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

Presented by
Paul Below, CCRA, CCRT
P. Below Consulting, Inc.

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

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.

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


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


Importance to Industry

• Reduced development time
and cost
• Easier to submit a new drug
application simultaneously
in many countries
• Facilitates intra-company
globalization


ICH History

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


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


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)


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

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

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)


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


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


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

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

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

Specific Differences
Between ICH GCP and
the FDA Regulations


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

IRB Responsibilities (3.1)

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


IRB Responsibilities (cont.)
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 Composition (3.2)

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 (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

Investigator Agreements (4.1)

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


Investigator Resources (4.2)

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


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)


Subject Medical Care (cont.)

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).


Protocol Compliance (ICH 4.5)

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


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


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


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)


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.”


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

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


Sponsor QA / QC (5.1)

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


Record Keeping (5.5)

ICH requires sponsors to inform investigators in
writing of:
• Study record retention
requirements
• Notification of when
records are no longer
needed


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


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


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


Supplying IP (5.14)

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


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)


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

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)


Essential Documents (8)

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 (cont.)
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)


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

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

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