Good clinical practice

1. GCP ICH
Dr. Ghiath Alahmad

2. Goals and Objectives
• To understand:
▫ The affect of Good Clinical Practices on institutions conducting Clinical
Research
• To discuss:
▫ What is GCP
▫ Guidelines for GCP
▫ The history of GCP
▫ Basic principles of GCP

3. ICH definition - GCP
Monitoring
Standard
Design ReportingAuditing Recording AnalysesConduct Performance
Clinical
Trials
Data and Reported
Results are credible and
accurate
Rights, Integrity, &
Confidentiality of Trial
Subjects are protected

4. ICH-GCP
• ICH is the International
Conference on Harmonisation
of Technical Requirements for
Registration of
Pharmaceuticals for Human
Use.
• ICH-GCP is Good Clinical
Practice guidelines agreed at
the conference
ICH
GCP

5. • Derived from the International Conference on
Harmonization (ICH)
• Based on the Declaration of Helsinki
• Assures protection of human subjects
• Assures unified, high standards for designing,
conducting, recording and reporting trials
Good Clinical Practices

6. Good Clinical Practices
• Applies to Clinical Data intended to be
submitted to regulatory authorities
• Also applies to:
Clinical
Interventions
Observational
Studies

7. History of Good Clinical Practice
The Nuremburg Code of 1947
Experiments performed in Germany
during WWII opened the eyes of the world
for guidance for clinical testing on
humans.
The code did set ethical guidelines, but it
lacked legislation to back it up.
Declaration of Helsinki
In 1964, the World Medical Association
established recommendations guiding
medical doctors in biomedical research
involving human subjects. These
guidelines influenced national
legislation, but there was no set
standard between nations
Prior to an actual set of
guidelines to follow for GCP
Clinical Studies
were Dangerous
Serous Disease
Possibly Death

8. Declaration of Helsinki
Adapted from the Nuremberg Code by The World Medical
Association to address the needs of the biomedical community
First published in 1964, revised five time most recently in 2001
Lists 31 principles
It is the international standard for the conduct of clinical
research

9. Key Points: Declaration of Helsinki
• “Concern for the interests of the subjects
must always overcome over the interests of
science and society”
• The experimental protocol must be reviewed by
a “specially-appointed committee independent
of the investigator and the sponsor.”

10. Key Points: Declaration of Helsinki
• Distinguishes between research “in which the
aim is essentially diagnostic or therapeutic for a
patient” and research “which is purely scientific”
Diagnostic &
Therapeutic Purely
Scientific

11. Key Points: Declaration of Helsinki
• In research which does not offer the hope of
direct benefit to the participant is restricted to
healthy volunteers or volunteers “for whom the
experimental design is not related to the patient
illness.”
Diagnostic &
Therapeutic Purely
Scientific

12. History of Good Clinical Practice
(Continued)
• The formation of the International Conference on
Harmonization (ICH) led to the creation of the Consolidated
Guidance on GCP
▫ The ICH consisted of the governments of the
United States, EU and Japan coming together
to develop common regulations for the
pharmaceutical markets among member countries

13. Harmonization Process
Japan
EU
ICH
USA
ICH

14. Milestones in Good Clinical Practice
1977 Federal Registers published in U.S. by FDA (Food and Drug
Administration)
1986 UK published guidelines ‘Good Clinical Research Practice’
1987 France and Nordic Countries published laws
1990 European GCP Guidelines published
1996 International Conference on Harmonisation produced ICH
GCP E6 document.

15. ICH Structure: founding parties
• European Commission - European Union
(EU)
• European Federation of Pharmaceutical
Industries' Associations (EFPIA)
• Ministry of Health, Labour and Welfare,
Japan (MHW)
• Japan Pharmaceutical Manufacturers
Association (JPMA)
• US Food and Drug Administration (FDA)
• Pharmaceutical Research and
Manufacturers of America (PhRMA)

16. The Observers
• The World Health Organization (WHO)
• The European Free Trade Association (EFTA),
represented by Switzerland
• Canada, represented by Drugs Directorate,
Health Canada
• The International Federation of Pharmaceutical
Manufacturers Association (IFPMA)

17. ICH topics
Q "Quality" Topics, i.e., those relating to pharmaceutical quality
assurance (24 guidelines).
S "Safety" Topics, i.e., those relating to in vitro and in vivo pre-
clinical studies (15 guidelines).
E "Efficacy" Topics, i.e., those relating to clinical studies in
human subject (18 guidelines).
M Multidisciplinary Topics, i.e., cross-cutting topics which do not
fit uniquely into one of the above categories such as:
 Medical Terminology
 Electronic Standards for Transmission of Regulatory
Information (ESTRI)
 The Common Technical Document
(5 guidelines)

