ICH GUIDELINES MULTIDISCIPLINARY

This slide describes about the ICH GUIDELINES ON MULTIDISCIPLINARY

1. ICH GUIDELINES MULTIDISCIPLINARY(M) Presented by C.Haribabu M.Pharm I Year, Pharmaceutics PSG college of pharmacy

2. INTRODUCTION The International Conference on Harmonisation(ICH) is a unique project that brings together the regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of product registration.

3. The ICH Topics are divided into four major categories and ICH Topic Codes are assigned according to these categories . Q S E M "Quality" i.e., those relating to chemical and Pharmaceutical Quality Assurance (Stability Testing, Impurity Testing, etc.) " Safety" i.e., those relating to in vitro and in vivo pre-clinical studies (Carcinogenicity Testing, Genotoxicity Testing, etc.) "Efficacy" i.e., those relating to clinical studies in human subject (Dose Response Studies, Good Clinical Practices, etc.) "Multidisciplinary” i.e., crosscutting Topics which do not fit uniquely into one of the above categories (MedDRA, ESTRI, M3, CTD, M5)

4. Multidisciplinary M1 -MedDRA Terminology M2 -Electronic Standards M3 -Non-clinical Safety Studies M4 -Common Technical Document M5 -Data elements & Standards for Drug dictionaries M6 -Gene Therapy M7 -Genotoxic Impurities M8 -Electronic common Technical Document (eCTD) M9 -Biopharmaceutics Classification System (BCS)-based Biowaivers M10- Bioanalytical method validation M11- Clinical electronic Structured Harmonised Protocol (CeSHarP) M12- Drug Interaction Studies M13 -Bioequivalence for Immediate-Release Solid Dosage Form

5. MedDRA Terminology(M1) MedDRA is a rich and highly specific standardised medical terminology developed by ICH to facilitate sharing of regulatory information internationally for medical products used by humans.  MedDRA was developed by the working group of ICH and is owned by the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) acting as trustee for the ICH steering committee The development of a Medical Dictionary for Regulatory Activities (MedDRA) was approved by the ICH Steering Committee in 1997, and the terminology was launched in 1999

6. It is used for registration, documentation and safety monitoring of medical products both before and after a product has been authorised for sale. Products covered by the scope of MedDRA include pharmaceuticals, vaccines and drug-device combination products. The current ICH M1 Points to Consider Working Group develops and maintains two documents on the use of MedDRA for data entry (coding) and data retrieval/analysis The latter includes guidance on the use of SMQs, Standardised MedDRA Queries , as powerful tools for assisting with safety signal detection. Both documents are updated twice a year , with every MedDRA release .

7. Electronic Standards for the Transfer of Regulatory Information (ESTRI)(M2) The M2 Expert Working Group (EWG) was established by the ICH Steering Committee in 1994 with the objective of facilitating international electronic communication by evaluating and recommending the specifications The first Specification developed by the M2 EWG was the Individual Case Safety Report (ICSR), created as the electronic message for the ICH E2B(R2 ) The second Specification developed by the M2 EWG was the Electronic Common Technical Document (eCTD) created as the electronic message for the CommonTechnical Document developed by the ICH M4 ICH development of specifications for electronic messages for the E2B(R2) ICH Guideline on Clinical Safety Data Management for Transmission of Individual Case Safety Reports, as well as the M4 Common Technical Document (CTD) In November 2010 , the ICH Steering Committee modified the mandate of the M2 EWG, which responsible for the evaluation and recommendation of standards

8. M3(R2): Guidance on Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals The present guidance represents the consensus that exists regarding the type and duration of nonclinical safety studies and their timing to support the conduct of human clinical trials and marketing authorization for pharmaceuticals . The nonclinical safety assessment for marketing approval of a pharmaceutical usually includes pharmacology studies , general toxicity studies, toxicokinetic and nonclinical pharmacokinetic studies, reproduction toxicity studies , genotoxicity studies and for drugs that have special cause for concern are intended for a long duration of use

9. The goals of the nonclinical safety evaluation generally include a characterisation of toxic effects with respect to target organs , dose dependence, relationship to exposure, and, when appropriate, potential reversibility This information is used to estimate an initial safe starting dose and dose range for the human trials and to identify parameters for clinical monitoring for potential adverse effects .

10. M4 Common Technical Document The agreement to assemble all the Quality, Safety and Efficacy information in a common format (called CTD - Common Technical Document ) has revolutionised the regulatory review processes , enabled implementation of good review practices . The Common Technical Document provides a harmonised structure and format for new product applications. The Common Technical Document was agreed upon in November 2000 in San Diego, USA This Common Technical Document is divided into four separate sections. The four sections address the application organisation (M4 organise), the Quality section (M4Q), the Safety section (M4S) and the Efficacy section (M4E) of the harmonised application

11. QUALITY SECTION(M4Q) The Quality section of the Common Technical Document (M4Q) provides a Harmonised structure and format for presenting CMC (Chemistry, Manufacturing and Controls ) information in a registration dossier. The table of contents includes sections on Drug Substance and Drug Product. A new section on Pharmaceutical Development has been included to replace the Development Pharmaceutics Report (currently a part of the EU submission requirements). Also, a new CMC summary document, the Quality Overall Summary, has been developed.

