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1 CNE Disclosures Successful Completion: Participants must complete an evaluation form to receive a certificate of completion Contact Hours: 1 contact hour is available to those who meet the successful completion requirements Sponsorship & Commercial Support: This activity has received no sponsorship or commercial support Conflict of Interest: No conflicts of interest were identified Non-Endorsement: Accreditation approval refers only to MONAs continuing education activities and does not imply MONA or ANCC Commission on Accreditation endorsement of any commercial products Off Label Use: There will be no discussion of uses of products other than what is approved by the FDA. Expiration: Contact Hours expire on October 29, International Conference on Harmonization Good Clinical Practice (ICH-GCP) Training Washington University Rod Walker, Quality Assurance Manager Chessa Williams, Quality Manager CSMQM 05 Jun 2014 Copyright 2013 Quintiles 1

2 Objectives Define Good Clinical Practice (GCP) Outline the goals of GCP Provide a historical perspective on GCP Common findings/observations Best practices 3 What is GCP? GCP is defined as a standard for the design, conduct, performance, monitoring, auditing, recording, analysis and reporting of clinical trials or studies 4 2

3 Why is GCP important? GCP compliance provides public assurance that the rights, safety and well-being of human subjects involved in research are protected 5 What are the goals of GCP? To protect the rights, safety and welfare of humans participating in research To assure the quality, reliability and integrity of data collected To provide standards and guidelines for the conduct of clinical research Good Clinical Practice = Ethics + Quality Data 6 3

4 What are the foundations for the ethical conduct of clinical research? The Nuremberg Code (1947) The Declaration of Helsinki (1964) The Belmont Report (1979) International Conference on Harmonisation (ICH- GCP) International Standards Organization Code of Federal Regulations 7 GCP: A Historical Perspective Nuremberg Code (1947) > Voluntary participation > Informed Consent > Minimization of risk 8 4

5 GCP: A Historical Perspective Declaration of Helsinki (1964) Well-being of subject takes precedence Respect for persons Protection of subjects health and rights Special protection for vulnerable populations 9 Belmont Report Ethical Principles (1979) Respect for Persons Informed consent Protection of vulnerable populations Beneficence Non-malfeasance Justice Fairness 10 5

6 The International Conference on Harmonisation (ICH-GCP) GCP is an international quality standard that is provided by the International Conference on Harmonization (ICH) Goals: Harmonize technical procedures and standards; improve quality; speed time to market In 1997, the FDA endorsed the GCP Guidelines developed by ICH ICH guidelines have been adopted into law in several countries, but used as guidance for the FDA in the form of GCP 11 Exercise You are being invited to participate in a clinical research study as a study subject. What considerations would be important to you? 12 6

7 Principles of GCP Conducted according to GCP, local regulations & ethical principles of Declaration of Helsinki (for countries where DoH is incorporated into the GCP directive) Risks and inconveniences weighed against anticipated benefits for the subject and society Rights, safety and well-being of subjects prevail over interests of science and society Adequate clinical and non-clinical justification Scientifically sound, clear, detailed protocol Medical care given by qualified physician Study team qualified by education, training & experience Freely given informed consent from every subject Information recorded handled & reported to allow reporting, interpretation and verification Confidentiality of subjects protected IP manufactured, handled and stored according to GMP IMP used according to the protocol Systems & procedures for quality assurance 13 Who is responsible for GCP compliance? Sponsors Clinical Investigators (CIs) Independent Ethics Committees (IECs) > Institutional Review Boards (IRBs) Contract Research Organizations (CROs) Research nurses Clinical Research Coordinators (CRCs) Clinical Research Associates (CRAs) Medical monitors Data entry personnel Others 14 7

8 Chapter 3 The Institutional Review Board/Independent Ethics Committee 15 An IRB/IEC should safeguard the rights, safety, and well-being of all trial subjects. Special attention should be paid to trials that may include vulnerable subjects 16 8