18. ICH topics
Q "Quality" Topics, i.e., those relating to pharmaceutical quality
assurance (24 guidelines).
S "Safety" Topics, i.e., those relating to in vitro and in vivo pre-
clinical studies (15 guidelines).
E "Efficacy" Topics, i.e., those relating to clinical studies in
human subject (18 guidelines).
M Multidisciplinary Topics, i.e., cross-cutting topics which do not
fit uniquely into one of the above categories such as:
 Medical Terminology
 Electronic Standards for Transmission of Regulatory
Information (ESTRI)
 The Common Technical Document
(5 guidelines)

19. Efficacy Guidelines
• E2 - Clinical Safety Data Management
• E3 - Structure and Content of Clinical Study Reports
• E6 - Good Clinical Practice
• E7 - Studies in Support of Special Populations/Geriatrics
• E8 - General Consideration of Clinical Trials
• E9 - Statistical Principles for Clinical Trials
• E11 - Clinical Investigation in the Pediatric Population
• E12 - Clinical Evaluation of New Antihypertensive Drugs

20. ICH GCP Guidelines documents
• Guideline for Good Clinical Practices (released
5/96)
▫ Essential Documents for the Conduct of a Clinical
Trial
▫ Investigator's Brochure
• Clinical Safety Data Management: Definition
and Standard for Expedited Reporting (released
10/94)
• Structure and Content of Clinical Study Reports
(released 11/95)

21. Who must comply with GCP?
• All individuals involved
in any aspect of the trial
must be suitably
‘qualified’ to be able to
comply with GCP

22. Who must comply with GCP?
• Sponsors/ Clinical
Investigators are
responsible for ensuring
that all staff are able to
comply with GCP
• All individuals involved
in any aspect of the trial
must be suitably
‘qualified’ to be able to
comply with GCP
Sponsors/CIs

23. Who is responsible for ensuring adherence to
GCP?
You

24. Principles of ICH GCP
1. Clinical trials should be conducted in accordance with
the ethical principles that have their origin in the
Declaration of Helsinki, and that are consistent with
GCP and the applicable regulatory requirements
Declaration
of Helsinki
RegulationsGCP

25. Principles of ICH GCP continued
2. Before a trial is initiated, foreseeable risks and
inconveniences should be weighed against the
anticipated benefit for the individual trial subject &
society. A trial should be initiated and continued only if
the anticipated benefits justify the risks.
Risks Benefits

26. Principles of ICH GCP continued
3. The rights, safety, and well-being of the trial
subjects are the most important considerations
and should prevail over interests of science &
society.
Science & SocietyTrial Subjects

27. 4. The available non-clinical & clinical
information on an investigational product
should be adequate to support the proposed
clinical trial.
Principles of ICH GCP continued
Clinical Trial

28. 5. Clinical trials should be scientifically sound, and
describe in a clear, detailed protocol.
Principles of ICH GCP continued
Scientifically
Sound

29. 5. A trial should be conducted in compliance with the
protocol that has received prior IRB (or IEC) approval.
Principles of ICH GCP continued
IRB

30. 7. The medical care given to, and medical decisions made
on behalf of, subjects should always be the
responsibility of a qualified physician or, when
appropriate, of a qualified dentist.
Principles of ICH GCP continued

31. 7. Each individual involved in conducting a trial should
be qualified by education, training & experience to
perform his or her respective tasks.
Principles of ICH GCP continued
Education
Training
Experience

32. 9. Freely given informed consent should be obtained from
every subject prior to clinical trial participation.
Principles of ICH GCP continued

33. 9. All clinical trial information should be recorded,
handled, and stored in a way that allows its accurate:
1. Reporting
2. Interpretation
3. Verification.
Principles of ICH GCP continued

34. 11. The confidentiality of records that could identify
subjects should be protected, respecting the privacy
and confidentiality rules in accordance with the
applicable regulatory compliance.
Principles of ICH GCP continued

35. 12. Investigational products should be manufactured,
handled, and stored in accordance with applicable
Good Manufacturing Practice (GMP). They should be
used in accordance with the approved protocol.
Principles of ICH GCP continued
Good
Manufacturing
Practice

