•E1: Exposure
•E2: Clinical Safety
E2A, E2B(M), EM2,
E2C
•E3: Study Reports
•E4 Dose Response
•• E5: Ethnic Factors E5: Ethnic Factors
•E6: GCP
E7: Special Populations
•E8,9,10: CT Design
•E11: Pediatrics
•E12: Evaluation by Therapeutic Categories
E1: Exposure
Objective:
•To present an accepted set of principles for the safety evaluation of drugs intended for the long-term treatment of non-life-threatening diseases.
E1: Exposure (cont.)
General Agreement:
1.Agree on a harmonisedregulatory standard, but also provide exceptions.
2.Regulatory standards for safety evaluation should be based on ADE-related experiences, statistical consideration and practical considerations.
3.If ADE occurrence information is incomplete, further investigation will be useful.
4.No. of patients treated for 6 months at dosage levels intended for clinical use should be adequate to characterisepattern of ADEsover time.
5.In the absence of more information about relationship of ADEsto treatment duration, selection of a specific no. of patients (100 patients) to be followed for 1 year can be judged based on probability of detecting a given ADE frequency level and practical consideration.
6.Total number of individuals treated with the investigational drug, including short-term exposure, will be about 1500.
7.Followings are reasons where, in many circumstances, the harmonisedgeneral standards are not applicable:
a.Late developing ADEsor DEsthat increase in severity or frequency over time;
b.A need to quantitatethe occurrence rate of an expected specific low-frequency ADE will require a greater long-term data base.
c.Larger safety data bases may be needed to make risk/benefit decisions in situations where the benefit from the drug is either small or experienced by only a fraction of the patients or is of uncertain magnitude.
d.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.
e.A smaller number of patients may be accepted.
8.In general filing of approval usually be possible based on data from patients treated through 6 months.
E2: Clinical Safety
E2A: Definitions and Standards for Expedited Reporting
E2B: Data Elements for Transmission of ADR Reports (Maintenance) including M2
E2C: Periodic Safety Update Reports
E2A: Definitions and Standards for Expedited Reporting
Objective:
Agreed definitions and terminology, as well as procedures, will ensure uniform Good Clinical Practice standards in this area.
E2A: Definitions and Standards for Expedited Reporting
Objective:
Agreed definitions and terminology, as well as procedures, will ensure uniform Good Clinical Practice standards in this area.
•Definitions and Terminology
–Basic terms: AE, ADR, Unexpected ADR
–Serious AE: death, life-threatening, etc.
–Expectedness of an ADR
•Standards for Expedited Reporting
–What should be reported: ADR, unexpected ADR…
–Reporting time frame: Death, life-threatening: ASAP, w/n 7 days; Other: w/n 15 days; Minimum criteria for reporting
–How to report
–Managing Blinded Therapy Cases
–Misc: reactions assoc. w/ active comparator/placebo treatment, products w/ more than one presentation or use
E2B(M): Data Elements for Transmission of ADR Reports (Maintenance) including M2
Objectives:
•To standardize data elements for transmission of individual case safety reports, regardless of source and destination.
•Maintenance of the Electronic Transmission of Individual Case safety reports message specification.
•Guideline Content of Data Elements
A.Administrative and Identification Information:
•Identification of the report, source of information, sender and receiver
B.Information on the Case
•Patient characteristics, reactions, test result, drug information, case summary
EM2: Electronic Transmission of Individual Case Safety Reports Message Specification
•There is need for an electronic format capable of accommodating direct database to database transmission using message transfers in the worldwide exchange of information.
•To be successful, the information transmission relies on definition of common data elements, and standard transmission procedures (information transfer over internet and electronic document) to be specified by the ICH Electronic Standards for the Transfer of Regulatory Information Expert Working Group (M2).
Some concerns about E2B(M) E5 & E12
•E2B(M) requires specific equipment to handle electronic data & document transfer which is too early to apply between ASEAN countries.
•E12 is considered as “ICH Principle Document”rather than a guideline.
•E5 (Ethnic factor) is excluded since BALI’s Meeting
E2C: Periodic Safety Update Reports for Marketed Drug
Objective:
•To avoid duplication of effort and to ensure that important data are submitted with consistency to regulatory authorities in different markets
Means:
•Develop Scope of the Guideline on format and content of periodic safety update reports
E2C: Periodic Safety Update Reports for Marketed Drug•Model for a Periodic Safety Update Report (PSUR)–Title page–Table of Contents•Introduction•Worldwide market authorization status•Update of regulatory authority actions taken for safety reasons•Changes to Reference Product Information•Patient Exposure•Presentation of Individual Case Histories•Studies•Other Information•Overall Safety Evaluation•Conclusion•Appendix: Company Core Data Sheet
E3: Structure and Content of Clinical Study Reports
Objectives:
•To allow the compilation of a single core clinical study report acceptable to all regulatory authorities of the ICH regions
•Assist sponsors in the development of a report that is complete, free from ambiguity, well organisedand easy to review
E3: Structure and Content of Clinical Study Reports (cont.)
