Good Clinical Practices (GCP)

Dr. Ranjeet Prasad (MBA,CCRP,BDS)

Agenda
Evolution of GCP. ICH-GCP. Differences and Similarities between ICH-GCP , Indian GCP and Schedule-Y Key Players in Clinical Research and their checklists

Evolution
Nuremberg Code, 1947 Declaration of Helsinki, 1964 2001 ICH GCP guidelines, 1996 Ethical Guidelines for Biomedical Research in Human Subjects (ICMR), 2000 GCP Guidelines, CDSCO, New Delhi, 2001

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- Objective

To provide a unified standard for the EU, Japan & the US to facilitate the mutual acceptance of clinical data by regulatory authorities in these jurisdictions Should be followed when generating data that are intended to be submitted to regulatory authorities (only then??)

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 & Investigators 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.

ICH GCP-Section 2 Cont..

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

ICH GCP-Section 2 Cont..

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

ICH GCP-Section 2 Cont..

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 investigators current curriculum vitae and/or other documentation evidencing qualifications, and any other documents that the IRB/IEC may need to fulfil its responsibilities

Section 3.1: IRB/IEC Responsibilities Cont..

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 3.2: 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 4.1 Investigator 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 trials 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

Section 4.8: Informed Consent cont..

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 4.9 :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 trials 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 sponsors 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 Responsibilities Cont.

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 Responsibilities Cont.

Audit (Section 5.19) Noncompliance (Section 5.20) Premature Termination or Suspension of a Trial (Section5.21) Multicentre Trials (Section 5.22)

ICH-GCP: Section 6
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 components Cont

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 Design Cont.

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

ICH-GCP: Section 7
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

Introduction Definition Purpose Information form Edition Type & extent Review & revise Up-date General consideration Contents of the IB Conclusion

ICH-GCP: Section 8
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 Brochure Signed protocols, amendments (if any) and sample CRF Information given to the trial subjects Informed Consent Applicable translations of informed consent (if any) Any other written information Advertisements for subject recruitment Subject compensation Financial aspects of the trial Compensation document for trial-related injury Signed agreements of all involved parties Investigator and sponsor Investigator and CRO (if any) Investigator/institution and regulatory authorities (if any) Approval letter from the IRB IRB Composition Authorization 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 protocol Medical/laboratory and technical procedures of tests Certification Accreditation Established Quality control (QC assessments) Other validations Sample labels attached to investigational product containers Instructions for handling investigational products and trial-related materials (sometimes this information is included in the investigators brochure) Shipping records of investigational products and trial-related materials Certificates of analysis of investigational products shipped Decoding procedures for blinded trials Master randomization list Pretrial monitoring report Trail initiation monitoring report

Essential Documents to be Kept During the Trial

Investigators brochure updates Any revisions to: Protocol, amendments and CRF Informed consent form Written information provided to subjects/LAR Advertisement Dated, IRB approved documents of: Protocol amendments Revisions of informed consent, information to subjects/LAR Advertisements and any other documents given Continuing review of trial Dated Regulatory approved documents of: Authorizations and notifications Protocol amendments and other documents

Essential Documents to be Kept During the Trial

Curriculum Vitae of new investigators and sub-investigators Updates to normal value(s) range(s) for medical lab technical procedure(s), test(s) included in the protocol Updates on medical/laboratory/technical procedure tests Certificates Accreditation Established quality control/external quality assessment Other validations Documentation of investigational products and trial-related materials shipment Certificate(s) of analysis for new batches of investigational products Monitoring visit reports Relevant communications other than site visits (Letters, meeting notes and notes of telephone calls) Signed informed consent forms Source documents Signed, dated and completed CRF Documentation of CRF Corrections

Essential Documents to be Kept During the Trial

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 sire Documentation of investigational product(s) destruction Completed 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 report Treatment allocation and decoding documentation returned to sponsor to document any decoding that may have occurred Final report by investigator to IRB where required Final report by investigator to regulatory authorities where applicable to document completion of the trial Clinical study report to document results and interpretation

Differences and similarities between ICH-GCP and Indian GCP

Indian GCP :Dec 2001

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 70 by the Indian Council of Medical Research.

STRUCTURE ICH E6
Glossary Principles IRB/IEC Investigator Sponsor Protocol Investigators Brochure Essential Documents

Indian GCP
Definitions Pre-requisites Responsibilities Records & Data Quality Assurance Statistics Special Concerns Appendices

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GCP - A Shared Responsibility

Sponsor Investigator

Regulatory Authority
Ethics Committee
72

GCP IMPLEMENTATION
Want to

Attitude

Performance
Knowledge
What to Why to

Skills
How to
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Schedule Y DRUGS AND COSMETICS (IIND AMENDMENT) RULES, 2005 NOTIFICATION the 20th January, 2005
Amendment

to Drugs and Cosmetics Act, 1940

Enacted by Parliament in the Fifty-sixth year of Republic of India Published in the Gazette of India Part-II, section 3, sub-section (i) vide G.S.R. 32(E), dated 20th January, 2005
74

Schedule Y
Regulation and guidelines for permission to import and / or manufacture of new drugs for sale or to undertake clinical trials

