Gcp 112070804017

A seminar
On
GOOD CLINICAL PRACTICE
(GCP)
Prepared by :PARTH Patel GUIED BY:MR.Musir I.Mansuri
M.pharm-(SEM-1)
Quality Assurance
Roll no:09

APMC College of Pharmaceutical Education And Research.

OBJECTIVES
 Review research and development process
 Review trial design measurements

 IND drugs

 Early stopping rules

 Good clinical practice

RESEARCH & DEVELOPMENT
PROCESS
 Includesall of the activities required to
move the Investigational Product from
discovery to market
 Discovery
 Pre-clinical testing
 Permission to test in humans
 Phase I, II, III testing
 Process & interpret the data
 Obtain approval to market the product
 Market the product
 Phase IV testing

KEY PLAYERS IN A CLINICAL TRIAL
 Sponsor
 Investigation Site Team

 IRB/IEC

 Regulatory Authority/Competent Authority

 Subject/Participant

 Contract Research Organization

TRIAL DESIGN:
MEASUREMENTS
 Safety
 Efficacy

 Primary endpoint/objective

 Secondary endpoint/objective

TRIAL DESIGN:
BLIND OR OPEN
 Blind
 SingleBlind
 Double Blind
 Open or open-label
 All parties know the identity of the subject’s
treatment

TRIAL DESIGN:
RANDOMIZATION
 Treatment assigned by some element of chance.

 Treatment groups may be stratified (divided) into
different sub-groups based on characteristics
such as age, gender, and race.

TRIAL DESIGN:
SAMPLE SIZE
 Anadequate
sample includes a
population large
enough to make
generalizations
from the data.
 Statisticians will
help answer
question

CLINICAL TESTING:
TIMELINE
Stage/Phase Time to Complete
PreClinical 4 Years
Phase I 1.3 Years
Phase II 2.1 Years
Phase III 1.5-Several Years
Phase IV

Total Time to Complete Testing 15 Years

IND REQUIREMENTS
 Must show the drug is safe for clinical trials
 Required for all clinical trials, except
 Drugs not subject to pre-market approval
 Approved drugs

STOPPING THE CLINICAL TRIAL
 Development can be stopped at any time
 Safety
 Efficacy
 Business Reasons/$$$
 Clinical trial can be halted at one site or all
 Clinical trial can be halted by the PI, IRB/IEC,
Sponsor, or the CRO

INTERNATIONAL CONFERENCE
ON HARMONIZATION (ICH)

OBJECTIVES OF ICH GUIDELINES
 Provide a unified standard
 EU; US; Japan

 To facilitate mutual acceptance of clinical data

 Developed in accordance with existing standards
in US, EU, Australia, Canada, Nordic Countries,
and WHO

GOOD CLINICAL PRACTICE
Definition
“ a standard for the design, conduct,
performance, monitoring, auditing, recording,
analyses, and reporting of clinical trials that
provides assurance that the data and reported
results are credible and accurate, and that the
rights, integrity and confidentiality of trial
subjects are protected.”
(ICH GCP)

GCP is not a wallpaper you
paste over your Clinical
Development; it is to be built
into the Structure.

GCPs

FDA OHRP ICH
21 CFR International
45 CFR 46
•Electronic •Glossary
•IRBs
•Documents •Principles
•Informed Consent
•Informed Consent •IRBs
•Women
•Financial Disclosure •Investigator
•Prisoners
•IRBs •Sponsor
•Children
•IND Regulations •Essential Documents

PRINCIPLES OF ICH GCP
 Conduct trials according to GCP
 Weigh risks vs. benefits
 Protect the subjects
 Have adequate information to justify trial
 Write a sound protocol
 Receive IRB/IEC approval
 Use qualified physicians

FORM FDA 1572
 Contract between FDA and the Investigator
 Includes logistics such as names and addresses

 Section 9
 Commitments of the Investigator

ICH GCP
 Glossary
 Principles of ICH GCP
 Information regarding
 IRB/IEC
 Investigator
 Sponsor
 Protocol
 Investigator’s
Brochure
 Essential Document

GCP-ICH-GLOSSARY: DEFINITIONS
RELATED TO CLINICAL STUDY
ISSUES
 Investigator  Case Report Forms (CRF)
 Monitoring  Clinical study report
 Monitoring report  Clinical trial
 Multicenter trial  Coordinating investigator
 Nonclinical study  Identification code (of trial
 Protocol subjects)
 Randomization  Interim clinical study
report
 Sponsor
 Investigational product
 Sponsor-initiated
 Subject
 Subinvestigator
 Trial Site

RELATED TO SAFETY ISSUES
 Adverse drug reaction (ADR)
 Adverse events (AE)

 Serious adverse events

 Unexpected adverse drug reaction

RELATED TO REGULATORY ISSUES
 Amendments  Good clinical practice
 Applicable regulatory  Institution (medical)
requirement  Investigator Brochure
 Contract Research  Legally acceptable
Organization (CRO) representative
 Direct access  Standard operating
 Documentation procedures

