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

Conducting Studies to the International Gold StandardGoing Beyond What the FDA Requires

Presented by

Paul Below, CCRA, CCRTP. Below Consulting, Inc.

Learning Objectives

• Define what the “internationalgold 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.

• 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?


http://www.ich.org/

• 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

ICH Purpose


• Reduced development time and cost

• Easier to submit a new drug application simultaneously in many countries

• Facilitates intra-company globalization


Importance to Industry

European Union (EU) began to successfully harmonize member country regulatory requirements in the 1980's

ICH History


• 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

ICH History (cont.)


• 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)

ICH Guideline Categories


• 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

• 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

ICH Guideline for GCP (E6)


• 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)

ICH GCP Objective



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

• 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


ICH Implementation in US

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


ICH Adopted as Regulation

• “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

• 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


Device Harmonization

http://www.ghtf.org/

Recent paper in ACRP’s The Monitor (10/2011)


Specific Differences Between ICH GCP and the FDA Regulations


• 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


ICH GCP Chapters

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


IRB Responsibilities (3.1)

In addition, 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 (cont.)

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 do not have a voting role


IRB Composition (3.2)

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


IRB Composition (cont.)

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


Investigator Agreements (4.1)

ICH states that investigators should be able to demonstrate the potential for recruiting the required number of patients within the agreed recruitment period:

• Retrospective data

• Patient database analysis

• Chart screening


Investigator Resources (4.2)

• 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)


Subject Medical Care (4.3)

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 (cont.)

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


Protocol Compliance (ICH 4.5)

• 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


Investigational Product (4.6)

• ICH allows the delegation of conducting the informed consent process to a designee


Informed Consent (4.8)

• 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

• 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)


Informed Consent (cont.)

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)



FDA has recently added a new informed consent element that is unique to the US (amended 21 CFR Part 50.25)



New rule requires informed consent documents for applicable drug and device clinical trials to include the following statement:

“A description of this clinical trial will be available on http://www.clinicaltrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.”



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 (4.9)

• 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


Records and Reports (cont.)

• ICH compliance generally requires a longer retention time than the FDA regulations

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


Sponsor QA / QC (5.1)

ICH requires sponsors to inform investigators in writing of:

• Study record retention requirements

• Notification of when records are no longer needed


Record Keeping (5.5)

• ICH requires sponsors to provide insurance or indemnify the investigator against claims arising from the trial

• Clinical trial insurance is a common part ofdoing studies in the EU


Compensation (5.8)

• 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


Financing (5.9)

• 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


IRB Review (5.11)

ICH requires sponsors to obtain documentation of IRB approval prior to shipping investigational product to an investigator


Supplying IP (5.14)

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)


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


Monitoring (5.18)

• 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)


Protocol and IB (6 & 7)

ICH has a comprehensive set of tables that give rich detail on the regulatory documents that should be on file with the investigator and the sponsor before, during, and after a study


Essential Documents (8)

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 (cont.)

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.)

A manuscript of this presentation was published in the SoCRA Source in August 2008

Questions