36. 12. Systems with procedures that assure the quality of
every aspects of the trial should be implemented.
Principles of ICH GCP continued
Quality

37. Areas Addressed in
the GCP
Gu idelin es
IRB/EC
Investigator
Responsibilities
Investigator’s
Brochure Clinical Trial
Protocol
Sponsor
Responsibilities
Essential
Documents
Principles of GCP

38. IRB/Ethics
Committee
• All studies must be
approved prior to recruiting
participants
• IRB must review all
documents given to
participants
• Composition of the IRB
• Reporting from protocol to
the IRB
• Maintenance of Records
IRB/EC

39. Review
Approval
Recruiting
IRB must review all documents
given to participants
All studies must be approved
Reporting from protocol to the IRB
IRB/EC
IRB/Ethics
Committee
• All studies must be
approved prior to recruiting
participants
• IRB must review all
documents given to
participants
• Composition of the IRB
• Reporting from protocol to
the IRB
• Maintenance of Records

40. SCENE
Investigator Responsibilities
Qualifications & Agreements
1
2
3
Up to date CV
Compliance with GCP
Familiar with investigational product
Permit of monitoring by sponsor
Maintenance of a list of qualified personnel
4
5

41. What counts as ‘qualified’?
• Education
• Training
• Experience

42. What counts as ‘qualified’?
• Education
• Training
• Experience
There is no GCP ‘qualification’

43. Education
Individuals must be educated to be able to
competently perform their specific trial task
▫ Clinicians must be clinically qualified
▫ Statisticians must be qualified
▫ Managers must be appropriately educated

44. Training
There are variety of courses and seminars
currently available
Employer orientation courses
Industry courses
E-learning (some Institute of Clinical Research)
Private courses (usually run by self-employed consultant)
Host institution courses
Trial specific workshops
Investigators meetings

45. Experience
On-the-job learning
▫ Discovering what is required
▫ Doing the job (sometimes wrongly)
▫ Following information and knowledge through teams/units
▫ Talking to other trialists

46. Adequate Resources
Time
Staff
Informed
Recruitment
Investigator Responsibilities
SCENE

47. Adequate Resources
Time
Staff
Informed
Recruitment
Investigator Responsibilities
SCENE
Time

48. Adequate Resources
Time
Staff
Informed
Recruitment
Investigator Responsibilities
SCENE

49. Adequate Resources
Time
Staff
Informed
Recruitment
Investigator Responsibilities
SCENE
Time

50. Medical Care
Investigator Responsibilities

51. Medical Care
 A qualified MD (or dentist) responsible for trial-related
medical decisions
 Provide adequate medical care for AEs or other
significant medical condition
 Inform subject's primary physician about participation
in trial
 Make a reasonable effort to ascertain why participant
withdrawals from study
Medical Care
Investigator Responsibilities

52. Medical Care
 A qualified MD (or dentist) responsible for trial-related
medical decisions
 Provide adequate medical care for AEs or other
significant medical condition
 Inform subject's primary physician about participation
in trial
 Make a reasonable effort to ascertain why participant
withdrawals from study
Medical Care
Investigator Responsibilities

53. Medical Care
 A qualified MD (or dentist) responsible for trial-related
medical decisions
 Provide adequate medical care for AEs or other
significant medical condition
 Inform subject's primary physician about participation
in trial
 Make a reasonable effort to ascertain why participant
withdrawals from study
Medical Care
Investigator Responsibilities

54. Medical Care
 A qualified MD (or dentist) responsible for trial-related
medical decisions
 Provide adequate medical care for AEs or other
significant medical condition
 Inform subject's primary physician about participation
in trial
 Make a reasonable effort to ascertain why participant
withdrawals from study
Medical Care
Investigator Responsibilities

55. The investigator/institution
should have:
• Written and dated approval
opinion from the IRB/IEC for
the trial protocol,
• Written informed consent
form, consent form updates,
• Subject recruitment
procedures
• Any other written
information to be provided to
subjects.
The investigator/institution
•Should provide to the
IRB/IEC all documents
subject to review.
The investigator's/institution
should provide the IRB/IEC
with a current copy of the
Investigator's Brochure.
If the Investigator's Brochure
is updated during the trial, the
investigator/institution should
supply a copy of the updated
Brochure to the IRB/IEC.
Investigator Responsibilities
Communication with IRB
Before the Trial During the Trial Investigator`s Brochure

56. Protocol
If deviations occur, they should be
reported
Investigator Responsibilities
Compliance with protocol
The investigator may
implement a deviation
As soon as possible should be
submitted:
a) to the IRB/IEC for review and approval
opinion,
b) to the sponsor for agreement and, if required,
c) to the regulatory authorities.

