Ich Fda Socra 09 2007

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  • 1. Where the FDA Regulations End and ICH GCP Begins The Differences & Similarities Between the Two Paul Below, CCRA GCP Trainer Medical Research Management, Inc. SoCRA 16 th Annual Conference Adams Mark Hotel, Denver, CO September 29, 2007
  • 2.
    • This presentation was inspired by Norman Goldfarb, Managing Director of First Clinical Research.
    • At the 2006 SoCRA Annual Meeting, he asked the question during a session on monitoring, “How many in the audience know at least three differences between the FDA regulations and the ICH GCP Guidelines?”
  • 3.
    • Define what ICH is and what role the ICH guidelines play in clinical research
    • Review the ICH Guidelines for Good Clinical Practice (GCP) and how they differ from the FDA regulations
    • Discuss the impact of ICH GCPs on Investigator sites
    Learning Objectives
  • 4.
    • International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use
    • Working group of pharmaceutical industry experts and regulatory authorities from the European Union, Japan, and the United States
    What is ICH?
  • 5.
    • Aim to produce a single set of technical requirements for the registration of new drug drug products to streamline development
    • Reduce or obviate duplicate testing
    • More economical use of human, animal and material resources
    • Eliminate unnecessary delays in the availability of new medicines
    ICH Purpose
  • 6.
    • Reduced development time and cost
    • Easier simultaneous new drug submission in many countries
    • Facilitates intra-company globalization
    Importance of ICH to Industry
  • 7.
    • European Union began to successfully harmonize member country regulatory requirements in the 1980's
    • WHO Conference of Drug Regulatory Authorities (Paris, 1989) was start of the harmonization process between Europe, U.S. and Japan
    • First meeting held in 1990 (Brussels) with biennial meetings held since
    • 37 guidelines produced to date
    ICH History
  • 8.
    • Quality (24 guidelines) - related to chemical and pharmaceutical quality assurance
    • Safety (15 guidelines) - related to pre-clinical studies
    • Efficacy (18 guidelines) - related to clinical research in human subjects
    • Multidisciplinary (5 guidelines) – i.e., Medical Terminology (MedDRA)
    ICH Categories
  • 9.
    • E2 - Clinical Safety Data Management
    • E3 - Structure and Content of Clinical Study Reports
    • E6 - Good Clinical Practice
    • E7 - Studies in Support of Special Populations/Geriatrics
    • E8 - General Consideration of Clinical Trials
    • E9 - Statistical Principles for Clinical Trials
    • E11 - Clinical Investigation in the Pediatric Population
    • E12 - Clinical Evaluation of New Antihypertensive Drugs
    Efficacy Guidelines
  • 10.
    • International ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve participation of human subjects
    • Compliance assures rights, safety and well-being of trial subjects are protected (consistent with Declaration of Helsinki)
    ICH Guideline for GCP (E6)
  • 11.
    • Facilitate the mutual acceptance of clinical data by the regulatory authorities of the EU, Japan, and the U.S.
    • Prior to ICH, criteria for acceptance by FDA of foreign clinical studies outlined in 21 CFR 312.120 (required to conduct trials in accordance with Declaration of Helsinki)
    ICH GCP Objective
  • 12.
    • Published as “guidance document” in the Federal Register , Vol. 62, May 9, 1997
    ICH GCP Implementation in US
  • 13.
    • Represents FDA's “current thinking” on ways to comply with regulations
    • Not legally binding
    • Non-compliance should not be cited in a FDA Form 483
    FDA Guidance Documents
  • 14.
    • E2A Guideline - Requirements and procedures for expedited pre- and post-marketing safety reporting.
    • “ Expedited Safety Reporting Requirements for Human Drug and Biological Products” published Federal Register , October 7, 1997.
    • Incorporated into CFR 21 part 312.32 on April 6, 1998.
    ICH as FDA Regulation
  • 15. Specific Differences Between ICH GCP and the FDA Regulations
  • 16.
