ICH and GCP by Naveen

* GOOD MORNING TO ALL

EVOLUTION OF ICH

GUIDELINES &

GOOD CLINICAL PRACTICES

The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)

* ICH

Historical Perspective

*GCP born in USA – mid 1970s

*Rigorous IND procedures enforced

*Various national GCPs

USA + Europe + Japan

ICH GCP

Six founder members1. European Commission2. European Federation of

Pharmaceutical Industries’ Associations (EFPIA)

I. Ministry of Health, Labor and Welfare (MHLW)

II. Japanese Pharmaceutical Manufacturers Association (JPMA)

A. Food & Drug Administration (FDA)B. Pharmaceutical Research and

Manufacturers of America (PhRMA)

Initiation of ICH

*Birth of ICH took place at a meeting in April 1990, hosted by the EFPIA in Brussels*Europe, Japan and the USA met*To plan an International Conference but the meeting also discussed the wider implications and terms of reference of ICH.*The ICH Steering Committee which was established at that meeting has since met at least twice a year, with the location rotating between the three regions.

*The Triggers

*1930s – Sulfanilamide tragedy Sulfonilamide+diethelene glycol

*1960s – Thalidomide tragedy

*1960s & 1970s*Rapid increase in laws, regulations &

guidelines

*Industry marketing – Global

*Basic evaluation – similar

*Detailed technical requirements – varied

* OBJECTIVE

-Elimination of unnecessary delay in global development-Make new medicines available while maintaining safeguards on -quality, safety, and efficacy, and regulatory obligations to - - protect public health-More economical use of human, animal and material resources

*Why harmonize?

Avoid duplication in tests to conform to different regulatory guidelines

*More effective utilization of results

*Timely access of patients to safe and effective new drugs

*Promote public health

*Minimize animal testing without compromising safety & effectiveness

*The Early Meetings

*Terms of Reference were agreed and it was decided that the Topics selected for harmonization would be divided into Safety, Quality and Efficacy to reflect the three criteria which are the basis for approving and authorizing new medicinal products

*It was also agreed that six-party Expert Working Groups (EWGs) should be set up to discuss scientific and technical aspects of each harmonization Topic

*STRUCTURE OF THE ICH

*Where is the ICH located

*ICH does not have "offices" as such because it is a voluntary cooperative effort of cosponsors from the three regions.

*The ICH Secretariat is based in Geneva.

*The biennial meetings and conferences of the ICH Steering Committee rotate between the EU, Japan, and the USA.

*How is ICH structured?

*The ICH structure consists of the

*ICH Steering Committee,

*ICH Coordinators,

*ICH Secretariat and

*ICH Working Groups.

*Current Status of Harmonization: (over 50 harmonized guidelines)

*Efficacy - 12 topic headings/14 guidelines*Safety - 7 topic headings/14 guidelines

*Quality - 7 topic headings/19 guidelines*Medical Dictionary - MedDRA*Electronic Standards - ESTRI, E2B

*Industry proposed taking the information generated by these harmonized guidances and putting it the same order

*Safety Guidelines(animal studies/Pre clinical

studies )

*Carcinogenicity Studies

*Genotoxicity Studies

*Toxicokinetics and Pharmacokinetics

*Toxicity Testing

*Reproductive Toxicology

*Biotechnological Products

*Pharmacology Studies

*Immunotoxicology Studies

*Joint Safety/Efficacy (Multidisciplinary) Topic

*Quality Topics

*Stability *Analytical Validation *Impurities *Pharmacopoeias*Quality of Biotechnological Products*Specifications*Good Manufacturing Practice*Pharmaceutical Development*Quality Risk Management

*Efficacy guidelines (Clinical studies)

*Clinical Safety*Clinical Study Reports*Dose-Response Studies*Ethnic factors*Good Clinical Practice*Clinical Trials on special population*Guidelines for Clinical Evaluation by Therapeutic Category*Clinical Evaluation-( statistical consideration)*Pharmacogenomics

*M "Multidisciplinary" Topics

*Cross-cutting Topics which do not fit uniquely into one of the above categories.

*M1: Medical Terminology (MedDRA) *M2: Electronic Standards for Transmission of Regulatory Information (ESTRI) *M3: Timing of Pre-clinical Studies in Relation to Clinical Trials *M4: The Common Technical Document (CTD) *M5: Data Elements and Standards for Drug Dictionaries

*GCP GUIDELINES

* ICH-GCP-Introduction

*Good Clinical Practices (GCP) is an international ethical & scientific quality standard for designing, conducting, recording & reporting trials that involve the participation of human subjects.