57. Investigator Responsibilities
Investigational Product
Records
Storing
Using Explaining
Responsibility

58. Participant should
be given a copy
Informed Consent
All contents
of the
informed consent
Informed Consent
Signed & dated
by participant
Informed Consent
Provide ample
time to review
& ask questions
Informed Consent
Ubderstandable
Language
Informed Consent
No language of
a waiver of
legal rights
Informed Consent
Fully inform
participant
of all aspects
of the trial
Informed Consent
Investigator Responsibilities
Informed Consent
•No coercion
•No influence
Informed Consent
•Written
•Can be revised
Informed Consent
GCP
IRB
Informed Consent

59. Investigator Responsibilities
Records & Reports
Accuracy, Completeness, Legibility & Timeliness of
data reported
CRF consistent with Source documentation
Changes to CRF should be Dated, Singed &
Explained
Maintain Trial documents
Financial aspects noted in contract
Make available all records for monitor, auditor, IRB,
or other regulatory authority

60. Investigator Responsibilities
Progress Report
IRB
Annually
If requested

61. Investigator Responsibilities
Progress Report
IRB
Annually
If requested

62. Investigator Responsibilities
Progress Report
IRB
Sponsor
Authorities
Annually
If requested

63. 1. Quality Assurance & Quality Control
2. Contract Research Organization (CRO)
3. Medical Expertise
4. Trial Design
Sponsor Responsibilities
• Provide written Standard Operating
Procedures (SOP)s
• Secures agreement between all parties
• Data handling
Hired by the sponsor to implement trial-
related duties
Designated medical personnel to advise on
trial-related medical questions and
problems
• Designs Case Report Form (CRF)s
• Planning analyses

64. 5. Management, Data Handling,
Recordkeeping, & Data Monitoring
Committee
6. Investigator Selection
7. Allocation of Duties & Functions
8. Compensation to Subjects &
Investigators
Sponsor Responsibilities
Qualified personnel to supervise overall conduct
of the study
DMC assesses the progress of the clinical trial
Maintain SOPs for electronic data processing
Inform Investigator of guidelines for record
retention
Qualifications by training and experience
Sponsor should define, establish and
allocate all trial-related duties and
functions
Insure investigator/institution against
claims arising from the trial
Coverage for the cost of treatment
Compensation for the subject

65. 9. Financing
10. Notification/Submission to Regulatory
Authorities
11. Confirmation of Review by IRB
12. Information on Investigational
Products
Sponsor Responsibilities
Submission of required applications to
authorities for review, acceptance, and/or
permission to begin trial
Sufficient safety & efficacy data from non-
clinical studies are available to support
human exposure
Update Investigator’s Brochure as new
info becomes available
Should obtain name & address of
institutional IRB, statement that they
comply with GCPs and applicable laws
and regulations
Documentation of approval
Financing

66. 13. Manufacturing, Packaging, Labeling, &
Coding Investigational Products
14. Supplying & Handling Investigational
Products
15. Record Access
16. Safety Information
Sponsor Responsibilities
Timely delivery of product
Maintenance of records (shipment,
receipt, return)
System for disposition of unused product
Ongoing safety evaluation
Sponsor should have access to records
Manufactured in accordance with GMPs
Coded and labeled in a manner that
protects blinding
PI should be informed of storage
information

67. 17. Adverse Drug Reaction Reporting
18. Monitoring
19. Auditing
20. Noncompliance
Sponsor Responsibilities
Rights and well being of human subjects
are protected
Trial data are accurate and complete
Noncompliance
Evaluate trial conduct and compliance
with protocol, SOPs, GCPs and other
regulatory requirements
Report all adverse drug reactions that are
serious and unexpected
Submit all safety updates and DSM
reports

68. 21. Premature Termination or Suspension
of a Trial
22. Clinical Trial/Study Reports
23. Multicenter Trials
Sponsor Responsibilities
Communication is facilitated between all
investigators
Clinical Trial/Study Reports
Promptly notify investigators/institution
with reason for the termination

69. Resources
• http://www.fda.gov/oc/gcp/guidance.htm
• http://www.clinicaltrials.gov/
• http://www.fda.gov/oc/ohrt/irbs/websites.html
• http://ohrp.osophs.dhhs.gov/
• http://privacyruleandresearch.nih.gov/