Where the FDA Regulations Where the FDA Regulations End and ICH GCP BeginsEnd and ICH GCP BeginsThe Differences & Similarities Between the TwoThe Differences & Similarities Between the Two

Paul Below, CCRAPaul Below, CCRAGCP TrainerGCP TrainerMedical Research Management, Inc.Medical Research Management, Inc.

SoCRA 16SoCRA 16thth Annual Conference Annual Conference Adams Mark Hotel, Denver, COAdams Mark Hotel, Denver, COSeptember 29, 2007September 29, 2007

This presentation was inspired by Norman This presentation was inspired by Norman Goldfarb, Managing Director of First Clinical Goldfarb, Managing Director of First Clinical Research.Research.

At the 2006 SoCRA Annual Meeting, he asked At the 2006 SoCRA Annual Meeting, he asked the question during a session on monitoring, the question during a session on monitoring, “How many in the audience know at least three “How many in the audience know at least three differences between the FDA regulations and differences between the FDA regulations and the ICH GCP Guidelines?”the ICH GCP Guidelines?”

Define what ICH is and what role the ICH Define what ICH is and what role the ICH guidelines play in clinical research guidelines play in clinical research

Review the ICH Guidelines for Good Review the ICH Guidelines for Good Clinical Practice (GCP) and how they differ Clinical Practice (GCP) and how they differ from the FDA regulationsfrom the FDA regulations

Discuss the impact of ICH GCPs on Discuss the impact of ICH GCPs on Investigator sitesInvestigator sites

Learning ObjectivesLearning Objectives

International Conference on Harmonization International Conference on Harmonization of Technical Requirements for Registration of of Technical Requirements for Registration of Pharmaceuticals for Human UsePharmaceuticals for Human Use

Working group of pharmaceutical industry Working group of pharmaceutical industry experts and regulatory authorities from the experts and regulatory authorities from the European Union, Japan, and the United European Union, Japan, and the United StatesStates

What is ICH?What is ICH?

Aim to produce a single set of technical requirements Aim to produce a single set of technical requirements for the registration of new drug drug products to for the registration of new drug drug products to streamline developmentstreamline development

Reduce or obviate duplicate testingReduce or obviate duplicate testing

More economical use of human, animal and material More economical use of human, animal and material resourcesresources

Eliminate unnecessary delays in the availability of new Eliminate unnecessary delays in the availability of new medicines medicines

ICH PurposeICH Purpose

Reduced development time and costReduced development time and cost

Easier simultaneous new drug submission in Easier simultaneous new drug submission in many countriesmany countries

Facilitates intra-company globalizationFacilitates intra-company globalization

Importance of ICH to IndustryImportance of ICH to Industry

European Union began to successfully harmonize European Union began to successfully harmonize member country regulatory requirements in the 1980'smember country regulatory requirements in the 1980's

WHO Conference of Drug Regulatory Authorities (Paris, WHO Conference of Drug Regulatory Authorities (Paris, 1989) was start of the harmonization process between 1989) was start of the harmonization process between Europe, U.S. and JapanEurope, U.S. and Japan

First meeting held in 1990 (Brussels) with biennial First meeting held in 1990 (Brussels) with biennial meetings held sincemeetings held since

37 guidelines produced to date37 guidelines produced to date

ICH HistoryICH History

QualityQuality (24 guidelines) - related to chemical and (24 guidelines) - related to chemical and pharmaceutical quality assurancepharmaceutical quality assurance

SafetySafety (15 guidelines) - related to pre-clinical studies (15 guidelines) - related to pre-clinical studies

EfficacyEfficacy (18 guidelines) - related to clinical research (18 guidelines) - related to clinical research in human subjectsin human subjects

MultidisciplinaryMultidisciplinary (5 guidelines) – i.e., Medical (5 guidelines) – i.e., Medical Terminology (MedDRA)Terminology (MedDRA)

ICH CategoriesICH Categories

E2 - Clinical Safety Data ManagementE2 - Clinical Safety Data Management

E3 - Structure and Content of Clinical Study ReportsE3 - Structure and Content of Clinical Study Reports

E6 - Good Clinical PracticeE6 - Good Clinical Practice

E7 - Studies in Support of Special Populations/GeriatricsE7 - Studies in Support of Special Populations/Geriatrics

E8 - General Consideration of Clinical TrialsE8 - General Consideration of Clinical Trials

E9 - Statistical Principles for Clinical TrialsE9 - Statistical Principles for Clinical Trials

E11 - Clinical Investigation in the Pediatric PopulationE11 - Clinical Investigation in the Pediatric Population

E12 - Clinical Evaluation of New Antihypertensive DrugsE12 - Clinical Evaluation of New Antihypertensive Drugs