*Compliance with this standard provides public assurance that rights, safety & 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

* ICH GCP-Section 1

Section 1- Glossary of various terms, eg...

* Adverse drug reaction & Adverse Event

*Case report form & Clinical Study Report

*Coordinating Committee & Contract Research Organization

*Independent Ethics Committee & Institutional Review Board

*Investigator & Investigator’s Brochure

* ICH GCP-Section 1 Cont…

*Monitoring & Monitoring report

*Protocol & Protocol Amendment

*Serious Adverse Event

*Source data & Source documents

*Sponsor & Sponsor investigator

*Standard Operating Procedures

*Vulnerable subjects

* ICH GCP-Section 2

Section 2- Principles of ICH-GCP.2.1 Clinical Trials should be conducted in accordance with the

ethical principles consistent with GCP and applicable regulatory requirements

2.2 Before a trial is initiated, forseeable risks & inconveniences should be weighed against anticipated benefit for the trial subject & society.

2.3 The rights, safety, and well being of the trial subjects are the most important considerations & should prevail over interests of science and society

2.4 The available nonclinical & clinical information on an investigational product should be adequate support the proposed clinical trial.

2.5Clinical trials should be scientifically sound, and described in a clear, detailed protocol.

ICH GCP-Section 2 Cont..

2.6 Trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/ independent ethics committee (IEC) approval/favourable opinion.

2.7 The medical care and medical decisions for subjects should be the responsibility of a qualified physician

2.8 Each individual involved in conducting a trial should be qualified by education, training & experience to perform his respective task


2.9 Freely given informed consent should be obtained from every subject prior to clinical trial participation

2.10 All clinical information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification

2.11 The confidentiality of records that could identify patients should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirements


2.12 Investigational products should be manufactured, handled and stored in accordance with applicable GMP, and used in accordance with the protocol

2.13 Systems with procedures that assure the quality of every aspect of the trial should be implemented


* ICH-GCP-Section 3

Institutional Review Boards/ Independent Ethics Committee

* Section 3.1: IRB/IEC Responsibilities

*Should safeguard the rights, safety & well being of all trial subjects.*Should obtains following Documents: Protocol & their

amendments, Patient Information sheet & consent form, subject recruitment procedures (e.g. advertisements), Investigator's Brochure (IB), available safety information, information about payments and compensation available to subjects, the investigator’s current curriculum vitae and/or other documentation evidencing qualifications, and any other documents that the IRB/IEC may need to fulfil its responsibilities

*should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk to human subjects, but at least once per year.

*Review Protocol/ ICD/ recruitment procedures/ IB/payments

*Continuing review for Ongoing Progress/Adverse events

Section 3.1: IRB/IEC Responsibilities Cont..

* Section 3.2: IRB/IEC Composition

*At least 5 members

*At least one non scientific member

*At least one independent member

*Maintain list of members and qualifications

*Only independent members to vote

*Quorum to be present

* Section 3.3: Procedures

The IRB/IEC should establish, document in writing, and follow its procedures, which should include

*Composition

*Meeting Scheduling & conduct

*Specify that trial starts only after IRB review

*Specify regarding changes in protocol

*Specify prompt reporting of adverse events

* Section 3.4: Records

*The IRB/IEC should retain all relevant records (e.g., written procedures, membership lists, lists of occupations/affiliations of members, submitted documents, minutes of meetings, and correspondence) for a period of at least 3 years after completion of the trial and make them available upon request from the regulatory authority(ies).

*The IRB/IEC may be asked by investigators, sponsors or regulatory authorities to provide its written procedures and membership lists.

* ICH-GCP: Section 4

Investigator

* Section 4.1Investigator qualifications & Agreements

*Qualified (documented) by education, training & experience to assume responsibility for proper trial conduct

*Should be familiar with the appropriate use of the investigational product, IB, and other information provided by sponsor

*Should be aware of, & should comply with, GCP and the applicable regulatory requirements

*Should permit monitoring, auditing and inspection

*Delegation of duties to appropriately qualified persons

* Section 4.2: Adequate Resources

*Potential for recruitment

*Sufficient time for trial conduct and completion

*Staff, facilities

*Ensure training to staff

* Section 4.3: Medical care of trial subjects

*Qualified physician investigator/sub investigator for the trial, should be responsible for all trial related medical decisions