1.Title page2.Synopsis3.Table of Contents for individual clinical study report4.List of abbreviations and definition of terms5.Ethics6.Investigators and study administrative structure7.Introduction8.Study Objectives9.Investigational Plan (indetails)10.Study Patients11.Efficacy Evaluation12.Safety Evaluation13.Discussion & Overall Conclusions14.Tables, Figures, Graphs15.Reference List16.Appendices
E4: Dose Response Information to Support Drug Registration
Objectives:
•Knowledge of the relationships among dose, drug-concentration in blood and clinical response is important for the safe and effective use of drugs in individual patients. Benefits of dose response data:-
–Choose appropriate doses
–Use of concentration-response data
–Problems with Titration Designs
–Interaction between Dose-Response and Time
E4: Dose Response Information to Support Drug Registration (cont.)
Obtaining dose response information
•Part of drug development
•Studies in life-threatening diseases
•Regulatory consideration
•Examining entire database
Study designs for assessing dose response
•Parallel dose response; Cross over dose response; Forced titration study; Optional titration
E5: Ethnic Factors
•Excluded at the moment.
E6: Good Clinical Practice (GCP)
Objective:
•To provide unified standard to facilitate mutual acceptance of clinical data by the regulatory authorities.
Major Principles
•Should be followed when generating clinical trial data that are intended to be submitted to regulatory authorities.
•Compliance shall provide public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki and that the clinical trial data are credible.
E6: Good Clinical Practice (cont.)
Key Stakeholders to Implement GCP:
•Institutional Review Board/Independent Ethics Committee
•Investigator
•Sponsor
Tools:
•Clinical trial protocol and protocol amendment(s)
•Investigator’s brochure
•Essential documents for the conduct of clinical trial
E7: Clinical Trials in Special Populations: Geriatrics
Objective:
•Provide recommendations on special considerations which apply in the design and conduct of clinical trials on medicines that are likely to have significant use in elderly
Scope of guideline:
•Drug that have significant use in elderly
•Patients aged 65 years or older
•Should be included in the phase 3 (or Phase 2)
•Pharmacokinetic, pharmacodynamic
•Drug-Drug interaction studies
E8: General Considerations for Clinical Trials
Objectives:
a)Describe internationally accepted principles and practices
b)Facilitate the evaluation and acceptance of foreign clinical trials data
c)Present an overview of the ICH clinical safety and efficacy documents and facilitate the user’s access to guidance
d)Provide a separate glossary of terms used
Principles:
•Protection of clinical trial subjects
•Scientific approach in design and analysis
•Development Methodology
–Consideration for the Development Plan
•Non-clinical studies
•Quality of investigational medicinal products
•Phases of clinical development
•Special considerations
–Considerations for Individual Clinical Trials
•Objective
•Design (E4, E6, E0, E10, E3)
•Conduct (E2A, E2B, E6)
•Analysis (E3, E6, E9)
•Reporting (E3, E6)
E9: Statistical Principles for Clinical Trials
Objective:
To harmonisethe principles of statistical methodology applied to clinical trials for marketing applications
Scope:
•Focus on statistical principles
•Do not address the use of specific statistical procedures or methods as such steps to ensure that principles are implemented are the responsibility of the sponsor.
•Aim to minimisingbias and maximisingprecision
Contents:
•Considerations for overall clinical development
•Trial design considerations
•Trial conduct considerations
•Data analysis considerations
•Evaluation of safety and tolerability
•Reporting
E10: Choice of Control Group & Related Issues in Clinical Trials
Objective:To make sure that a trial could have detected a difference between treatments when there was a difference in non-inferiority/equivalence trials by•Indicating choice of control group in clinical trials with respect to efficacy and safety; and•Determining intrinsic efficacy and to the need for comparison with other groups
Types of Controls:
•Placebo control
•No-treatment control
•Dose-response control
•Active (positive) control
•External control
•Multiple control groups
E11: Clinical Investigation of Medicinal Products in the Pediatric Population
Objectives:
•To encourage and facilitate timely pediatric medicinal product development internationally.
•Provide an outline of critical issues in pediatric drug development and approaches to the safe, efficient and ethical study of medicinal products in the pediatric population.
Guidelines
•Issues when initiating a pediatric medicinal product development program
•Pediatric formulations
•Timing of Studies
•Types of Studies
•Age Classification of Pediatric Patients
•Ethical Issues in Pediatric Studies
E12: Guidelines for Clinical Evaluation by Therapeutic Category
Objective:
•To focus on guidance which can be applied for some therapeutic classes. The first guidance is under E12A: Principles for Clinical evaluation of New AntihypertensiveDrugs
E12A: Principles for Clinical Evaluation of New AntihypertensiveDrugs
Focus on common:
•Type of study design
•Development phase
This is taken as Principle Document rather than guideline as there are a few major differences in the requirements of the 3 participating regions.
Conclusion
Propose to adopt ICH Guideline E1-E12
E1 & E2Yes
E2B(M)Pending
E3 & E4Yes
E5Pending
E6 & E11Yes
E12Pending
Some concerns about E2B(M) E5 & E12
•E2B(M) requires specific equipment to handle electronic data & document transfer which is too early to apply between ASEAN countries.
•E12 is considered as “ICH Principle Document”rather than a guideline.
•E5 (Ethnic factor) is excluded since BALI’s Meeting
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