1. Overview of Good Clinical Practices (GCPs)
Barbara Pennington, RN, MS
PPD

2. Why Regulate Clinical Research?
Ensure the rights, safety, and well-being of participants
Scientific Integrity of data 3

3. Good Clinical Practices (GCPs)
Standards for designing, conducting, performing, monitoring, auditing, recording, analyzing, and reporting clinical trials.
GCPs are not located in a single document - they are the collective body of knowledge that provide the industry standards, regulatory requirements, etc. 5

4. GCP OHRP ICH 21 CFR 45 CFR 46 International FDA Electronic Docs.
Inf. Consent
$ Disclosure
IRBs
IND regs.
IRBs
Inf. Consent
Women
Prisoners
Children
glossary
principles
IRBs
Investigator
Sponsor
Essential Docs

5. U.S. FDA (Food and Drug Administration)
Branch of the United States Department of Health and Human Services
Regulates all aspects of pharmaceutical industry
Title 21 of the Code of Federal Regulations (CFR)
Note that complete listing of specific sections of 21 CFR are on next slide and on page B-15 of module 10

6. CFR Title 21 Parts applicable to clinical research:
Part 11 - Electronic Records and Signatures
Part 50 - Protection of Human Subjects
Part 54 - Financial Disclosure by Clinical Investigators
Part 56 - Institutional Review Boards
Part Investigational New Drug Application
Part Applications for FDA Approval to Market a New Drug or an Antibiotic Drug
Part Biological Products
Part Medical Devices 11

7. Form FDA 1572 Contract between FDA and Investigator
Logistics such as names and addresses
Section 9
Commitments of the Investigator

8. Investigator of Record (IOR) Agreement
For Non-IND studies
Identifies key personnel, facilities, labs, IRBs
Also lists the commitments of the investigator

9. Commitments of the IOR Comply with protocol
Ensure compliance of IRB and consent process with 45CFR 46
Report AEs
Accurate record keeping and access
No changes to study without permission of Sponsor and IRB

10. This is a Non-IND Study
Do we have to worry about FDA?

11. Office for Human Research Protections (OHRP)
OHRP responsible for ensuring the safety and welfare of people who participate in HHS sponsored research
Under the DHHS Assistant Secretary of Health
45 CFR part 46
Formerly OPRR
The HHS (Health and Human Services Department) now has oversight for OHRP, previously known as OPRR, where this department reported to NIH.

12. 45 CFR part 46 IRB Informed Consent
Protection of Fetuses, Pregnant Women
Protection of Prisoners
Protection of Children
Per the Code of Federal Regulations (CFR), this policy applies to all research involving human subjects conducted, supported or otherwise subject to regulation by any Federal Department or Agency.
This policy does not affect any State or local laws or regulations which may otherwise be applicable and which provide additional protections for human subjects. In other words, if the local regulations are more stringent, those additional local requirements will still apply. The same is true of foreign laws or regulations.

13. 45CFR 46 Subpart A The “Common Rule” Protection of Human Subjects
IRB/IEC
Informed Consent
Variations from FDA Regulations

14. 45CFR 46 Subpart B
Protections for Pregnant Women, Fetuses and Neonates
Definitions
Recent revisions

15. 45CFR 46 Subpart C
Additional Protections for Prisoners involved in research
Definition of Prisoner
Additional IRB Duties
Permitted Research

16. 45CFR 46 Subpart D
Additional Protections for Children involved in Research
Assent
Minimal risks

17. International Conference on Harmonisation (ICH)
Guidelines for Good Clinical Practices

18. 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, Japan, Australia, Canada, Nordic Countries, and WHO
The ICH guidelines were an attempt on the part of the European Union, Japan and the US to standardize the practice of clinical trials. So if a pharmaceutical company in the US has gone through the rigors of taking a drug through the approval process in the US and they want to market the drug in Japan, they don’t have to reinvent the wheel, so to speak. The Japanese regulatory authorities will recognize that if ICH guidelines have been adhered to, then the product should be able to go through the approval process in Japan without having to perform phase I-III testing all over again.
Several other countries recognize the ICH guidelines as a standard of clinical trials practice as well.