*Adequate medical care during and after trail participation

*Make reasonable efforts ascertaining for premature withdrawal from trial

* Section 4.4: Communication with IRB

*Written & dated approval for trial protocol, ICD, recruitment procedures etc prior to trial initiation

*Should provide latest copies of IB to IRB

*Should provide all relevant documents for review during trial

* Section 4.5: Compliance with Protocol

*Should conduct trial in accordance with the protocol version agreed & documented by the sponsor, IRB and regulatory authority

*No changes allowed in the protocol except in case of immediate hazard to the patient; which should be submitted to all immediately

* Section 4.6: Investigational Product

*Responsible for accountability at site

*May be assigned to pharmacist/individual

*Stored as specified by sponsor or regulatory authority

*Used only in accordance with the protocol

* Section 4.7: Randomization Procedures and unblinding

*Should follow the trial’s randomization procedure

*Any premature unblinding to be explained to sponsor

* Section 4.8: Informed Consent

*Comply with regulatory requirement, GCP and ethical principles

*Documented Communication of revised ICD to IRB and patient

*No influence or coercion to participate

*Subject or their legal representative should be fully informed in their own language

*Non technical language

*Ample time for consent and opportunity for questions

*Impartial witness for illiterate patients

*Subject should receive a copy of the signed and dated ICD/ amendment

Section 4.8: Informed Consent cont..

* Section 4.9 :Records and reports

*Should ensure accuracy, completeness, legibility and timeliness of data to sponsor in CRF

*Correction in CRF should be signed, dated

*Maintain trial related documents

*Financial agreements in place

*Access to records by monitor, regulatory agency or auditors

*Progress reports to IRB

* Section 4.10 :Progress reports

*The investigator should submit written summaries of the trial status to the IRB/IEC annually, or more frequently, if requested by the IRB/IEC.

*The investigator should promptly provide written reports to the sponsor, the IRB/IEC (see 3.3.8) and, where applicable, the institution on any changes significantly affecting the conduct of the trial, and/or increasing the risk to subjects

* Section 4.11:Safety Reporting

*SAE should be reported immediately to sponsor, and timely as required to IRB/regulatory agency

*Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations should be reported to the sponsor according to the reporting requirements and within the time periods specified by the sponsor in the protocol.

*For reported deaths, the investigator should supply the sponsor and the IRB/IEC with any additional requested information (e.g., autopsy reports and terminal medical reports).

* Section 4.12: Premature termination of trial

If the trial is prematurely terminated or suspended for any

reason , Investigator :

*Should inform subjects

*Should assure therapy and follow up

*Should inform regulatory authorities

*Should inform sponsor/IRB with explanation

* Section 4.13: Final Report

*Upon completion, should inform institution, IRB, and regulatory authorities with a summary of the trial’s outcome

*ICH-GCP: Section 5

Sponsor Responsibilities

* Sponsor

*An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial

* Section 5.1: Quality Assurance & Quality Control

*Implementing & maintaining QA and QC systems with written SOPs to ensure GCP compliance

*Securing agreements from all sites for monitoring, auditing, and inspections

*QC of data handling

*Payment agreements

* Section 5.2: CRO

A person or an organization (commercial, academic, or other)

contracted by the sponsor to perform one or more of a sponsor’s

trial related duties and functions

*Sponsor may transfer all or some duties to CRO

*Ultimate responsibility for quality lies with the sponsor

*Document of all duty delegation required

* Sponsor Responsibilities

*Designate Medical Expertise :who will be readily available to advise on trial related medical questions or problems. (Section 5.3)

*Trial design (Section.5.4), Trial management, Data handling and Record Keeping (Section 5.5) and Investigator selection (Section 5.6), Allocation of Responsibilities (Section 5.7)

*Compensation to Subjects and Investigators (Section 5.8), Financing (Section 5.9)

*Submission to regulatory authorities (Section 5.10)

*Confirmation of review by IRBs (Section5.11)

* Sponsor ResponsibilitiesCont….

*Information on investigational product (Section 5.12)

*Manufacturing, labeling, packaging & coding of product (Section 5.13)

*Supplying and Handling Investigational Product(s) (Section 5.14) and Record Assess (Section 5.15)

*Safety Evaluation (Section 5.16) and Adverse Drug Reaction Reporting (Section 5.17)

*Monitoring (Section 5.18)

* Monitoring

*The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, SOPs, GCP, and the applicable regulatory requirements

* Sponsor ResponsibilitiesCont….

