ICH and GCP by Naveen

*

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

* GCP born in USA – mid 1970s
* Rigorous IND procedures enforced
* Various national GCPs

USA + Europe + Japan

ICH GCP

1.
2.
I.
II.
A.
B.

European Commission
European Federation of
Pharmaceutical Industries’
Associations (EFPIA)
Ministry of Health, Labor and
Welfare (MHLW)
Japanese Pharmaceutical
Manufacturers Association (JPMA)
Food & Drug Administration (FDA)
Pharmaceutical Research and
Manufacturers of America (PhRMA)

*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.

*
*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

*
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

* 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

*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

*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.

*
*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

*
*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

*
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

*
*Monitoring & Monitoring report
*Protocol & Protocol Amendment
*Serious Adverse Event
*Source data & Source documents
*Sponsor & Sponsor investigator
*Standard Operating Procedures
*Vulnerable subjects

*
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.

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

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

*
Institutional Review Boards/ Independent Ethics
Committee

*
*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

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

*
*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

*
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

*
*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.

*
*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

*
*Potential for recruitment
*Sufficient time for trial conduct and completion
*Staff, facilities
*Ensure training to staff

*
*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

*
*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

*
*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

*
*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

*
*Should follow the trial’s randomization procedure
*Any premature unblinding to be explained to sponsor

*
*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

*
*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

*
*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

*
*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).

*
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

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

*
*An individual, company, institution, or organization which

takes responsibility for the initiation, management, and/or
financing of a clinical trial

*
*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

*
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

*
*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)

*
*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)

*
*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

*
*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)

*
*Document describing all aspects of the study
*Well designed and thoroughly considered
*Well structured
*Complete

*
*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)

*
*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)

*
*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

*
*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

*
*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

*
*Proposed date of initiation of study
*Discontinuation criteria for subjects
*Instructions on suspending or terminating the study
*Procedures for monitoring compliance

*

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

*
*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)

*
*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

*
*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

*
*Steps & procedures for monitoring study
*Instructions for protocol deviations
*Allocation of duties & responsibilities within research teams
*Quality control of methods & evaluation procedures

*
*Description of how patients/volunteers would be informed

*

*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

*
*Budget, financial aspects
*Sources of economic support
*Subject payments
*Reimbursement to team members
*Insurance details of study subjects

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

*
* Introduction
Definition
Purpose
Information form
Edition
Type & extent
Review & revise
Up-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 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 investigator’s 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
Investigator’s 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

*
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

*
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

* 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 by
the Indian Council of Medical Research.
86

* 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
87
* Appendices

ICH and GCP by Naveen

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