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Conducting Studies to the International Gold Standard: Going Beyond What the FDA Requires

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This presentation was given at the Clinical Research Symposium of the Children’s Medical Center, Dallas, TX in November 2011.

This presentation was given at the Clinical Research Symposium of the Children’s Medical Center, Dallas, TX in November 2011.


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  • 1. Presented by Paul Below, CCRA, CCRT P. Below Consulting, Inc. Conducting Studies to theInternational Gold StandardGoing Beyond What the FDA Requires
  • 2. Learning Objectives• Define what the “international gold standard” is for conducting clinical trials (aka, ICH Guidelines)• Review the ICH Guidelines for Good Clinical Practice (GCP) and how they differ from the FDA regulations• Discuss the impact of the ICH Guidelines for GCP on investigator sites Copyright © 2011 - P. Below Consulting, Inc.
  • 3. What is ICH?• 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 Copyright © 2011 - P. Below Consulting, Inc.
  • 4. ICH Purpose• Aim to produce a single set of technical requirements for the registration of new 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 Copyright © 2011 - P. Below Consulting, Inc.
  • 5. Importance to Industry • Reduced development time and cost • Easier to submit a new drug application simultaneously in many countries • Facilitates intra-company globalization Copyright © 2011 - P. Below Consulting, Inc.
  • 6. ICH HistoryEuropean Union (EU)began to successfullyharmonize membercountry regulatoryrequirements in the1980s Copyright © 2011 - P. Below Consulting, Inc.
  • 7. ICH History (cont.)• WHO Conference of Drug Regulatory Authorities (Paris, 1989) was the start of the harmonization process between Europe, U.S. and Japan• First ICH meeting was held in 1990 (Brussels) with biennial meetings since Copyright © 2011 - P. Below Consulting, Inc.
  • 8. ICH Guideline Categories• Quality - related to chemical and pharmaceutical quality assurance• Safety - related to pre-clinical studies• Efficacy - related to clinical research in human subjects• Multidisciplinary - i.e., Medical Terminology (MedDRA) Copyright © 2011 - P. Below Consulting, Inc.
  • 9. Efficacy Guidelines• 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
  • 10. ICH Guideline for GCP (E6)• 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 the Declaration of Helsinki)• Finalized April 1996 Copyright © 2011 - P. Below Consulting, Inc.
  • 11. ICH GCP Objective• Facilitate the mutual acceptance of clinical data by the regulatory authorities of the EU, Japan, and the US• Prior to ICH, only criteria for acceptance by FDA of foreign clinical studies was outlined in 21 CFR 312.120 (required to conduct trials in accordance with the Declaration of Helsinki) Copyright © 2011 - P. Below Consulting, Inc.
  • 12. ICH Implementation• Japanese Ministry of Health adopted ICH GCP as law – however, they still require some local studies for product approval there• EU codified ICH GCP into their Clinical Trial Directives – member countries must model their laws to comply with the directives• There are still major differences in clinical trial regulations across the EU member countries but ICH has created a common starting foundation Copyright © 2011 - P. Below Consulting, Inc.
  • 13. ICH Implementation in US • Published by FDA as a Guidance Document in the Federal Register, Vol. 62, May 9, 1997 • After publication, many pharma companies completely revamped their clinical SOPs to come into compliance Copyright © 2011 - P. Below Consulting, Inc.
  • 14. ICH Adopted as Regulation• E2A Guideline - Requirements & 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 Copyright © 2011 - P. Below Consulting, Inc.
  • 15. Device Harmonization• Global Harmonization Task Force (GHTF) Guidelines• EU Medical Device Directives• ISO 14155 (2011) Standard for Conducting Clinical Trials with Medical Devices• Many device companies have incorporated ICH Guidelines into their SOPs Copyright © 2011 - P. Below Consulting, Inc.
  • 16. Recent paper in ACRP’s The Monitor (10/2011) Copyright © 2011 - P. Below Consulting, Inc.
  • 17. Specific DifferencesBetween ICH GCP and the FDA Regulations Copyright © 2011 - P. Below Consulting, Inc.
  • 18. ICH GCP Chapters• Chapter 1 - Glossary• Chapter 2 - Principles of ICH GCP• Chapter 3 - Institutional Review Board• Chapter 4 - Investigator• Chapter 5 - Sponsor• Chapter 6 - Protocol & Amendments• Chapter 7 - Investigator’s Brochure• Chapter 8 - Essential Documents Copyright © 2011 - P. Below Consulting, Inc.
  • 19. IRB Responsibilities (3.1)FDA and ICH both require the IRB to review theinformed consent, protocol, advertisements, andInvestigators Brochure. Copyright © 2011 - P. Below Consulting, Inc.
  • 20. IRB Responsibilities (cont.)In addition, ICH also requires IRB submission of: • Subject recruitment procedures • Written information provided to subjects • Information about subject compensation • Investigators current CV and/or other documents evidencing qualifications Copyright © 2011 - P. Below Consulting, Inc.
  • 21. IRB Composition (3.2)Both FDA and ICH require IRBs to be composedof the following members: • At least five members • One non-scientific member • One member not affiliated with the institution • Members involved in the protocol do not have a voting role Copyright © 2011 - P. Below Consulting, Inc.
  • 22. IRB Composition (cont.)FDA also requires the following (21 CFR 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 Copyright © 2011 - P. Below Consulting, Inc.
  • 23. Investigator Agreements (4.1) ICH requires investigators to maintain a list of appropriately qualified persons to whom significant trial- related duties have been delegated. Copyright © 2011 - P. Below Consulting, Inc.
  • 24. Investigator Resources (4.2)ICH states that investigators should be able todemonstrate the potential for recruiting therequired number of patients within the agreedrecruitment period: • Retrospective data • Patient database analysis • Chart screening Copyright © 2011 - P. Below Consulting, Inc.