RELATED TO ETHICAL ISSUES
 Confidentiality  Independent ethics
 Contract committee (IEC)
 Impartial witness  Informed consent

 Institutional review  Minimal risk

board (IRB)  Opinion

 Vulnerable subjects

 Well-being

RELATED TO COMPLIANCE/AUDITING
ISSUES
 Audit
 Audit certificate
 Audit report
 Compliance (in relation to trials)
 Inspection
 Quality assurance
 Quality control
 Source data
 Source documents

HOW TO COMPLY WITH ICH GCP
 Use qualified support staff
 Obtain informed consent

 Record information appropriately

 Protect confidentiality

 Handle investigational products appropriately

 Implement quality systems

INVESTIGATOR RESPONSIBILITIES *
 Ensure the study is conducted according
to the investigator statement/agreement,
protocol and regulatory requirements
 Ensure the protection of the participant’s
rights, safety and welfare.
 Ensure the control of investigational drug.

 Obtain informed consent
 *(21 CFR 312.60 and 312.61)

INVESTIGATOR RESPONSIBILITIES
 Maintenance of records
 Investigator Qualifications and
Agreements
 Adequate Resources
 Medical Care of Subjects
 Communication with IRB
 Compliance with protocol
 Investigational product
 Randomization
 Informed Consent

REGULATORY AUTHORITIES WILL
INQUIRE ABOUT:
 Source of study subjects
 Did they have the disease under study

 Did the meet the eligibility criteria

 Was the protocol precisely followed

 Were AE’s reported appropriately

COMMON FINDINGS VIA FDA AND
OHRP

 Failures to adhere to protocol
 Eligibility
criteria
 Randomization
 Required efficacy tests
 Changes unauthorized by the sponsor

OHRP

 Failures to maintain adequate/accurate records
 Data changed to could not be verified
 Records destroyed or otherwise missing
 Medical course not documented

OHRP

 Failures to report concomitant therapy
 Failures to maintain drug acct. records

 Failures to obtain proper consent
 Verbal
 Obtained after admission

OHRP

 IRB failed to review the research at a convened
meeting
 Investigators failed to promptly report
unanticipated problems involving risks to
subjects to IRB, OHRP, and sponsor
 Continuing review of research was NOT
substantive nor meaningful

OHRP

 IRB did not ensure additional protections for
vulnerable subjects
 IRB members inappropriately participated in
new and continuing review of protocols of which
they had a conflicting interest

INFORMED CONSENT
 An agreement
between
researchers and
participants
 A mutual
commitment
 Both parties agree
to…

ICH GCP PRINCIPLES OF THE
INFORMED CONSENT PROCESS
 The investigator must comply with all applicable
regulations
 The investigator must obtain prior written
IRB/IEC approval of the consent form, and any
other information given to the participant
 The informed consent process must be free of any
coercion or undue influence

 The investigator must provide ‘want to know”
information to participant, including risks and
benefits
 Clinical trial information must be presented in a
way that ensures understanding
 Subjects must have adequate time to ask
questions and get answers

 Subjects must understand that they are able to
withdraw consent at any time
 The informed consent form/process must contain
no language that implies the waiver of rights
 The consenting process must be clearly
documented in the subject’s chart

INFORMED CONSENT DOCUMENT
 Templates are
provided by the
sponsor (MH, or
pharmaceutical
companies)
 Templates may be
modified by the
site to meet the
local
requirements

INFORMED CONSENT DOCUMENT
 Must contain elements of informed consent
relevant to your clinical trial
 Protocol title

 Version date of the consent form

 Page numbers

 Participant signature line

INFORMED CONSENT
REVIEW/APPROVAL
 IRB must approve the form prior to use by any
subject
 IRB must approve of all information provided to
participants including written material such as
handouts or brochures, verbal instruction and
videotapes

SIGNATURES
 Participants must sign and date the most current
IRB approved form
 The person administering the consent signs and
dates the form
 The investigator and/or a witness may sign and
date
 Participants are given a copy of the consent form
and the originals are filed with the participants’
records

SPECIAL CIRCUMSTANCES
 Vulnerable participants
 May have a legal representative
 Underage participants
 Must have a parent or legal guardian sign the
consent form
 Depending on the age of the subject, assent may be
required
 Problems with literacy
A witness must be present

COMMON CONSENTING
ERRORS
 State and local requirements for legally
authorized representatives are not
adhered to
 Informed consent form is not properly
signed and dated as indicated on the form
and according to the regulations
 Subject signing informed consents that
sections of the consent have been crossed
out

COMMON CONSENTING
ERRORS
 Subject not signing informed consent prior
to administration of protocol required
procedures.
 Subjects are provided the informed
consent document, but are told to read
and sign it without opportunity to ask
questions or obtain clarification
 Document not approved by the IRB or is
an outdated version

