nominates non- voting participants to attend the ICH Steering Committee Meetings. IFPMA also participates as a non-voting member. 10. The Coordinators The Coordinators are fundamental to the smoothrunning of the ICH and are nominated by each of thesix parties. An ICH Coordinator acts as the main contact pointwith the ICH Secretariat. Due to structural differenceswithin the EU and MHLW, ICH Technical Coordinators are also designated fromthe EMA and PMDA respectively. 11. The ICH SecretariatThe Secretariat operates from the IFPMA offices, in Geneva, and isprimarily concerned with preparations for, and documentation of,meetings of the Steering Committee.At the time of ICH Conferences, the Secretariat is responsible for thetechnical documentation and for liaison with the speakers for theConference. 12. Working GroupsSAFETYEFFICACYQUALITY MULTIDISCIPLINARYSTEERING COMMITTEEEndorses topics, guidelines and monitors progress 13. Global Cooperation Group (GCG) The ICH Global Cooperation Group (GCG) was formedon March 11, 1999, as a subcommittee of the ICHSteering Committee. It is made up of one representative from each of the sixparties on the ICH Steering Committee, plus theIFPMA. The ICH Observers, WHO, Canada and EFTA are alsopart of the GCG. 14. Members of ICH ICH is comprised of representatives from six parties that represent theregulatory bodies and research-based industry in the European Union,Japan and the USA. In Japan, the members are the Ministry of Health, Labour and Welfare(MHLW), and the Japan Pharmaceutical Manufacturers Association(JPMA). In Europe, the members are the European Union (EU), and the EuropeanFederation of Pharmaceutical Industries and Associations (EFPIA). In the USA, the members are the Food and Drug Administration (FDA),and the Pharmaceutical Research and Manufacturers of America(PhRMA). Additional members include Observers from the World HealthOrganization (WHO), European Free Trade Association (EFTA), andCanada. This important group of non-voting members represent non-ICHcountries and regions. The International Federation of Pharmaceutical Manufacturers &Associations (IFPMA) has been closely involved with ICH since itsinception and participates as a non-voting member. 15. ICH parties The ICH Parties are the founding members of ICH and represent the regulatory bodies and research-based industry in the EU, US and Japan. 16. ICH parties6 parties EU EFPIA (European federation of pharmaceutical industries associations)MHLW (Ministry of health, Labor and welfare, Japan) JPMA (Japan Pharmaceuticals manufacturers Association) US FDA PhRMA Observers : WHO, TPP(canada) International federation of Pharmaceutical manufacturersassociation 17. The ObserversThe ICH Observers include the European Free Trade Association (EFTA) -currently represented by Swiss medic (Swiss Agencyfor Therapeutic Products), Health Canada and World Health Organization(WHO). The Observers have been associated with the ICHprocess from the beginning to act as a link with non-ICH countries and regions. 18. ICH Harmonisation Process The ICH Steering Committee is responsible for the governanceof ICH. This includes deciding on the adoption of every ICHproject, whether a new topic, maintenance of an existingGuideline, or a specific implementation work. Each harmonisation activity is initiated by a Concept Paperwhich is a short summary of the proposal. Depending on thecategory of harmonisation activity a Business Plan may also berequired. Any ICH Party or Observer is welcomed to submit a proposal fora new ICH activity. The ICH Steering Committee decides on the adoption of everyICH project and then endorses the creation of an EWG/IWG. ICH harmonisation activities fall into 4 categories: Formal ICHProcedure, Q&A Procedure, Revision Procedure andMaintenance Procedure. 19. Process of Harmonisation 20. Steps of ICH 21. 5 Steps in the ICH process Consensus building Rapporteur prepares initial draft of a guideline/rcommendation for comment with fixed deadline for comment (fax, e-mail). Interim report made to SC meeting, if consensus is reached, sign-off - all members Start of regulatory action Wide ranging regulatory consultation EU: published as a draft CPMP guideline; US: published as a draft guidance in the Federal Register; Japan: translated & issued by MHLW for internal and external consultation. A Regulatory Rapporteur is dessignated to draw up the final document and sign-off Adoption of a tripartite harmonised text Both regulatory and industry parties of SC must be satisfied. Adoption takes place on the signatures from the 3 regulatory parties to ICH, affirming that the Guideline is recommended for adoption by the 3 regulatory bodies Implementation 22. ICH Products ICH has developed over 50 