  • 25. Subject Medical Care (4.3)• 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) Copyright © 2011 - P. Below Consulting, Inc.
  • 26. Subject Medical Care (cont.)ICH requires investigators to make everyreasonable effort to ascertain the reason(s) forsubject early withdrawal (although the subject is notobliged to give a reason). Copyright © 2011 - P. Below Consulting, Inc.
  • 27. Protocol Compliance (ICH 4.5) ICH requires investigators (or their designees) to document and explain any deviation from the approved protocol Copyright © 2011 - P. Below Consulting, Inc.
  • 28. Investigational Product (4.6)• ICH allows the delegation of study drug dispensing, patient counselling, and drug accountability to a designee• FDA has no regulations concerning this but has recently published guidances that address the delegation of these duties Copyright © 2011 - P. Below Consulting, Inc.
  • 29. Informed Consent (4.8) • ICH allows the delegation of conducting the informed consent process to a designee• FDA has no regulations concerning this but this is addressed in depth in the FDA Information Sheets and October 2009 FDA Guidance on the Investigator Supervisory Responsibilities Copyright © 2011 - P. Below Consulting, Inc.
  • 30. Informed Consent (cont.)• ICH requires that the person conducting the informed consent process 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) Copyright © 2011 - P. Below Consulting, Inc.
  • 31. Informed Consent (cont.)ICH requires the following informed consentelements 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) Copyright © 2011 - P. Below Consulting, Inc.
  • 32. Informed Consent (cont.)FDA has recentlyadded a new informedconsent element that isunique to the US(amended 21 CFRPart 50.25) Copyright © 2011 - P. Below Consulting, Inc.
  • 33. Informed Consent (cont.)New rule requires informed consent documentsfor applicable drug and device clinical trials toinclude the following statement:“A description of this clinical trial will be availableon http://www.clinicaltrials.gov, as required byU.S. Law. This Web site will not includeinformation that can identify you. At most, theWeb site will include a summary of the results.You can search this Web site at any time.” Copyright © 2011 - P. Below Consulting, Inc.
  • 34. Records and Reports (4.9)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 Copyright © 2011 - P. Below Consulting, Inc.
  • 35. Records and Reports (cont.)• 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 the FDA regulations Copyright © 2011 - P. Below Consulting, Inc.
  • 36. Sponsor QA / QC (5.1)ICH requires sponsors tosecure agreement from allinvolved parties to ensuredirect access of studyrecords to foreignregulatory authorities Copyright © 2011 - P. Below Consulting, Inc.
  • 37. Record Keeping (5.5)ICH requires sponsors to inform investigators inwriting of: • Study record retention requirements • Notification of when records are no longer needed Copyright © 2011 - P. Below Consulting, Inc.
  • 38. Compensation (5.8)• ICH requires sponsors to provide insurance or indemnify the investigator against claims arising from the trial• Clinical trial insurance is a common part of doing studies in the EU Copyright © 2011 - P. Below Consulting, Inc.
  • 39. Financing (5.9)• FDA requires extensive disclosure of the Investigator’s financial relationship with the sponsor (21 CFR Part 54)• ICH has no comparable disclosure and only requires that financial aspects of the trial be documented in an agreement between the sponsor and investigator Copyright © 2011 - P. Below Consulting, Inc.
  • 40. IRB Review (5.11)• 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• In the US, if an IRB holds a Federal Wide Assurance Number, it has made a commitment to HHS that it will comply with the requirements in the HHS Protection of Human Subjects regulations at 45 CFR Part 46 Copyright © 2011 - P. Below Consulting, Inc.
  • 41. Supplying IP (5.14)ICH requires sponsors toobtain documentation ofIRB approval prior toshipping investigationalproduct to an investigator Copyright © 2011 - P. Below Consulting, Inc.
  • 42. Monitoring (5.18) FDA Regulations specify that sponsors shall monitor the progress of all clinical investigations (21 CFR Part 312.56) and that monitors shall be qualified by training and experience (21 CFR Part 312.53) Copyright © 2011 - P. Below Consulting, Inc.
  • 43. Monitoring (5.18)• FDA has an old guidance document on the topic, “Guideline for the Monitoring Clinical Investigations” (January 1988)• It was recently retracted to issue a new draft guidance “Oversight of Clinical Investigations: A Risk-Based Approach to Monitoring” (August 2011)• The new draft guidance added many items to make it consistent with ICH but it also has a few new ideas that go beyond ICH Copyright © 2011 - P. Below Consulting, Inc.
  • 44. Protocol and IB (6 & 7)• ICH has a more detailed outline of the contents of the protocol and Investigator Brochure than specified by the FDA regulations (21 CFR Part 312.23a)• ICH has a unique requirement that the protocol identify any data to be recorded directly on the CRFs that will be considered source data (ICH 6.4.9) Copyright © 2011 - P. Below Consulting, Inc.
  • 45. Essential Documents (8)ICH has a comprehensive set of tables that giverich detail on the regulatory documents that shouldbe on file with the investigator and the sponsorbefore, during, and after a study Copyright © 2011 - P. Below Consulting, Inc.
  • 46. Essential Documents (cont.)ICH requires the following documents notspecified 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) Copyright © 2011 - P. Below Consulting, Inc.
  • 47. Essential Documents (cont.)ICH requires the following documents be filedat 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) Copyright © 2011 - P. Below Consulting, Inc.
  • 48. A manuscript of this presentation was published in the SoCRA Source in August 2008
  • 49. Questions

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