Efficacy GuidelinesEfficacy Guidelines

International ethical and scientific quality International ethical and scientific quality standard for designing, conducting, recording, standard for designing, conducting, recording, and reporting trials that involve participation of and reporting trials that involve participation of human subjectshuman subjects

Compliance assures rights, safety and well-Compliance assures rights, safety and well-being of trial subjects are protected (consistent being of trial subjects are protected (consistent with Declaration of Helsinki)with Declaration of Helsinki)

ICH Guideline for GCP (E6)ICH Guideline for GCP (E6)

Facilitate the mutual acceptance of clinical Facilitate the mutual acceptance of clinical data by the regulatory authorities of the EU, data by the regulatory authorities of the EU, Japan, and the U.S. Japan, and the U.S.

Prior to ICH, criteria for acceptance by FDA of Prior to ICH, criteria for acceptance by FDA of foreign clinical studies outlined in 21 CFR foreign clinical studies outlined in 21 CFR 312.120 (required to conduct trials in 312.120 (required to conduct trials in accordance with Declaration of Helsinki)accordance with Declaration of Helsinki)

ICH GCP ObjectiveICH GCP Objective

Published as “guidance document” in the Published as “guidance document” in the Federal RegisterFederal Register, Vol. 62, May 9, 1997, Vol. 62, May 9, 1997

ICH GCP Implementation in USICH GCP Implementation in US

Represents FDA's “current thinking” on ways Represents FDA's “current thinking” on ways to comply with regulationsto comply with regulations

Not legally bindingNot legally binding

Non-compliance should not be cited in a FDA Non-compliance should not be cited in a FDA Form 483Form 483

FDA Guidance DocumentsFDA Guidance Documents

E2A Guideline - Requirements and procedures for E2A Guideline - Requirements and procedures for expedited pre- and post-marketing safety expedited pre- and post-marketing safety reporting. reporting.

““Expedited Safety Reporting Requirements for Expedited Safety Reporting Requirements for Human Drug and Biological Products” published Human Drug and Biological Products” published Federal RegisterFederal Register, October 7, 1997., October 7, 1997.

Incorporated into CFR 21 part 312.32 on Incorporated into CFR 21 part 312.32 on April 6, 1998.April 6, 1998.

ICH as FDA RegulationICH as FDA Regulation

Specific Differences Between Specific Differences Between ICH GCP and the FDA ICH GCP and the FDA

RegulationsRegulations

Chapter 1 - GlossaryChapter 1 - Glossary

Chapter 2 - Principles of ICH GCPChapter 2 - Principles of ICH GCP

Chapter 3 - Institutional Review BoardChapter 3 - Institutional Review Board

Chapter 4 - Investigator Chapter 4 - Investigator

Chapter 5 - SponsorChapter 5 - Sponsor

Chapter 6 - Protocol and AmendmentsChapter 6 - Protocol and Amendments

Chapter 7 - Investigator’s BrochureChapter 7 - Investigator’s Brochure

Chapter 8 - Essential DocumentsChapter 8 - Essential Documents

ICH GCP SectionsICH GCP Sections

FDA and ICH both require the IRB to review informed consent, FDA and ICH both require the IRB to review informed consent, protocol, advertisements, and the Investigator's Brochure.protocol, advertisements, and the Investigator's Brochure.

ICH also requires IRB submission of:ICH also requires IRB submission of:

Subject recruitment proceduresSubject recruitment procedures

Written information provided to subjectsWritten information provided to subjects

Information about subject compensationInformation about subject compensation

Investigator's current CV and/or other documents evidencing Investigator's current CV and/or other documents evidencing qualificationsqualifications

IRB Responsibilities (ICH 3.1)IRB Responsibilities (ICH 3.1)

Both FDA and ICH require IRBs to be Both FDA and ICH require IRBs to be composed of the following members:composed of the following members:

At least five membersAt least five members

One non-scientific memberOne non-scientific member

One member not affiliated with the institutionOne member not affiliated with the institution

Members involved in the protocol not have a voting Members involved in the protocol not have a voting rolerole

IRB Composition (ICH 3.2)IRB Composition (ICH 3.2)

FDA also requires the following (FDA also requires the following (56.107a-f56.107a-f):):

One scientific memberOne scientific member

Diversity in race, gender, cultural backgroundsDiversity in race, gender, cultural backgrounds

Varying backgrounds - not composed of only one professionVarying backgrounds - not composed of only one profession

Members qualified to assess the acceptability of the protocol Members qualified to assess the acceptability of the protocol with institutional SOPs & professional practice standardswith institutional SOPs & professional practice standards

Members with a conflicting interest cannot vote for protocol Members with a conflicting interest cannot vote for protocol approvalapproval

IRB Composition cont.IRB Composition cont.