harmonised Guidelines aimed at eliminating duplication in the development and registration process, so that a single set of studies can be generated to demonstrate the quality, safety and efficacy of a new medicinal product. Quality-21 Guidelines Safety -14 Guidelines Efficacy -20 Guidelines Multidisciplinary -5 Guidelines Electronic Standards for the Transfer of Regulatory Information (ESTRI,E2B) Common Technical Document (CTD & eCTD) Medical dictionary for adverse event reporting and coding of clinicaltrial data (MedDRA) Considerationdocuments 23. ICH GuidelinesThe ICH Topics are divided into four major categories and ICH TopicCodes are assigned according to these categories. QSE M"Quality" Topics,"Safety" Topics, "Efficacy" Topics, "Multidisciplinary"i.e., those relating i.e., those relating i.e., those relating Topics, i.e., cross-to chemical andto in vitro and in to clinical studiescutting Topicspharmaceutical vivo pre-clinicalin human subject which do not fitQualitystudies(Dose Response uniquely into oneAssurance(Carcinogenicity Studies, Goodof the above(Stability Testing,Testing, Clinical Practices,categoriesImpurity Testing,Genotoxicity etc.)(MedDRA,etc.)Testing, etc.)ESTRI, M3, CTD, M5) 24. Safety Guidelines ICH has produced a comprehensive set of safety guidelines to uncover potential risks like carcinogenicity, genotoxicity and reprotoxicity. A recent breakthrough has been a non-clinical testing strategy for assessing the QT interval prolongation liability: the single most important cause of drug withdrawals in recent years. 25. ICH GUIDELINES ON SAFETY OF ANIMALS S1A Guideline on the Need for Carcinogenicity Studies ofPharmaceuticals Nov. 1995 S1B Testing for Carcinogenicity of Pharmaceuticals July 1997 S1C(R2) Dose Selection for Carcinogenicity Studies ofPharmaceuticals Mar. 2008 S2(R1) Guidance on Genotoxicity Testing and DataInterpretation for Pharmaceuticals Intended for Human Use Nov. 2011 S3A Note for Guidance on Toxicokinetics: The Assessment ofSystemic Exposure in Toxicity Studies Oct. 1994 S3B Pharmacokinetics: Guidance for Repeated Dose TissueDistribution Studies Oct. 1994 S4 Duration of Chronic Toxicity Testing in Animals (Rodentand Non Rodent Toxicity Testing) Sept. 1998 26. S5(R2) Detection of Toxicity to Reproduction forMedicinal Products and Toxicity to Male Fertility June1993 S6(R1) Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals June 2011 S7A Safety Pharmacology Studies for HumanPharmaceuticals Nov. 2000 S7B The Non-clinical Evaluation of the Potential forDelayed Ventricular Repolarization (QT IntervalProlongation) by Human Pharmaceuticals May 2005 S8 Immunotoxicity Studies for Human PharmaceuticalsSept. 2005 S9 Nonclinical Evaluation for AnticancerPharmaceuticals Oct. 2009 S10 Photo safety Evaluation Nov. 2012 27. S1A (Nov. 1995) Need for Carcinogenicity Studies of Pharmaceuticals This document provides a consistent definition of thecircumstances under which it is necessary to undertakecarcinogenicity studies on new drugs. Theserecommendations take into account the known risk factorsas well as the intended indications and duration ofexposure. Results from genotoxicity studies, toxicokinetics, andmechanistic studies can now be routinely applied inpreclinical safety assessment. 28. S1B (July 1997) Testing for Carcinogenicity of Pharmaceuticals Guidance on the need to carry out carcinogenicity studiesin both mice and rats, and guidance is also given onalternative testing procedures which may be appliedwithout jeopardizing safety. 29. S1C-R2 (March 2008) Dose Selection for Carcinogenicity Studies ofPharmaceuticals addresses the criteria for the selection of the high dose to beused in carcinogenicity studies on new therapeutic agents toharmonise current practices and improve the design of studies. the pharmacokinetic endpoint of 25 is declared to be applicablealso for pharmaceuticals with positive genotoxicity signals. This change has implications on reducing the pain or discomfortof the animals at the maximally tolerated dose (MTD). 30. S2-R1 (March 2008) Guidance On Genotoxicity Testing And Data Interpretation ForPharmaceuticals Intended For Human Use S2A: Guidance on Specific Aspects of Regulatory GenotoxicityTests for Pharmaceuticals :specific guidance and recommendationsfor in vitro and in vivo tests and on the evaluation of test results. Itincludes a glossary of terms related to genotoxicity tests to improveconsistency in applications. S2B: Genotoxicity: A Standard Battery for Genotoxicity Testingfor Pharmaceuticals; the identification of a standard set of assays tobe conducted for registration, and the extent of confirmatoryexperimentation in any particular genotoxicity assay in the standardbattery. 