AE/SAE/EAE
Adverse Events/Serious Adverse Events/Expedited Adverse Events

ADVERSE EVENTS
 What are Adverse Events?
 Any untoward medical occurrence in a clinical trial
participant who has received test article/intervention
that may or may not have a causal relationship with
this treatment

ADVERSE EVENTS
 Why is complete, accurate reporting of AE
data important?
 Allows timely methodical evaluation of clinical
safety data for clinical trial participants both
individually and as a group
 Maximizes individual participation safety
 Develops accurate drug toxicity profiles
 Compliance with regulatory requirements

INTENSITY OF THE EVENT
 All adverse events will be assessed by a sponsor
and/or protocol defined grading system
 The following guidelines are often used to
quantify intensity
 Mild: events require minimal or no treatment and do
not interfere with the patient’s daily activities
 Grade I

 Moderate: events result in a low level of
inconvenience or concern with the therapeutic
measures. Moderate events may cause some
interterence with functioning
 Grade II
 Severe: events interrupt a patient’s usual daily
activity and may require systemic drug
therapy or other treatment. Severe events are
usually incapacitating
 Grade III

 Lifethreatening: any adverse drug experience that
places the patient or subject in the view of the
investigator, at immediate risk of death from the
reaction as it occurred, i.e., it does not include a
reaction that had it occurred in a more severe form,
might have caused death
 Grade IV
 Death

 Grade V

RELATIONSHIP TO STUDY PRODUCTS
 Alladverse events must have their
relationship to study product assessed
using the following terms:
 DefinitelyRelated
 Probably Related
 Possibly Related
 Probably Not Related
 Not Related
 Pending (temporary assignment for death)

ASSOCIATION WITH STUDY PRODUCT
 Determination of association with the study
product must be done by a qualified staff member
 What makes someone qualified to assess
association with a study product?

SAE DEFINITION
 ANY adverse
event that at any
dose:
 Results in death
 Is life threatening
 Requires inpatient
hospitalization or
prolongs
hospitalization 21 CFR 312.32

SAE DEFINITION
 Results in persistent or significant
disability/incapacity
 Is a congenital anomaly or birth defect

 Important medical event

 Other conditions as specified in the
protocol
21 CFR 312.32

REPORTING TIMEFRAMES
 Per MH IRB
 Internal AE –unexpected and related-report in
10 days
 External AE-serious and unexpected and
related-report in 10 days
 Death-Report within 24 hours of discovery
 Must be reported within 24 hours
 If patient died within 30 days of participating
and is deemed related to study

RESOLUTION OF EVENT
 All AE/SAE should be followed:
 Untilevent has stabilized
 Condition returns to baseline
 Condition is resolved
 Condition no longer meets the SAE criteria

TRENDS
 Adverse events and serious adverse
events are reviewed throughout the
course of all clinical trials for potential
trends
 Review of these “data snapshots” allows
for identification of potential trends
which can be related to:
 Concomitant medications
 Toxicities
 Secondary indications

SAUMMARY/INVESTIGATOR
RESPONSIBILITIES
 Report all SAEs per sponsor/protocol defined
timelines
 Notify IRB of AEs/SAEs per IRB policy

 Comply with all applicable regulatory
requirements related to the reporting of
unexpected serious adverse events

WORKING DEFINITION OF SOURCE
DOCUMENTS
 All written and printed documents that are
pertinent to a research participant’s:
 Exposure to the investigational agents
 Exposure to other treatments
 Progress of the disease course
 Response to therapy

DEFINITIONS
 Source Documents are “original documents,
data, and records” and may include:
 Hospital records, clinic charts, laboratory notes,
memoranda, subject diaries, x-rays, subject file

ICH 1.52

DEVIATIONS FROM PROTOCOL
 Referred to as Protocol Violations and/or
Protocol Deviation/Departures
 Occur when there is non-adherence to
Protocol
 All deviations from Protocol must be
addressed in clinical trial subject source
document
 The documentation should include the
reasons for the deviation and all attempts
to prevent or correct them

ELECTRONIC MEDICAL RECORDS
 Monitors are permitted at MH to have direct
access into the Epic system if a DRA amendment
has been approved by the IRB
 Copies of electronic medical records DO NOT
need to be certified for the sponsors to accept
them

VERIFYING SOURCE DOCUMENTS
 Ensure that
source data are
complete,
accounted for,
follow a logical
sequence of events
 Ensure that
source data
support entries in
CRF

PROTOCOL REQUIRED
DOCUMENTATION
 Allinclusion/exclusion criteria be
addressed
 Clinical trial required tests and
procedures done on time or if not, why not
 Withdrawals, dropouts, lost to follow up

 AEs/SAEs properly documented/reported

 Endpoints of the clinical trial

RESOURCES
 21 CFR 11
 21 CFR 312.62
 ICH section 4.9,5.5
 FDA form 3500A Medwatch
 21 CFR 312.32
 ICH section 4.11, 5.16, 5.17 and 7.3
 ICH E2A
 21 CFR 50
 21 CFR 312.60
 ICH 4.8
 ICH 5.18.4e
 45 CFR 46

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