ICH requires Investigators to maintain a list of ICH requires Investigators to maintain a list of appropriately qualified persons to whom appropriately qualified persons to whom significant trial-related duties have been significant trial-related duties have been delegated.delegated.

Investigator Agreements (ICH 4.1)Investigator Agreements (ICH 4.1)

ICH requires Investigators to demonstrate ICH requires Investigators to demonstrate potential for recruiting the required number of potential for recruiting the required number of patients within the agreed recruitment period. patients within the agreed recruitment period.

Retrospective data Retrospective data

Patient database analysisPatient database analysis

Investigator Resources (ICH 4.2)Investigator Resources (ICH 4.2)

ICH requires Investigators to inform subjects when ICH requires Investigators to inform subjects when medical care is needed for an intercurrent illness.medical care is needed for an intercurrent illness.

ICH recommends that Investigators inform the subject’s ICH recommends that Investigators inform the subject’s primary physician of trial participation (with the subject’s primary physician of trial participation (with the subject’s permission).permission).

ICH requires Investigators to make every reasonable ICH requires Investigators to make every reasonable effort to ascertain the reason(s) for subject early effort to ascertain the reason(s) for subject early withdrawal (although the subject is not obliged to give a withdrawal (although the subject is not obliged to give a reason).reason).

Subject Medical Care (ICH 4.3)Subject Medical Care (ICH 4.3)

ICH requires Investigators (or their ICH requires Investigators (or their designees) to document and explain any designees) to document and explain any deviation from the approved protocol. deviation from the approved protocol.

Protocol Compliance (ICH 4.5)Protocol Compliance (ICH 4.5)

ICH allows the delegation of study drug ICH allows the delegation of study drug dispensing, patient counselling, and drug dispensing, patient counselling, and drug accountability to a designee.accountability to a designee.

FDA has no regulations or guidance FDA has no regulations or guidance concerning delegation of these duties.concerning delegation of these duties.

Investigational Product (ICH 4.6)Investigational Product (ICH 4.6)

ICH allows the delegation of the informed ICH allows the delegation of the informed consent process to a designee.consent process to a designee.

FDA has no regulations concerning FDA has no regulations concerning delegation of this duty although it is delegation of this duty although it is discussed in the FDA Information Sheets.discussed in the FDA Information Sheets.

Informed Consent (ICH 4.8)Informed Consent (ICH 4.8)

ICH requires the person conducting the ICH requires the person conducting the informed consent process to sign and date informed consent process to sign and date the consent form.the consent form.

ICH requires that the subject receive a ICH requires that the subject receive a signed signed and datedand dated copy of the consent form. FDA copy of the consent form. FDA only requires that a copy be provided.only requires that a copy be provided.

Informed Consent cont.Informed Consent cont.

ICH requires the following informed consent elements not ICH requires the following informed consent elements not required by the FDA:required by the FDA:

Discussion of trial treatments and probability of random assignmentDiscussion of trial treatments and probability of random assignment

Subject responsibilitiesSubject responsibilities

Anticipated payment, if any, to the subjectAnticipated payment, if any, to the subject

Important potential risks and benefits of alternative treatmentImportant potential risks and benefits of alternative treatment

Authorization to access medical records by regulatory authorities Authorization to access medical records by regulatory authorities (FDA and foreign)(FDA and foreign)

Informed Consent cont.Informed Consent cont.

ICH requires Investigators (or designees) to:ICH requires Investigators (or designees) to:

Document explanations for discrepancies between Document explanations for discrepancies between data in the CRFs and the source documents.data in the CRFs and the source documents.

Initial, date and explain (if necessary) all CRF Initial, date and explain (if necessary) all CRF changes/corrections. CRF designees must be changes/corrections. CRF designees must be documented.documented.

Endorse & retain records of all CRF changes made by Endorse & retain records of all CRF changes made by the Sponsor.the Sponsor.

Records and Reports (ICH 4.9)Records and Reports (ICH 4.9)

ICH requires the retention of “essential ICH requires the retention of “essential documents” for at least two years after the documents” for at least two years after the approval of a marketing application in anapproval of a marketing application in an ICH ICH regionregion or until there is no pending or or until there is no pending or contemplated applications in an contemplated applications in an ICH regionICH region or or development is formally discontinued. development is formally discontinued.

ICH compliance generally requires a longer ICH compliance generally requires a longer retention time than FDA regulations.retention time than FDA regulations.

Records and Reports (ICH 4.9)Records and Reports (ICH 4.9)

ICH requires Sponsors to secure agreement ICH requires Sponsors to secure agreement from all involved parties to ensure direct from all involved parties to ensure direct access of study records to foreign regulatory access of study records to foreign regulatory authorities.authorities.