31. S3A (Oct. 1994) Note For Guidance On Toxicokinetics:The Assessment Of Systemic Exposure In ToxicityStudies gives guidance on developing test strategies intoxicokinetics and the need to integrate pharmacokineticsinto toxicity testing, in order to aid in the interpretation ofthe toxicology findings and promote rational study designdevelopment. 32. S3B (Oct. 1994) Pharmacokinetics: Guidance For Repeated DoseTissue Distribution Studies This study is required when appropriate data cannot bederived from other sources A comprehensive knowledge of the absorption,distribution, metabolism and elimination of a compound isimportant for the interpretation of pharmacology andtoxicology studies. useful for designing toxicology and pharmacology studies 33. S4 (Sep. 1998) Duration Of Chronic Toxicity Testing In Animals(Rodent And Non Rodent Toxicity Testing) safety evaluation of a medicinal product for the development of medicinal products with theexception of those already covered by the ICH Guideline onSafety Studies for Biotechnological Products, e.g.,Monoclonal antibodies, recombinant DNA proteins. 34. S5-R2 (Nov. 2000) Detection Of Toxicity To ReproductionFor Medicinal Products & Toxicity To Male Fertility This document provides guidance on tests for reproductivetoxicity. It defines the periods of treatment to be used inanimals to better reflect human exposure to medicalproducts and allow more specific identification of stages atrisk 35. S6 (Oct. 2009) Addendum To Ich S6: Preclinical Safety Evaluation OfBiotechnology-derived Pharmaceuticals It addresses the use of animal models of disease,determination of when genotoxicity assays andcarcinogenicity studies should be performed, and theimpact of antibody formation on duration of toxicologystudies Clarification on species selection, study design,immunogenicity, reproductive and developmental toxicityand assessment of carcinogenic potential. 36. S7A (Nov. 2000) Safety Pharmacology Studies for HumanPharmaceuticals addresses the definition, objectives and scope of safetypharmacology studies also addresses which studies are needed before initiation ofPhase 1 clinical studies as well as information needed formarketing. 37. S7B (May 2005) The Non-clinical Evaluation Of The Potential ForDelayed Ventricular Repolarization (Qt IntervalProlongation) By Human Pharmaceuticals This Guideline describes a non-clinical testing strategy forassessing the potential of a test substance to delayventricular repolarization. Includes non-clinical assays and integrated riskassessments 38. S8 (Sep. 2005) Immunotoxicity Studies for Human Pharmaceuticals addresses the recommendations on nonclinical testing forimmunosuppression induced by low molecular weightdrugs (non-biologicals and how each immunotoxicitystudy should be performed It applies to new pharmaceuticals intended for use inhumans, as well as to marketed drug products proposed fordifferent indications or other variations on the currentproduct label in which the change could result inunaddressed and relevant toxicologic issues Also applicable during CT and following approval tomarket. 39. S9 (Oct. 2009) Nonclinical Evaluation for AnticancerPharmaceuticals provides information for pharmaceuticals that are onlyintended to treat cancer in patients with late stage oradvanced disease regardless of the route of administration,including both small molecule and biotechnology-derivedpharmaceuticals. It describes the type and timing ofnonclinical studies in relation to the development ofanticancer pharmaceuticals and references other guidanceas appropriate. 40. S10 (June 2010) Photosafety Evaluation of Pharmaceuticals This new Guideline on photosafety testing will be avaluable adjunct to the guidance provided in the M3(R2)Guideline. 41. ICH-E Guidelines 42. Efficacy Guidelines The work carried out by ICH under the Efficacy heading is concerned with the design, conduct, safety and reporting of clinical trials. It also covers novel types of medicines derived from biotechnological processes and the use of pharmacogenetics/ pharmacogenomics techniques to produce better targeted medicines. 43. Efficacy Guidelines Clinical Safety E1-E2F Clinical Study Reports E3 Dose Response Studies E4 Ethnic Factors E5 Good Clinical Practice E6 Clinical Trials E7-E11 Guidelines for Clinical Evaluation by Therapeutic CategoryE12 Clinical Evaluation E14 Pharmacogenomics E15-E16 Joint Safety / Efficacy Topic M3 44. E1 (Oct. 1994) E1 The Extent Of Population Exposure To Assess Clinical SafetyFor Drugs Intended For Long-term Treatment Of Non-life-threatening Conditions The tripartite harmonized ICH Guideline was finalised under Step 4 inOctober 1994. This document gives recommendations on the numbersof patients and duration of exposure for the safety evaluation of drugsintended for the long-term treatment of non-life-threateningconditions. Events where the rate of occurrence changes over a longer period oftime may need to be characterized depending on their severity andimportance to the risk-benefit assessment of the drug. The safety evaluation during clinical drug development is not expectedto characterise rare adverse events, for example, those occurring in lessthan 1 in 1000 patients. 