International Conference on Harmonization Good Clinical Practices Kelly

International Conference on Harmonization Good Clinical Practices Kelly O’Berry, BS, CIP IRB Education & Outreach Manager Human Subjects Office

Outline of Presentation Federal regulations for the protection of human subjects A Brief History of the ICH Requesting GCP review by the IRB Purpose of GCP Guidance Additional requirements in GCP Guidelines

Federal Regulations The Food and Drug Administration (FDA) ▪ Research of FDA regulated products ▪ Drug Research: 21 CFR 50, 54, 56 and 312 ▪ Device Research: 21 CFR 812 and 814 The Department of Health and Human Services (HHS) ▪ Research supported by HHS ▪ UI applies these regulations to all research, regardless of funding source ▪ 45 CFR 46, Subparts A-D

Published Guidance Help IRB’s and investigators comply with regulations Current interpretation of regs Address new study procedures The guidance is just a recommendation, but researchers MUST comply with the regulations.

Good Clinical Practice Guidelines

ICH – Brief History Representatives from Europe, Japan and the United States met in Brussels in 1990 to address: • The rising cost of health care • The escalating cost of R&D • The need to reduce delays in making safe and effective new treatments available to patients • Duplication of efforts in both animal and human trials in order to bring new drugs to market internationally.

ICH Purpose The objective of ICH is to increase international harmonisation of technical requirements to ensure that safe, effective, and high quality medicines are developed and registered in the most efficient and cost-effective manner. These activities have been undertaken to promote public health, prevent unnecessary duplication of clinical trials in humans, and minimize the use of animal testing without compromising safety and effectiveness. http: //www. ich. org/about/faqs. html

ICH Today Harmonized guidelines and recommendations in the EU, Japan, and the U. S. as well as Australia, Canada, the Nordic countries and the World Health Organization (WHO). Four categories: Safety (S) Quality (Q) Efficacy (E) Multidisciplinary Topics (M)

ICH Efficacy Guidelines http: //www. ich. org/products/guidelines/efficacy/article/efficacy-guidelines. html

Benefits of GCP Compliance Protect rights, safety and welfare of subjects Ensures that clinical trial data are credible Acceptance of clinical trial data in the EU and Japan More stringent than FDA requirements

IRB Review of Documents Section 3. 1. 2 Protocol and protocol amendments Informed Consent Documents Recruitment advertisements Written information for subjects Investigator’s Brochure Available safety information Investigator’s CV or other documentation of qualifications

Additional Elements of Consent Potential risks and benefits of alternative procedures (Section 4. 8. 10(i)) Compensation/treatment for study-related injury (Section 4. 8. 10(j)) Trial treatments and probability of assignment (Section 4. 8. 10(c)) Subject responsibilities (Section 4. 8. 10(e)) Anticipated benefits OR if no intended clinical benefit (Section 4. 8. 10(h)) Payment, if any (Section 4. 8. 10(k))

Documentation of Consent Section 4. 8. 8 The subject AND the person who obtains consent sign and date the informed consent document.

Signed Copy of the Document Section 4. 8. 11 Signed and dated copy of the Informed Consent Document for the subject or Legally Authorized Representative (LAR) Also a HIPAA requirement

Access to Records Section 4. 8. 1 o(n) The ICH guidelines require broader notice to subjects regarding potential access to identifiable medical records. Monitor(s), Auditor(s), The IRB, and Regulatory authority(ies) Disclose this in the Confidentiality and HIPAA Privacy sections of the Informed Consent Document – and in the Hawk. IRB application

Non-Therapeutic Trials Section 4. 8. 13 Only enroll subjects who have the capacity to consent for themselves Describe that in Section VI. 28 -VI. 31. b. i of the Hawk. IRB application

Exceptions Non-Therapeutic Trials Objectives of the trial can not be met if only enrolling subjects who can consent for themselves Foreseeable risks to subjects are low Negative impact on the subject well-being is minimized and low Trial is not prohibited by law IRB approval to enroll subjects who cannot consent for themselves - explicitly sought AND granted

Assent to Participate Section 4. 8. 12 Subjects who cannot consent for themselves should: be informed about the trial Indicate agreement to participate (as they are able) - sign and date the Informed Consent Document The Legally Authorized Representative (LAR) must sign and date the Informed Consent Document Plan for obtaining assent from minors and decisionally- impaired adults

Illiterate Subjects Section 4. 8. 9 Witness signature Indicates that study information was accurately explained and apparently understood Documents that informed consent was freely given by the subject or LAR

Adequate Resources Section 4. 2 The investigator must demonstrate the potential for recruiting the required number of subjects in Section VI. 14 and VI. 15 of the Hawk. IRB application.

Adequate Resources Section 4. 2 Time Staffing Facilities Training

GCP Compliant IRB Review Section 5. 11 A statement that the IRB is organized and operates according to GCP and the applicable laws and regulations. The investigator or the institution may be asked to provide this to the sponsor.

