ICH-GCP & FDA Regulations Differences

1. ICH-GCP & FDA Regulations Differences John D. Burke Director, Human Subjects Protection Program University Of Louisville April 21, 2009

2. International Conference on Harmonisation (ICH) The International Conference on Harmonisation (ICH) ……. for Registration of Pharmaceuticals for Human Use ….. brings together the regulatory authorities of Europe, Japan, and the United States and experts from the pharmaceutical industry …. to discuss scientific and technical aspects of product (development) registration.

3. International Conference on Harmonisation (ICH) The purpose is to make recommendations on ways to achieve greater harmonisation in the interpretation and application of technical guidelines and requirements for product registration (development) in order to reduce or obviate the need to duplicate the testing carried out during the research and development of new medicines.

4. International Conference on Harmonisation (ICH) The objective of such harmonisation is a more economical use of human, animal and material resources, and the elimination of unnecessary delay in the global development and availability of new medicines whilst maintaining safeguards on quality, safety and efficacy, and regulatory obligations to protect public health.

5. International Conference on Harmonisation (ICH) • The ICH Topics are divided into four major categories (Q, S, E, M) and ICH Topic Codes are assigned according to these categories. • Quality (32) - those relating to chemical and pharmaceutical Quality Assurance • Safety (14) - those relating to in vitro and in vivo pre-clinical studies • Efficacy (17)- those relating to clinical studies in human subject • Multidisciplinary (5)- cross-cutting Topics which do not fit uniquely into one of the above categories

6. International Conference on Harmonisation (ICH) • E6(R1): Good Clinical Practice : Consolidated Guideline • This Good Clinical Practices document describes the responsibilities and expectations of all participants in the conduct of clinical trials, including investigators, monitors, sponsors and IRBs.

7. International Conference on Harmonisation (ICH) • Principal Investigator Responsibilities • Sponsor Responsibilities • IRB Responsibilities

8. Investigator Responsibilitiesand Resources • ICH requires Investigators to maintain a list of appropriately qualified persons to whom significant trial-related duties have been delegated. • ICH requires Investigators to demonstrate potential for recruiting the required number of patients within the agreed recruitment period. • Retrospective data • Patient database analysis

9. Principal Investigator (PI) Responsibilities ICH requires Investigators (or designees) to: • Document explanations for discrepancies between data in the case report form (CRF) and the source documents. • Initial, date, and explain (if necessary) all CRF changes/corrections. CRF designees must be documented.

10. PI Responsibilities:Protocol Deviation(s) • Endorse & retain records of all CRF changes made by the Sponsor. • ICH requires Investigators (or their designees) to document and explain any deviation from the approved protocol.

11. PI Responsibilities: Medical Care for Subjects • ICH requires Investigators to inform subjects when medical care is needed for an concurrent current illness. • With the subject’s permission, ICH recommends that Investigators inform the subject’s primary physician of trial participation. • Although a subject is not obliged to give a reason, ICH requires Investigators to make every reasonable effort to ascertain the reason(s) for subject early withdrawal.

12. PI Responsibilities: Test Article (drug) Control • ICH allows the delegation of study drug/device dispensing, patient counselling, and drug accountability to a designee. • FDA has no regulations concerning delegation of these duties but recently published a draft guidance (May 2007) on the supervisory responsibilities of investigators (http://www.fda.gov/cber/gdlns/studysub.pdf).

13. PI Responsibilities:Records Retention • ICH requires the retention of “essential documents” for at least two years after the approval of a marketing application in an ICH region or until there is no pending or contemplated applications in an ICH region or development is formally discontinued. • ICH compliance generally requires a longer retention time than FDA regulations.

14. PI Responsibilities: Informed Consent Documentation • ICH allows the delegation of the informed consent process to a designee. • FDA has no regulations concerning delegation of this duty although it is discussed in the FDA Information Sheets. • UPDATE: Also discussed in detail in the May 2007 FDA draft guidance on the supervisory responsibilities of investigators.

15. PI Responsibilities: Informed Consent Documentation • ICH requires the person conducting the informed consent process to sign and date the consent form. • ICH requires that the subject receive a signed and dated copy of the consent form. FDA only requires that a copy be provided.