*Audit (Section 5.19)

*Noncompliance (Section 5.20)

*Premature Termination or Suspension of a Trial (Section5.21)

*Multicentre Trials (Section 5.22)


CLINICAL TRIAL PROTOCOL

AND

PROTOCOL AMENDMENT(S)

* Protocol

*Document describing all aspects of the study

*Well designed and thoroughly considered

*Well structured

*Complete

* Protocol- Relevant components

*General Information (Section 6.1)

*Background Information (Section 6.2)

*Trial Objectives and Purpose (Section 6.3)

*Trial Design (Section 6.4)

*Selection and Withdrawal of Subjects (Section 6.5)

*Treatment of Subjects (Section 6.6)

*Assessment of Efficacy (Section 6.7)

*Assessment of safety (Section 6.8)

* Protocol- Relevant componentsCont…

*Statistics (Section 6.9)

*Direct Access to Source Data/Documents (Section 6.10)

*Quality Control and Quality Assurance (section 6.11)

* Ethics (section 6.12)

*Data handling & management (Section 6.13)

*Financing and Insurance (Section 6.14)

*Publication Policy (Section 6.15)

*Supplements (Section 6.16)

* Sec 6.1: Protocol- General Information

*Protocol Title, identifying number & date. Amendment number

*Contact names, addresses

*Name and title of Authorized signatory

*Contact medical expert

*Contact investigator(s)

*Institution(s), Laboratories, department contact

* Sec. 6.2:Protocol- Objective & Justification

*Aims & objectives, phase of study

*Name & description of Inv product

*Summary of non clinical & clinical studies

*Summary of risks & benefits

*Description of route of administration, dosage

*Statement of GCP compliance

* Sec 6.4: Protocol- Trial Design

*Primary & secondary endpoints

*Randomized/comparator/blinded/open, placebo controlled

*Blinding technique(double blind/single blind)

*Randomization(method & procedure)

*Diagram of design, procedure & stages

*Medications permitted & not permitted during study

*Description of study treatments, dose, route during study conduct

*Packing/labeling description

*Duration of subject participation & sequence of all study periods, including follow up

* Sec 6.4: Protocol- Trial DesignCont….

*Proposed date of initiation of study

*Discontinuation criteria for subjects

*Instructions on suspending or terminating the study

*Procedures for monitoring compliance

* Sec 6.5: Selection and Withdrawal of Subjects

Inclusion/ Exclusion criteria:

*Specifications of the subjects to be included (age, gender, ethnic groups, prognostic factors, diagnostic criteria)

*Specify exclusion criteria

*Subject withdrawal criteria & procedures

* Sec 6.7: Protocol-Assessment of Efficacy *Specifications of efficacy parameters

*Descriptions of how these are measured and recorded

*Time & periodicity of recording

*Description of special analysis/ tests (PK, clinical, lab, radiology)

*Specifications of safety parameters

*Procedures for eliciting reports of and reporting ADR

*Time &method of recording

*Type, duration of follow up after adverse events)

* Sec 6.9: Protocol- Statistics

*Description of statistical methods employed

*Timing of interim analysis, if any

*Details of enrollment plan

*Significance level, power

*Procedures for reporting any deviations from the original statistical plan

*Selection of subjects to be included in final analysis

* Sec 6.10: Direct Access to Source Data/Documents

*The sponsor should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, and regulatory inspection(s), providing direct access to source data/documents

* Sec 6.11: Protocol- QC & QA

*Steps & procedures for monitoring study

*Instructions for protocol deviations

*Allocation of duties & responsibilities within research teams

*Quality control of methods & evaluation procedures

* Sec 6.12:Protocol- Ethical considerations

*Description of how patients/volunteers would be informed

* Sec 6.13:

Protocol-Data Handling and Record Keeping *Procedures for handling & processing records of

effects and adverse events

*Handling of Products:*Safe handling and storage measures

*System to be followed for labelling

*Labeling specifications

* Sec. 6.14: Protocol- Finance & insurance

*Budget, financial aspects

*Sources of economic support

*Subject payments

*Reimbursement to team members

*Insurance details of study subjects


Informed Consent

* Section 7: Investigator Brochure-Introduction

*Compilation of the clinical and nonclinical data on the investigational product that are relevant to the study of the products in human subjects

* Sec 7: Investigator Brochure: Contents

*IntroductionDefinitionPurposeInformation formEditionType & extentReview & reviseUp-date

*General consideration*Contents of the IB*Conclusion


ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL

* Sec 8: Essential Documents -Introduction

*Essential Documents are those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced.