Investigator Responsibilities Section 4. 3 Medical Care of Trial Subjects A physician (or dentist) Investigator or sub-Investigator is responsible for all trial-related medical/dental decisions Provide adequate medical care for any adverse events related to the trial, including clinically significant lab values

Investigator Responsibilities Section 4. 3 Medical Care of Trial Subjects Inform subjects of any intercurrent illness requiring medical care that come to the attention of the investigator With subject permission, inform the subjects’ primary physician of their participation in the trial

Investigator Responsibilities Section 4. 3 Medical Care of Trial Subjects Make a reasonable effort to ascertain the reason a subject withdraws early. (Note: subjects are not obligated to provide a reason. )

Record Keeping • Section 4. 9. 5 - Length of storage • Section 8 - Essential documents for three stages of the study: • Before the clinical trial begins • During the clinical trial • After completion or termination • GCP Essential Documents handout • document title • purpose of storage • where to store them (with investigator and/or sponsor

Essential Documents Timeliness Accuracy Legibility Completeness

Case Report Forms Section 4. 9. 2 and 4. 9. 3 Data must be consistent with the source document Changes to CRFs must be: • Dated • Initialed • Explained The original entry must remain visible to preserve an audit trail

Record Storage Requirements Keep me for…. . 'image: www. freeimages. co. uk'

Contract with the Sponsor Section 4. 9. 6 The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution. Work with Division of Sponsored Programs (DSP)

Progress Reports for the IRB (Section 4. 10) Continuing Review - Written summary of trial status Project Closure Form - Final Report upon completion of trial Written report of any changes affecting: ▪ Conduct of the trial ▪ Increased risk to subjects

Safety Reporting Section 4. 11 Immediately report all serious adverse events (SAEs) to the sponsor Unless immediate reporting is not required per the protocol or IB FDA reporting guidelines IRB reporting guidelines

Termination/Suspension of Trial Section 4. 12 Inform subjects Assure appropriate follow up / therapy Inform FDA, IRB and Sponsor as required Provide a written explanation of the termination or suspension to the IRB and the Sponsor.

Investigational Products Trial Site Responsible for accountability Investigational Drug Service (IDS) Store it properly Use it properly Explain proper use Following instructions

Training Requirements CITI Training – UI Investigators Good Clinical Practice Course (US FDA focus) GCP Course for Clinical Trials Involving Investigational Drugs (international/ICH focus) GCP Course for Clinical Trials Involving Investigational Medical Devices (international/ICH focus)

VA GCP Training Requirement For VAHCS Investigators: CITI Basic Course for those who have never taken the basic course on Human Subjects Protections and GCP through CITI. This course consists of nine modules. CITI 101 Refresher Course

Hawk. IRB Application This option may only be selected if the sponsor will not accept contract language that states the University of Iowa will “comply with ICH-GCP requirements as adopted by FDA. ” Regular review should be selected when contracts contain this language. If this option is selected, the Principal Investigator will be held solely responsible for ensuring all study procedures meet ICH-GCP standards. Additional standards are required under full ICH-GCP compliance. Specific information on those standards can be found here.

ICH-GCP Assurances ICH-GCP Guidelines ICH-GCP training Medical care for adverse events Notify subjects’ physician of participation Reason for early withdrawal

Curriculum Vitae Section 4. 1. 1 and Section 3. 1. 3 Satisfies 2 ICH-GCP requirements: Evidence of investigator qualifications (Section 4. 1. 1) IRB review responsibilities (Section 3. 1. 3)

Questions or Comments? Kelly O’Berry, BS, CIP Human Subjects Office https: //hso. research. uiowa. edu/ Ph: 319 -335 -6564 E-mail: irb@uiowa. edu

References Dorota. (2000). Principles of good clinical practice (GCP) in clinical research. Science and Engineering Ethics, 6(1), 71 -77. http: //search. proquest. com/docview/42975481? accountid=14663 Kaur, S. and Choy, C. Y. (2012), Ethical Considerations in Clinical Trials: A Critique of the ICH-GCP Guideline. Developing World Bioethics. https: //www. ncbi. nlm. nih. gov/pubmed/23170779 ICH E 6: Good Clinical Practice: Consolidated Guidance. http: //www. fda. gov/downloads/Drugs/Guidance. Compliance. Regulatory. Informati on/Guidances/UCM 073122. pdf ICH website: http: //www. ich. org/ Comparison of FDA and HHS Human Subject Protection Regulations: http: //www. fda. gov/Science. Research/Special. Topics/Running. Clinical. Trials/Educat ional. Materials/ucm 112910. htm Federal Register, Vol. 78, No. 37 Proposed Rules http: //www. gpo. gov/fdsys/pkg/FR-2013 -02 -25/pdf/2013 -04201. pdf IICH E 6 as adopted by the US FDA http: //www. fda. gov/downloads/Drugs/Guidance. Compliance. Regulatory. Informati on/Guidances/ucm 073122. pdf