It has outlined extensive study criteria in line with the globally accepted formats such as ICH and US FDA guidelines
REFER TO RULES 122A, 122B, 122D, 122DA, 122DAA and 122E
75

122-A : Application for permission to import new drug 122-B : Application for approval to manufacture new drug 122-D: Permission to import or manufacture FDC 122-DA : Permission to conduct clinical trials for New Drug / Investigational New Drug

122-DAA : Clinical trial

122-E:New drug
76

List of Appendices For Schedule Y

Appendix I Data to be submitted along with the application to conduct clinical trials / import / manufacture of new drugs for marketing in the country. Appendix II Structure, contents & format for clinical study reports Appendix IV Animal pharmacology Appendix VI Fixed Dose Combinations (Fdcs)

Appendix I-A Data required to be submitted by an applicant for grant of permission to import &/or manufacture a new drug already approved in the country. Appendix III Animal toxicology (non-clinical toxicity studies)

Appendix V Informed Consent

Appendix VII Undertaking by the Investigator

Appendix VIII Ethics Committee

Appendix X Contents Of The Proposed Protocol For Conducting Clinical Trials

Appendix IX Stability Testing Of New Drugs

Appendix XI 78 Data Elements For Reporting Serious Adverse Events Occurring In A Clinical Trial.

INFORMED CONSENT PROCESS

ICH GCP Indian GCP Schedule-Y Investigator should sign the form.(Appendix V)

Any one designated Investigator should by the investigator to sign the form. (2.4.3.1) conduct and to sign the consent form.(4.8.8)

79

ESSENTIAL ITEMS FOR INFORMED CONSENT

ICH GCP Not Explained Indian GCP cover issues of biological samples. (2.4.3.2) Schedule-Y Not Detailed

ETHICS COMMITTEE COMPOSITION

ICH GCP
At least 5 members. At least 1 member nonscientific area. Quorum members number not detailed.

Indian GCP

Schedule-Y

Fairly small (5-7 members). At least 7 members. Not Explained Not Explained. The quorum should have a The quorum should minimum of 5 members. have at least 5 members. Maximum number is not 12 to 15 is the maximum Maximum number is detailed. recommended number. not detailed. Not recommended. Member Secretary belongs Not recommended. to the same Institution.

DRUG LABEL
ICH GCP Not Explained Indian GCP Schedule-Y Should include name Not Explained and contact numbers of investigator and name of institution. (2.3.1.6)

DOCUMENT RETENTION
ICH GCP Indian GCP The records are Study related linked to marketing documents/materials approval should be safe guarded by the sponsor for 3 years. (3.1.5) Schedule-Y Not Explained

POWERS OF IEC
ICH GCP It is the responsibility of independent datamonitoring committee (IDMC) Indian GCP Schedule-Y IEC has power to Not Explained order discontinuation of a trial if goals of the trial have already been achieved or unequivocal results obtained. (2.4.2.6)

STANDARD OPERATING PROCEDURES

ICH GCP Expects the investigator to comply with the protocol and leaves the task of monitoring compliance to SOPs to monitors and auditors. Indian GCP Mandates that the sponsor and the investigator should sign a copy of the Standard Operating Procedures (SOPs). (3.1.3) Schedule-Y Not Explained

INVESTIGATORS QUALIFICATION
ICH GCP Not Recommended Indian GCP Should be qualified as per the requirement of the Medical Council of India (MCI). (3.3.1) Schedule-Y Not Explained

Key Players in Clinical Research and their checklists

Players in Clinical Research

Investigators Sponsors Regulatory agency Ethics Committee

Investigators checklist - 1
Interest, expertise, time and facilities Interaction with sponsor
Protocol, CRF, PIS and ICF Financial grant Publication policy

Interaction with ethics committee

Presentation and defense of protocol Compliance with conditions of approval

Investigators checklist - 2
Implementation Organizing, briefing and supervising the team Facilitating informed consent process Completing and signing CRFs Reporting SAE Interacting with monitor Reviewing and approving final report Archiving source documents Preparing for audit and/or inspection

Sponsors checklist - 1
Scientific, regulatory and ethical basis of the protocol, PIS and ICF Investigators qualifications, training and experience Regulatory and ethical approvals Publication policy Quality of trial supplies Initiation, monitoring and audit

Sponsors checklist - 2
Data management and analysis Drafting of study report Preparation for inspection Archives of source documents

Regulators checklist
Periodic review of current regulations from scientific and ethical angles Advance consultation to sponsors on protocols
Efficacy and safety criteria Comparator product

Advisory panels for review of applications and decision making Inspection of investigational centers

Ethics Committees checklist - 1

Need for trial Scientific aspects of protocol with ethical implications Participants Number Healthy volunteers or patients Vulnerable persons

Ethics Committees checklist - 2

Treatment Withdrawal of current treatment Assignment of placebo Dosage and route Assessment of response Nature and frequency Invasive or non-invasive Total blood drawn

Ethics Committees checklist - 3

Ethical aspects of protocol Information and consent form Content and language Risks and benefits Compensation or other payments Insurance for study-related injury Treatment after study Regulatory approval