16. PI Responsibilities: Informed Consent Documentation • ICH requires the following informed consent elements not required by the FDA: • Discussion of trial treatments and probability of random assignment • Subject responsibilities • Anticipated payment, if any, to the subject • Important potential risks and benefits of alternative treatment • Authorization to access medical records by regulatory authorities (FDA and foreign)

17. Protocol & Investigator Brochure • ICH has more detailed outline of contents of the protocol and Investigator Brochure than the FDA regulations [21 CFR 312.23(a)(5-6)] • ICH requires that the protocol identify any data to be recorded directly on the CRFs and to be considered source data (ICH 6.4.9)

18. Essential Documents • ICH requires the following documents not specified by the FDA: • Subject Screening Log (to document subjects who enter trial screening) • Subject Identification Code List (confidential list of subject names in case identity must be revealed for follow-up) • Signature Sheet (to document signatures/initials of persons authorized to make CRF entries and corrections)

19. Essential Documents • ICH requires the following documents be filed at the site: • Trial Initiation Monitoring Report (to document that trial procedures were reviewed with the Investigator and staff) • Relevant Communications (letters, meeting notes, notes of telephone calls)

20. Sponsor Responsibilities • ICH requires Sponsors to secure agreement from all involved parties to ensure direct access of study records to foreign regulatory authorities. • ICH requires Sponsors to inform the PI in writing of: • Study record retention requirements • Notification of PI when records are no longer needed

21. Sponsor Responsibilities ICH requires Sponsors to provide insurance or indemnify the investigator against claims arising from the trial.

22. Sponsor Responsibilities: Significant Financial Conflict of Interest • FDA requires extensive disclosure of the Investigator’s financial relationship with the Sponsor . • ICH has no comparable guideline and only requires that financial aspects of the trial be documented in an agreement between the Sponsor and Investigator.

23. Sponsor Responsibilities:Clinical Trial Monitoring • FDA specifies that Sponsors shall monitor the progress of all clinical investigations (21 CFR 312.56) and that monitors be qualified by training and experience (21 CFR 312.53). • FDA has a guidance document on the topic, “Guideline for the Monitoring Clinical Investigations” (January 1988).

24. Sponsor Responsibilities: Clinical Trial Monitoring • ICH includes the following items not addressed in the FDA guidance: • Monitor qualifications must be documented • Monitors must verify that trial functions have not been delegated to unauthorized individuals • Sponsors must document review and follow-up of the monitoring report

25. IRB Responsibilities • An independent body provides public assurance, among other things, by reviewing and approving / providing favorable • opinion on, the trial protocol, the suitability of the investigator(s), facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial subjects.

26. IRB Responsibilities • Both FDA and ICH require IRBs to be composed of the following members: • At least five members • One non-scientific member • One member not affiliated with the institution • Members involved in the protocol not have a voting role

27. IRB Responsibilities • FDA also requires the following: • One scientific member • Diversity in race, gender, cultural backgrounds • Varying backgrounds - not composed of only one profession • Members qualified to assess the acceptability of the protocol with institutional SOPs & professional practice standards • Members with a conflicting interest cannot vote for protocol approval

28. IRB Responsibilities • FDA and ICH both require the IRB to review informed consent, protocol, advertisements, and the Investigator's Brochure. • ICH also requires IRB submission of: • Subject recruitment procedures • Written information provided to subjects • Information about subject compensation • Investigator's current CV and/or other documents evidencing qualifications

29. Informed Consent DocumentAdditional Requirements due to ICH GCP • The subject's responsibilities; • The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important potential benefits and risks.

30. Impartial Witness • A person, who is independent of the trial, who cannot be unfairly influenced by people involved with the trial, who attends the informed consent process if the subject or the subject’s legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the subject.

31. IRB Review • ICH requires Sponsors to obtain a statement from Investigators that their local IRB is organized and operates according to ICH-GCP and applicable laws and regulations. • ICH requires Sponsors to obtain documentation of IRB approval prior to shipping investigational product to an Investigator.

32. IRB Review If the University of Louisville Human Subjects Protection Program were to become ICH-GCP compliant, the UofL IRB would provide the following statement to investigators who conduct Clinical Trials for sponsors intending to submit study results to European Union, Japanese or United States pharmaceutical manufacturers for drug approval.

33. IRB Review • The Biomedical Institutional Review Board (IRB) for the University of Louisville (UofL) and its affiliates assures the following: • The responsibilities of the UofL IRB are in agreement with the ICH-GCP section 3.1 requirements. • The composition, function, and operations of the UofL IRB are in agreement with the ICH-GCP section 3.2 requirements. • The UofL IRB operates under a written standard operating procedure, documenting all committee actions in agreement with ICH-GCP section 3.3 requirements. • The records of the UofL IRB are maintained in accordance with the ICH-GCP section 3.4 requirements. • For clinical trials conducted in the United States, the UofL IRB is established, constituted, and operated in agreement with the requirements of the Combined Federal Regulations 21 CFR 50 and 56.

34. ICH-GCP & FDA Regulations Differences harmonisation vs. harmonization