45. E2A (Oct. 1994) Clinical Safety Data Management: Definitions AndStandards For Expedited Reporting E2A There are two issues within the broad subject of clinical safety datamanagement that are appropriate for harmonization at this time: (1) the development of standard definitions and terminology for keyaspects of clinical safety reporting, and (2) the appropriate mechanism for handling expedited (rapid)reporting, in the investigational (i.e., pre-approval) phase. 46. E2B-R2 (Feb. 2001) Maintenance Of The ICH Guideline On Clinical Safety Data Management : Data Elements For Transmission Of Individual Case Safety Reports E2B(R2) to standardize the data elements for transmission of individual case safety reports by identifying, and where necessary or advisable, by defining the data elements for the transmission of all types of individual case safety reports, regardless of source and destination. 47. E2C-R1(Nov. 1996) Clinical Safety Data Management: Periodic Safety UpdateReports for Marketed Drugs E2C (R1) guidance on the format and content of safety updates, which need tobe provided at intervals to regulatory authorities after products havebeen marketed. The Guideline is intended to ensure that the worldwidesafety experience is provided to authorities at defined times aftermarketing with maximum efficiency and avoiding duplication of effort. E2C(R2) This Revision was endorsed by Steering Committee inDec.2010. It will Evaluate the ICH Pharmacovigilance documentation,conduct a gap and potential improvement analysis of ECH E2C, E2Eand E2F and draft a new ICH E2C R2 covering periodic benefic riskevaluation reporting. 48. E2D (Nov. 2003) Post Approval Safety Data Management: Definitionsand Standards for Expedited Reporting provides a standardized procedure for post-approval safetydata management including expedited reporting torelevant authority. The definitions of the terms and concept specific to post-approval phase are also provided. 49. E2E (Nov. 2004) Pharmacovigilance Planning planning of pharmacovigilance activities, especially inpreparation for the early post marketing period of a newdrug (chemical entities, biotech-derived products,vaccines) Main focus: Safety specification and PV plan that mightybe submitted at the time of license application 50. E2F (Aug. 2010) Development Safety Update Report The main focus of the DSUR is data from interventionalclinical trials (referred to in this document as "clinicaltrials") of investigational drugs including biologicals, withor without a marketing approval, whether conducted bycommercial or non-commercial sponsors. Intended for periodic reporting on drugs underdevelopment (including marketed drugs that are underfurther study) among the ICH regions. 51. E3 (Nov. 1995) Structure and Content of Clinical Study Reports is an "integrated" full report of an individual study of any therapeutic,prophylactic or diagnostic agent (referred to herein as drug ortreatment) conducted in patients, in which the clinical and statisticaldescription, presentations, and analyses are integrated into a singlereport, incorporating tables and figures into the main text of thereport, or at the end of the text, and with appendices containing theprotocol, sample case report forms, investigator related information,information related to the test drugs/investigational productsincluding active control/comparators, technical statisticaldocumentation, related publications, patient data listings, andtechnical statistical details such as derivations, computations, analyses,and computer output etc. 52. E4 (March, 1994) Dose-responseInformationToSupport DrugRegistration Knowledge of the relationships among dose, drug-concentration in blood, and clinical response (effectivenessand undesirable effects) is important for the safe andeffective use of drugs in individual patients. concepts of minimum effective dose and maximum usefuldose do not adequately account for individual differencesand do not allow a comparison, at various doses, of bothbeneficial and undesirable effects. Any given dose provides a mixture of desirable andundesirable effects, with no single dose necessarily optimalfor all patients. 