19. ICH GCP Consolidated Guideline E6
Glossary
Principles of ICH GCP
Information regarding:
IRB/IEC
Investigator
Sponsor
Protocol
Investigator’s Brochure
Essential Documents
Have class get out purple book and review Table of Contents on page 165.
Note page 163 contains information regarding inclusion in Federal Register. 12

20. 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
Encourage participants to look for the inclusion of these principles as they work through modules. 13

21. Principles of ICH GCP Use qualified support staff
Obtain informed consent
Record information appropriately
Protect confidentiality
Handle investigational products appropriately
Implement quality systems 14

22. Local Regulations
May have more detailed regulations that apply locally
Do not conflict with national regulations 15

23. Sponsor Policies US Department of Health and Human Services
NIH/DAIT/DAIDS
Essential Document and Source Document SOP

24. Internal SOPs Standard Operating Procedures (SOPs)
Detailed instructions describing the what, when, where, and by whom of performing an activity 18

25. Compliance =
Adherence to
GCPs
Sponsor policies
local regulations

26. Investigator Responsibilities

27. Investigator Responsibilities*
Investigator Qualifications and Agreements
qualified by education, training and experience
familiar with protocol, IB, IP
aware of and compliant with GCPs and applicable regs
permit monitoring
list of qualified personnel who are delegated duties
*(ICH 4.1-9)
These next few slides are taken from the ICH guidelines, chapter 4 which is all about the Investigator’s responsibilities. Investigator’s are required to ensure that the research staff (Subs, coordinators, data entry personnel) are qualified by education, training and experience to perform their study specific duties.
The delegation of duties list (noting study personnel and outlining each individuals’ responsibility) must be kept current throughout the duration of the study.

29. Investigator Responsibilities*
Adequate Resources
recruit adequate subjects
sufficient time
qualified staff and adequate facilities
Medical Care of Subjects
responsible for all trial related medical decisions
*(ICH )
There should also be documentation that notes site personnel have been informed and adequately trained to perform their research related responsibilities and that they understand their study specific duties.
Monitors will inspect the facilities at the research site at periodic intervals to ensure that the facilities and staff remain adequate to conduct the research.

30. Investigator Responsibilities*
Communication with IRB
approvals
ensure compliance
Compliance with Protocol
Investigational Product (IP)
proper delegation of duties
*(ICH )
This is something the FDA is really cracking down on lately as I’m sure you’ve heard about the recent problems with IRBs at institutions such as Duke, UAB, U of Colorado, and certainly the big issues with genetics studies at U Penn. IRB/ investigator relations problems have brought this issue to the headlines and therefore, have been and will continue to be more carefully scrutinized in the future by regulatory authorities.
The system of checks and balances as set forth in the CFR and ICH requires that the PI be responsible for ensuring that his/her local IRB is compliant with CFR part 56, which outlines the guidelines for IRBs.

31. How can the PI be held responsible for what the IRB does or does not do?
Document ALL interaction (verbal, electronic, written) with IRB including reminders of upcoming review requirements

32. Investigator Responsibilities*
Regulations require IRB is aware of changes in research activity
“…OHRP finds that changes to research protocol were implemented by investigators without IRB approval…”

33. Investigator Responsibilities*
Randomization & Unblinding
Informed Consent
Records and Reports
ensure accuracy, completeness, legibility and timeliness of data
data on CRF derived from Source Documents
changes made appropriately
allow direct access
*(ICH )
The PI is responsible for making sure that randomization codes remain secure and intact. The PI also ensures that records, whether regulatory documents, source documents or CRFs are legible and, if there are corrections, deletions, additions or any changes, that these are authorized by the PI.

34. Regulatory Authorities will inquire about:
Source of study subjects
Did they have the disease under study
Did they meet inclusion/exclusion criteria
Was the protocol precisely followed
Were AEs reported appropriately

35. Common OHRP Findings
IRB failed to review the research at a convened meeting
failure to review grant applications
Investigators failed to promptly report unanticipated problems involving risks to subjects to IRB, OHRP and Sponsor

36. Common OHRP Findings
Continuing review of research was NOT substantive nor meaningful
include a summary of AEs and unanticipated problems
# of subjects accrued
summary of recent literature, findings amendments, modifications since last review
relevant reports, information
current consent form

37. Common OHRP Findings
IRB did not ensure additional protections for vulnerable subjects
IRB members with conflicting interest participated in review
IRB meeting convened without Quorum (Non-scientist absent)

38. Common OHRP Findings IRB review of NIH approved consent
any changes to the sample consent form related to risks or alternative procedures must be justified in writing by the investigator, approved by IRB and reflected in the IRB minutes

39. OHRP Finds that the IRB:
Lacks diversity
is overburdened by large volume
level of staff support is insufficient
members lack detailed understanding of regs. for protection of human subjects
inadequate procedures for reporting of unanticipated problems

40. We Applaud COMPLIANCE GCPs Protocol DAIT/DAIDS procedures
Local regulations
Remember, if you are compliant with GCPs, the protocol, DAIDS procedural guidelines and your local state/country and IRB regulations, you will be “audit proof”.