Sponsor QA/QC (ICH 5.1)Sponsor QA/QC (ICH 5.1)

ICH requires Sponsors to inform Investigators ICH requires Sponsors to inform Investigators in writing of:in writing of:

Study record retention requirementsStudy record retention requirements

Notification of when records are no longer neededNotification of when records are no longer needed

Record Keeping (ICH 5.5)Record Keeping (ICH 5.5)

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

Compensation (ICH 5.8)Compensation (ICH 5.8)

FDA requires extensive disclosure of the FDA requires extensive disclosure of the Investigator’s financial relationship with the Investigator’s financial relationship with the Sponsor (21 CFR 54).Sponsor (21 CFR 54).

ICH has no comparable guideline and only ICH has no comparable guideline and only requires that financial aspects of the trial be requires that financial aspects of the trial be documented in an agreement between the documented in an agreement between the Sponsor and Investigator.Sponsor and Investigator.

Financing (ICH 5.9)Financing (ICH 5.9)

ICH requires Sponsors to obtain a statement ICH requires Sponsors to obtain a statement from Investigators that their local IRB is from Investigators that their local IRB is organized and operates according to GCP organized and operates according to GCP and applicable laws and regulations.and applicable laws and regulations.

IRB Review (ICH 5.11)IRB Review (ICH 5.11)

ICH requires Sponsors to obtain ICH requires Sponsors to obtain documentation of IRB approval prior to documentation of IRB approval prior to shipping investigational product to an shipping investigational product to an Investigator.Investigator.

Supplying IP (ICH 5.14)Supplying IP (ICH 5.14)

FDA specifies that Sponsors shall monitor the FDA specifies that Sponsors shall monitor the progress of all clinical investigations (21 CFR progress of all clinical investigations (21 CFR 312.56) and that monitors be qualified by 312.56) and that monitors be qualified by training and experience (21 CFR 312.53).training and experience (21 CFR 312.53).

FDA has a guidance document on the topic, FDA has a guidance document on the topic, “Guideline for the Monitoring Clinical “Guideline for the Monitoring Clinical Investigations” (January 1988).Investigations” (January 1988).

Monitoring (ICH 5.18)Monitoring (ICH 5.18)

ICH includes the following items not ICH includes the following items not addressed in the FDA guidance:addressed in the FDA guidance:

Monitor qualifications must be documentedMonitor qualifications must be documented

Monitors must verify that trial functions have not Monitors must verify that trial functions have not been delegated to unauthorized individualsbeen delegated to unauthorized individuals

Sponsors must document review and follow-up of Sponsors must document review and follow-up of the monitoring reportthe monitoring report

Monitoring cont.Monitoring cont.

ICH has more detailed outline of contents of ICH has more detailed outline of contents of the protocol and Investigator Brochure than the protocol and Investigator Brochure than the FDA regulations [21 CFR 312.23(a)(5-6)]the FDA regulations [21 CFR 312.23(a)(5-6)]

ICH requires that the protocol identify any ICH requires that the protocol identify any data to be recorded directly on the CRFs and data to be recorded directly on the CRFs and to be considered source data (ICH 6.4.9)to be considered source data (ICH 6.4.9)

Protocol and IB (ICH 6 & 7)Protocol and IB (ICH 6 & 7)

ICH requires the following documents not specified ICH requires the following documents not specified by the FDA:by the FDA:

Subject Screening LogSubject Screening Log (to document subjects who enter (to document subjects who enter trial screening) trial screening)

Subject Identification Code ListSubject Identification Code List (confidential list of subject (confidential list of subject names in case identity must be revealed for follow-up)names in case identity must be revealed for follow-up)

Signature SheetSignature Sheet (to document signatures/initials of (to document signatures/initials of persons authorized to make CRF entries and corrections)persons authorized to make CRF entries and corrections)

Essential Documents (ICH 8)Essential Documents (ICH 8)

ICH requires the following documents be filed ICH requires the following documents be filed at the site:at the site:

Trial Initiation Monitoring Report (to document that Trial Initiation Monitoring Report (to document that trial procedures were reviewed with the trial procedures were reviewed with the Investigator and staff) Investigator and staff)

Relevant Communications (letters, meeting notes, Relevant Communications (letters, meeting notes, notes of telephone calls)notes of telephone calls)

Essential Documents cont.Essential Documents cont.

This presentation and related references This presentation and related references are posted on my corporate website at:are posted on my corporate website at:

www.pbelow-consulting.com/ich-fda.htmlwww.pbelow-consulting.com/ich-fda.html

Office:Office: (952) 882-4083(952) 882-4083

E-mail:E-mail: pbelow@cra-training.compbelow@cra-training.com

Contact InformationContact Information