12. SAFETY SECTION M4S(R2) The CTD Safety (M4S) Guideline delineates the structure and format of the nonclinical summaries in Module 2 of the Common Technical Document, and provides the organisation of Module 4, the Nonclinical Study Reports. The Nonclinical Overview should present an integrated and critical assessment of the pharmacologic, pharmacokinetic, and toxicologic evaluation of the pharmaceutical, and generally should not exceed 30 pages . The Nonclinical Written Summaries (100 - 150 pages ) are recommended to provide more extensive summaries and discussion of the nonclinical information on pharmacology, pharmacokinetics and toxicology

13. EFFICACY SECTION M4E(R2) CTD Efficacy (M4E) describes the structure and format of the clinical data in an application, including summaries and detailed study reports. There are two high level clinical summaries in Module 2 of the CTD: the Clinical Overview , a short document that provides a critical assessment of the clinical data ; and the Clinical Summary , a longer document that focuses on data summarisation and integration . Clinical Study Reports and raw data (where applicable) are included in Module 5 of the CTD.

14. M4 COMMON TECHNICAL DOCUMENT

15. M5: Data Elements and Standards for Drug Dictionaries This document provides guidance on the harmonized standards related to core sets of medicinal product information and medicinal product terminology. Facilitate the exchange and practical use of medicinal product data by regulators and pharmaceutical industry. In particular, a need was identified to harmonise product information that would facilitate the electronic exchange of Individual Case Safety Reports (ICSRs) within and across ICH regions using the ICH E2B format in post-marketing pharmacovigilance.

16. M6 GENE THEARPY VIRUS AND GENE THERAPY VECTOR SHEDDING This new topic was endorsed by the ICH Steering Committee in September 2009. In September 2009, following the finalisation by the ICH Gene Therapy Discussion Group (GTDG) of the ICH Consideration document “General Principles to Address Virus and Vector Shedding” The ICH Steering Committee endorsed the development of an ICH Guideline on this topic with the aim of providing more extensive information to improve harmonisation amongst the ICH regions . This new topic was subsequently assigned the code “ M6” . In April 2011, this topic was ceased following the ICH Steering Committee discussion .

17. M7 MUTAGENIC IMPURITIES M7(R1) ASSESSMENT AND CONTROL OF MUTAGENIC IMPURITIES IN PHARMACEUTICALS TO LIMIT POTENTIAL CARCINOGENIC RISK The ICH M7 Guideline was finalised in 2014 offering guidance on analysis of Structure Activity Relationships (SAR) for genotoxicity. It is intended to resolve questions such as whether impurities with similar alerts that potentially have similar mechanism of action should not be combined in calculating a Threshold of Toxicological Concern (TTC) and whether the TTC may differ based on differences in the approved duration of use. The intent of this Addendum is to provide useful information regarding the acceptable limits of known mutagenic impurities/carcinogenic and supporting monographs

18. M7(R2) ASSESSMENT AND CONTROL OF MUTAGENIC IMPURITIES IN PHARMACEUTICALS TO LIMIT POTENTIAL CARCINOGENIC RISK The M7(R2) Maintenance EWG is currently undertaking a maintenance of the M7(R1) Guideline to incorporate acceptable limits (Acceptable Intakes (AIs) or Permitted Daily Exposures (PDEs)) for new DNA reactive (mutagenic) impurities and revising acceptable limits for impurities already listed in the Addendum as new data becomes available, which will result in the future ICH M7(R2) version. As a result, Q&As will be developed to clarify and address Quality and Safety issues and concerns that have been identified from experience through implementation of M7 since its publication in 2014 .

19. M8 ELECTRONIC COMMON TECHNICAl DOCUMENT(eCTD ) An electronic version of the Common Technical Document (eCTD) developed by the eCTD Implementation Working Group. The Electronic Common Technical Document (eCTD) allows for the electronic submission of the Common Technical Document (CTD ) by an applicant to regulator . Implemented 6 months behind CTD on May 2001 , Tokyo, Step 2 of the eCTD ICH process was agreed by Multidisciplinary Group 2 Expert Working Group (ICH M2 EWG). Specifications developed by ICH M2 EWG Maintained by eCTD IWG

20. M9 Biopharmaceutics Classification System (BCS)-based biowaivers . This topic was endorsed by the ICH Assembly in October 2016 . This new multidisciplinary Guideline is proposed to address Biopharmaceutics Classification System (BCS)-based biowaivers . BCS-based biowaivers may be applicable to BCS Class I and III drugs , however BCS-based biowaivers for these two classes are not recognised worldwide. This Guideline applies to the systems supporting the development and manufacture of pharmaceutical drug substances and drug products, including biotechnology and biological products This Guideline will provide recommendations to support the biopharmaceutics classification of medicinal products and will provide recommendations to support the waiver of bioequivalence studies

21. M10 BIOANALYTICAL METHOD VALIDATION This topic was endorsed by the ICH Management Committee in October 2016. This new multidisciplinary guideline will apply to the validation of bioanalytical methods and study sample analyses in non-clinical and clinical studies. This guideline will provide recommendations on the scientific regulatory requirements for bioanalysis conducted during the development of drugs of both chemical and biological origins. It will also address issues on method validation by considering the characteristics of the analytical methods used in bioanalysis, e.g., chromatographic assay and ligand binding assay .

22. RECENT GUIDELINES ON MULTIDISCIPLINARY M11- Clinical electronic Structured Harmonised Protocol (CeSHarP)- NOV 2018 M12- Drug Interaction Studies- JUNE 2018 M13 -Bioequivalence for Immediate-Release Solid Dosage Form- NOV 2019