9 IEC Responsibilities 1.The investigator may provide information on any aspect of the trial, but should not participate in the deliberations or in the vote. True or False? 2.The IRB/IEC should conduct continuing review of each ongoing trial. True or False? 3. If the prior consent of the trial subject or their legally acceptable representative is not possible (according to the protocol), the trial may not proceed. True or False? 4. All relevant records should be retained for at least 3 years True or False? 5. The IRB/IEC should establish and follow written procedures which include the authority under which it is established. True or False? 17 Chapter 4 Investigator Responsibilities 18 9

10 Investigator Obligations Qualifications Resources Medical care Institutional Review Board/Independent Ethics Committee Compliance with Protocol Investigational Product Randomization Unblinding Informed Consent Records/reports Progress reports Safety reporting Premature termination Final report Do all of these apply to Investigator Qualifications and Agreements Education, training, experience Regulatory requirements & GCP knowledge Use of Investigational Product Permit monitoring/auditing/inspection Maintain list of qualified staff to whom trial-related duties have been delegated Qualified staff should be informed about the protocol, IP, and their trial-related duties and functions 20 10

11 4.3 Medical Care of Trial Subjects Qualified physician Adequate medical care Inform primary physician Ascertain reasons for withdrawal Medical Care of Trial Subjects Common Observations / Findings Determination of eligibility was not documented by an Investigator Lack of documentation to indicate the PI's review of severity and causality of AEs Lab reports and ECGs not reviewed in a timely manner Lab reports and ECGs not assessed for clinical significance IP dose modifications not documented by the PI Not providing appropriate medical oversight Subjects randomized in error Delegation of responsibilities to site staff that are not appropriately trained or qualified

12 4.3 Medical Care of Trial Subjects Best Practices Routine meetings with study staff Routine meetings with the CRA Review and initial/date Follow-up letters Review IND Safety Letters Review study correspondence such as newsletters Conduct study procedures See study subjects at study visits QC check to verify that the Investigator has signed and dated and provided an assessment of clinical significance PI check Adverse Events at each visit and verify that all are assessed Provide prompts in the source to have Investigator sign and date Compliance with Protocol Protocol agreement Deviations clarify Eliminate immediate hazard Should document and explain any deviation from the protocol 24 12

13 4.6 Investigational Product (IP) PI accounts for IP Pharmacist Accountability Storage Usage Administration Informed Consent (1/2) RA, GCP, EC approval Revision of ICF No coercion No language about waiving legal rights PI/designate to inform subject Non-technical and practical language Time and questions opportunity Obtain prior to study procedures Sign and date Impartial witness 26 13

14 4.8 Informed Consent (2/2) Elements Copy of signed/dated ICF Minors: Assent compatible with understanding Subjects should personally give consent Non-therapeutic trials with consent of Legally Acceptable Representative (LAR) Emergency situations Informed Consent Common Observations / Findings Person obtaining consent did not sign and date the consent Subjects were not reconsented with new versions of the consent form in a timely manner Subjects were not consented with the most current version at the screening visit The subject did not initial each page of the consent form ICF process was not documented in the source documents Subjects were not consented in their native language 28 14

15 4.8 Informed Consent Best Practices QC Check Have a site staff member that did not consent the subject verify that each page is present and completed appropriately prior to making a photocopy of the consent form to give to the subject. That way if anything was incomplete it can be corrected while the subject is still on-site. Develop an ICF tracking log to document all versions of the consent form to help ensure that the current version is used at the screening visit. When a new ICF is received, photocopy it, and place in the front of each subject s source chart as a prompt to obtain at the next study visit. Develop a thorough, comprehensive template to document the ICF process in the source Records and Reports ALCOA Acronym for Good Documentation ttributable egible ontemporaneous riginal ccurate 30 15

16 4.9 Records and Reports CRFs should be derived from source documents and consistent with source data CRF/source changes line through and initial/date PI/institution to maintain trial documents until at least 2 years after the last approval of a marketing application Financial agreement Records and Reports Direct Access Upon request of the monitor, auditor, IRB, or regulatory authority the PI should make available for direct access to all requested trial related records

