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

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

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

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

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 312 - Investigational New Drug Application Part 314 - Applications for FDA Approval to Market a New Drug or an Antibiotic Drug Part 600 - Biological Products Part 812 - Medical Devices 11

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

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

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

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

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.

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.

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

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

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

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

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

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.

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

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

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

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

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

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

Compliance = Adherence to GCPs Sponsor policies local regulations

Investigator Responsibilities

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.

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 4.1-4.9) 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.

Investigator Responsibilities* Communication with IRB approvals ensure compliance Compliance with Protocol Investigational Product (IP) proper delegation of duties *(ICH 4.1-4.9) 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.

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

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…”

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 4.1-4.9) 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.

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

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

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

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)

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

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

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”.