*These documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements

* Essential Documents to be Kept before Trial Commences

Investigators BrochureSigned protocols, amendments (if any) and sample CRFInformation given to the trial subjects

Informed Consent Applicable translations of informed consent (if any)Any other written informationAdvertisements for subject recruitmentSubject compensation

Financial aspects of the trialCompensation document for trial-related injurySigned agreements of all involved parties

Investigator and sponsorInvestigator and CRO (if any)Investigator/institution and regulatory authorities (if any)

Approval letter from the IRBIRB CompositionAuthorization or notification from the regulatory agencies (where required)

* Essential Documents to be Kept before Trial Commences

CV of investigator and sub-investigators evidencing qualifications Normal values of labs /technical procedures included in the protocolMedical/laboratory and technical procedures of tests

CertificationAccreditationEstablished Quality control (QC assessments) Other validations

Sample labels attached to investigational product containersInstructions for handling investigational products and trial-related materials (sometimes

this information is included in the investigator’s brochure)Shipping records of investigational products and trial-related materialsCertificates of analysis of investigational products shippedDecoding procedures for blinded trialsMaster randomization listPretrial monitoring reportTrail initiation monitoring report

* Essential Documents to be Kept During the Trial

Investigator’s brochure updatesAny revisions to:

Protocol, amendments and CRFInformed consent formWritten information provided to subjects/LARAdvertisement

Dated, IRB approved documents of:Protocol amendmentsRevisions of informed consent, information to subjects/LARAdvertisements and any other documents givenContinuing review of trial

Dated Regulatory approved documents of:Authorizations and notifications Protocol amendments and other documents


Curriculum Vitae of new investigators and sub-investigatorsUpdates to normal value(s) range(s) for medical lab technical procedure(s), test(s)

included in the protocolUpdates on medical/laboratory/technical procedure tests

CertificatesAccreditationEstablished quality control/external quality assessmentOther validations

Documentation of investigational products and trial-related materials shipmentCertificate(s) of analysis for new batches of investigational productsMonitoring visit reportsRelevant communications other than site visits (Letters, meeting notes and notes of

telephone calls)Signed informed consent formsSource documentsSigned, dated and completed CRFDocumentation of CRF Corrections


Notification by the originating investigator to sponsor of serious adverse evens and related reports

Notification by investigator (if applicable) to regulatory authorities and IRB of unexpected serious adverse reactions and of other safety information

Notification by sponsor to investigators of safety information

Subject screening log

Subject identification code list

Subject enrolling log

Investigational product(s) accountability at the sire

Signature sheet

Record of retained body fluids/tissue samples (if any)

* Essential Documents to be Kept After Completion or Termination of the Trial

Investigational product(s) accountability at sireDocumentation of investigational product(s) destructionCompleted subject identification code list (to permit identification of all

subjects enrolled in the trial in case of follow up is required – this information should be kept in a confidential manner and for agreed period of time)

Audit certificate (if required)Final trial close-out monitoring reportTreatment allocation and decoding documentation returned to sponsor

to document any decoding that may have occurredFinal report by investigator to IRB where required Final report by investigator to regulatory authorities where applicable to

document completion of the trialClinical study report to document results and interpretation

* Differences and similarities between ICH-GCP and Indian GCP

Expert Committee set up by Central Drugs Standard Control Organization (CDSCO) in consultation with clinical expert has formulated this GCP guideline

• Drug Technical Advisory Board (DTAB), the highest technical body under D&C, Act, has endorsed adoption of this GCP guideline for streamlining the clinical studies in India

• These guidelines have been evolved with consideration of WHO, ICH, USFDA and European GCP guidelines as well as the Ethical Guidelines for Biomedical research on Human Subjects issued by the Indian Council of Medical Research. 86

* Indian GCP :Dec 2001

* STRUCTURE

* Glossary

* Principles

* IRB/IEC

* Investigator

* Sponsor

* Protocol

* Investigators’ Brochure

* Essential Documents

* Definitions

* Pre-requisites

* Responsibilities

* Records & Data

* Quality Assurance

* Statistics

* Special Concerns

* Appendices

ICH E6 Indian GCP

87

Q & A

THANK YOU

Health & Medicine

ICH and GCP by Naveen