17 4.9 Records and Reports Common Observations / Findings Medical records were not obtained or requested Access to Electronic Medical Records not provided Reports (Lab, ERT, ECG, IVRS, etc) not located in source. CRF entries are not supported by source Documented attributability (initials/signature and date) was not present to indicate who conducted study visit tasks and procedures. (ALCOA) Unreported Medical History events/concomitant Medications/AEs Records and Reports Best Practices Develop source document worksheets that provide a line for signature and date for the study coordinator and Investigator for each study procedure. Know where all source is located and provide all source documents to CRAs/Auditors. Including research chart and medical record chart (paper or EMR). QC Checks: Study Coordinator and PI to review the visits together during their routine meetings to spot-check each other. If there are multiple Study Coordinators on site, suggest that they spot-check each other s documentation as well. Compare Medical History, Concomitant Meds, and Adverse Events on a routine basis

18 4.10 Progress Reports Annually to IEC/IRB Reports to sponsor and IEC/IRB and Institution Premature Termination/Suspension Promptly inform subjects Investigator terminates trial Sponsor terminates IRB/IEC terminates 36 18

19 4.13 Final Report(s) by Investigator Institution IRB/IEC Regulatory Authorities Does GCP require the investigator to provide the IRB/IEC letter to the Sponsor? 37 Chapter 5 Sponsor/CRO Obligations 38 19

20 5.2, 5.3, 5.4, 5.5 :Sponsor/CRO Responsibilities Sponsor/CRO transfer of trial obligations Medical Expertise and Trial Design Trial Management, Data Handling, and Record Keeping Qualified individuals Independent data-monitoring committee (IDMC), if req. Validated data processing system when using electronic trial data systems Retention of sponsor-specific essential documents 39 5: Sponsor/CRO Responsibilities 5.6 Investigator Selection Investigators qualified by training and experience Adequate resources Investigator's/institution's agreement Signed protocol 40 20

21 Sponsor/CRO Responsibilities 5.18 Monitoring The purposes of monitoring are to verify: the rights and well-being of human subjects are protected the reported trial data are accurate, complete, and verifiable from source documents the conduct of the trial is in compliance with the protocol, GCP, and the applicable regulatory requirements Monitor appointed by the sponsor appropriately trained with the scientific and/or clinical knowledge qualifications documented 41 Sponsor/CRO Responsibilities 5.19 Quality Assurance (QA) and Quality Control (QC) implementing and maintaining QA and QC systems to ensure that trials are conducted and data are generated, recorded, and reported in compliance with Protocol, GCP, applicable regulatory requirement(s) What do you consider as a QC system? What is the definition of a QA system? securing agreement from all involved parties to ensure direct access to all trial related sites, source documents/ data and reports 42 21

22 1.6 What is an Audit? Audit is a part of implementing QA Does monitoring mean the same as the word audit? individuals who are independent of the clinical trial qualified by training and experience Noncompliance Non adherence to protocol, SOPs, GCP and/or applicable regulatory requirements by an investigator/ institution, or by member(s) of the sponsor staff. Identification of noncompliance should lead to prompt action by the sponsor to secure compliance Secure compliance or terminate the investigator s/institution s participation in the trial and. What else should the sponsor do if unable to secure site compliance? 44 22

23 Chapter 8 Essential Documents 45 Essential Documents Investigator brochure Signed protocol & amendments Informed consent documents Financial trial aspects Insurance statement Signed agreements between sponsor and investigators IEC/IRB approvals and annual reports IEC/IRB composition RA approval CVs of PI and Sub-Investigators Source documents CRFs SAE documents and safety information Subject ID list, screening and enrollment log Laboratory normal ranges, procedures and certifications Record of retained body fluids Sample of IP labels Instructions for handling IP IP shipping records and accountability and destruction documents Certificates of analysis Decoding procedures Randomisation list Monitoring reports Relevant communications Audit certificate Study report 46 23

24 Essential Documents - Time and Location Time to generate documents before trial commences during trial conduct after trial completion/termination Location of documents Investigator/Institution site Sponsor s office