Good Clinical Practices with differences b/w Indian GCP and ICH-GCP

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Good Clinical Practices with differences b/w Indian GCP and ICH-GCP

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Title: Good Clinical Practices with differences b/w Indian GCP and ICH-GCP

1
Good Clinical Practices (GCP)
Dr. Ranjeet Prasad (MBA,CCRP,BDS)
2
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

3
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

4
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

5
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??)

6
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

7
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

8
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.

9
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.

10
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

11
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

12
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

13
ICH-GCP-Section 3

Institutional Review Boards/ Independent Ethics
Committee

14
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

15
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

16
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

17
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

18
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.

19
ICH-GCP Section 4

Investigator

20
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

21
Section 4.2 Adequate Resources

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

22
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

23
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

24
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

25
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

26
Section 4.7 Randomization Procedures and
unblinding

Should follow the trials randomization procedure
Any premature unblinding to be explained to
sponsor

27
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

28
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

29
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

30
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

31
Section 4.11Safety 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).

32
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

33
Section 4.13 Final Report

Upon completion, should inform institution, IRB,
and regulatory authorities with a summary of the
trials outcome

34
ICH-GCP Section 5

Sponsor Responsibilities

35
Sponsor

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

36
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

37
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

38
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)

39
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)

40
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

41
Sponsor ResponsibilitiesCont.

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

42
ICH-GCP Section 6

CLINICAL TRIAL PROTOCOL
AND
PROTOCOL AMENDMENT(S)

43
Protocol

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

44
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)

45
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)

46
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

47
Sec. 6.2Protocol- 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

48
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

49
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

50
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

51
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)

52
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

53
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

54
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

55
Sec 6.12Protocol- Ethical considerations

Description of how patients/volunteers would be
informed

56
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

57
Sec. 6.14 Protocol- Finance insurance

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

58
ICH-GCP Section 7

Informed Consent

59
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

60
Sec 7 Investigator Brochure Contents

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

61
ICH-GCP Section 8

ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A
CLINICAL TRIAL

62
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

63
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)

64
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

65
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

66
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

67
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)

68
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

69
Differences and similarities between ICH-GCP and
Indian GCP
70
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 DC, 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.

70
71
STRUCTURE

Indian GCP

ICH E6

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

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

71
72
GCP - A Shared Responsibility
Sponsor Investigator Regulatory
Authority Ethics Committee
72
73
GCP IMPLEMENTATION
Attitude
Want to
Performance
Skills
Knowledge
How to
73
What to Why to
74
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
75
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
76
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-ENew drug
76
77
List of Appendices For Schedule Y
78
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 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 II Structure, contents format for
clinical study reports
Appendix III Animal toxicology (non-clinical
toxicity studies)
Appendix III Animal toxicology (non-clinical
toxicity studies)
Appendix V Informed Consent
Appendix IV Animal pharmacology
Appendix VII Undertaking by the Investigator
Appendix VI Fixed Dose Combinations (Fdcs)
Appendix IX Stability Testing Of New Drugs
Appendix VIII Ethics Committee
Appendix X Contents Of The Proposed Protocol For
Conducting Clinical Trials
Appendix XI Data Elements For Reporting Serious
Adverse Events Occurring In A Clinical Trial.
78
79
INFORMED CONSENT PROCESS
79
80
ESSENTIAL ITEMS FOR INFORMED CONSENT
81
ETHICS COMMITTEE COMPOSITION
82
DRUG LABEL
83
DOCUMENT RETENTION
84
POWERS OF IEC
85
STANDARD OPERATING PROCEDURES
86
INVESTIGATORS QUALIFICATION
87
Key Players in Clinical Research and their
checklists
88
Players in Clinical Research