    • Chapter 1 - Glossary
    • Chapter 2 - Principles of ICH GCP
    • Chapter 3 - Institutional Review Board
    • Chapter 4 - Investigator
    • Chapter 5 - Sponsor
    • Chapter 6 - Protocol and Amendments
    • Chapter 7 - Investigator’s Brochure
    • Chapter 8 - Essential Documents
    ICH GCP Sections
  • 17.
    • 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
    IRB Responsibilities (ICH 3.1)
  • 18.
    • 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
    IRB Composition (ICH 3.2)
  • 19.
    • FDA also requires the following ( 56.107a-f ):
      • 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
    IRB Composition cont.
  • 20.
    • ICH requires Investigators to maintain a list of appropriately qualified persons to whom significant trial-related duties have been delegated.
    Investigator Agreements (ICH 4.1)
  • 21.
    • ICH requires Investigators to demonstrate potential for recruiting the required number of patients within the agreed recruitment period.
      • Retrospective data
      • Patient database analysis
    Investigator Resources (ICH 4.2)
  • 22.
    • ICH requires Investigators to inform subjects when medical care is needed for an intercurrent illness.
    • ICH recommends that Investigators inform the subject’s primary physician of trial participation (with the subject’s permission).
    • ICH requires Investigators to make every reasonable effort to ascertain the reason(s) for subject early withdrawal (although the subject is not obliged to give a reason).
    Subject Medical Care (ICH 4.3)
  • 23.
    • ICH requires Investigators (or their designees) to document and explain any deviation from the approved protocol.
    Protocol Compliance (ICH 4.5)
  • 24.
    • ICH allows the delegation of study drug dispensing, patient counselling, and drug accountability to a designee.
    • FDA has no regulations or guidance concerning delegation of these duties.
    Investigational Product (ICH 4.6)
  • 25.
    • 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.
    Informed Consent (ICH 4.8)
  • 26.
    • 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.
    Informed Consent cont.
  • 27.
    • 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)
    Informed Consent cont.
  • 28.
    • ICH requires Investigators (or designees) to:
      • Document explanations for discrepancies between data in the CRFs and the source documents.
      • Initial, date and explain (if necessary) all CRF changes/corrections. CRF designees must be documented.
      • Endorse & retain records of all CRF changes made by the Sponsor.
    Records and Reports (ICH 4.9)
  • 29.
    • 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.
    Records and Reports (ICH 4.9)
  • 30.
    • ICH requires Sponsors to secure agreement from all involved parties to ensure direct access of study records to foreign regulatory authorities.
    Sponsor QA/QC (ICH 5.1)
  • 31.
    • ICH requires Sponsors to inform Investigators in writing of:
      • Study record retention requirements
      • Notification of when records are no longer needed
    Record Keeping (ICH 5.5)
  • 32.
    • ICH requires Sponsors to provide insurance or indemnify the investigator against claims arising from the trial.
    Compensation (ICH 5.8)
  • 33.
    • FDA requires extensive disclosure of the Investigator’s financial relationship with the Sponsor (21 CFR 54).
    • ICH has no comparable guideline and only requires that financial aspects of the trial be documented in an agreement between the Sponsor and Investigator.
    Financing (ICH 5.9)
  • 34.
    • ICH requires Sponsors to obtain a statement from Investigators that their local IRB is organized and operates according to GCP and applicable laws and regulations.
    IRB Review (ICH 5.11)
  • 35.
    • ICH requires Sponsors to obtain documentation of IRB approval prior to shipping investigational product to an Investigator.
    Supplying IP (ICH 5.14)
  • 36.
    • 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).
    Monitoring (ICH 5.18)
  • 37.
    • 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
    Monitoring cont.
  • 38.
    • 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)
    Protocol and IB (ICH 6 & 7)
  • 39.
    • 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)
    Essential Documents (ICH 8)
  • 40.
    • 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)
    Essential Documents cont.
  • 41.
    • This presentation and related references are posted on my corporate website at: www.pbelow-consulting.com/ich-fda.html
  • 42.
    • Office: (952) 882-4083
    • E-mail: [email_address]
    Contact Information