53. E5 R1 (Feb. 1998) Ethnic Factors In The Acceptability Of Foreign ClinicalData This document addresses the intrinsic characteristics of thedrug recipient and extrinsic characteristics associated withenvironment and culture that could affect the results ofclinical studies carried out in regions and describes theconcept of the "bridging study" that a new region mayrequest to determine whether data from another region areapplicable to its population. 54. E6-R1 (May 1996) Good Clinical Practice describes the responsibilities and expectations of allparticipants in the conduct of clinical trials, includinginvestigators, monitors, sponsors and IRBs. GCPs cover aspects of monitoring, reporting and archivingof clinical trials and incorporating addenda on theEssential Documents and on the Investigators Brochurewhich had been agreed earlier through the ICH process. 55. E7 (June 1993) Studies in Support of Special Populations: Geriatrics This document provides recommendations on the specialconsiderations which apply in the design and conduct ofclinical trials of medicines that are likely to have significantuse in the elderly. It requires special consideration due to the frequentoccurrence of underlying diseases, concomitant drugtherapy and the consequent risk of drug interaction. 56. E8 (July 1997) General Considerations for Clinical Trials This document sets out the general scientific principles forthe conduct, performance and control of clinical trials. The Guideline addresses a wide range of subjects in thedesign and execution of clinical trials. 57. E9 (Feb. 1998) Statistical Principles for Clinical Trials Thisbiostatistical Guideline describesessentialconsiderations on the design and analysis of clinical trials,especially the "confirmatory" (hypothesis-testing) trialsthat are the basis for demonstrating effectiveness. The document will also assist scientific experts chargedwith preparing application summaries or assessingevidence of efficacy and safety, principally from clinicaltrials in later phases of development. 58. E10 (July 2000) Choice of Control Group and Related Issues in Clinical Trials This document addresses the choice of control groups in clinical trials considering the ethical and inferential properties and limitations of different kinds of control groups. It points out the assay sensitivity problem in active control equivalence / non-inferiority trials that limits the usefulness of trial design in many circumstances. 59. E11 (July 2000) Clinical Investigation of Medicinal Products in thePediatric Population This document addresses the conduct of clinical trials ofmedicines in pediatric populations. This document willfacilitate the development of safe and effective use ofmedicinal product in pediatrics. 60. E12 (March 2000) Principlesfor Clinical Evaluation ofNewantihypertensive Drugs It provides a set of "Principles" on which there is generalagreement among all three ICH regions covering endpointsand trial designs. It will not be subject to the usual procedures leading to afully harmonized document. 61. E14 (May 2005) The Clinical Evaluation of QT/QTc Interval Prolongation andProarrhythmic Potential for Non-Antiarrhythmic Drugs. This document provides recommendations to sponsors concerning thedesign, conduct, analysis, and interpretation of clinical studies toassess the potential of a drug to delay cardiac repolarisation. This assessment should include testing the effects of new agents on theQT/QTc interval as well as the collection of cardiovascular adverseevents. The investigational approach used for a particular drug shouldbe individualised,dependingonthepharmacodynamic,pharmacokinetic, and safety characteristics of the product, as well ason its proposed clinical use. The assessment of the effects of drugs on cardiac repolarisation is thesubject of active investigation. When additional data (non-clinical and clinical) are accumulated inthe future, this document may be reevaluated and revised. 62. E15 (Nov. 2007) Definitions For Genomic Biomarkers, Pharmaco- genomics, Pharmacogenetics, Genomic Data And Sample Coding Categories Pharmacogenomics and pharmacogenetics have the potential to improve the discovery, development and use of medicines. 63. E16 (Aug. 2010) Biomarkers Related To Drug Or Biotechnology Product Development: Context, Structure And Format Of Qualification Submissions The Guideline describes recommendations regarding context, structure, and format of regulatory submissions for qualification of genomic biomarkers, as defined in ICH E15. 64. M3 R2 (June 2009) Guidance On Non-clinical Safety Studies For The Conduct Of Human Clinical Trials And Marketing Authorization For Pharmaceuticals Harmonisation of the guidance for non-clinical safety studies will help to define the current recommendations and reduce the likelihood that substantial differences will exist among regions. 65. Thank you