Transcript template

The ICH E5 Guidance:
An Update on Experiences with
its Implementation
Robert T. O’Neill, Ph.D.
Director, Office of Biostatistics
CDER, FDA
To be presented at the 3rd Kitasato University - Harvard School of
Public Health Symposium, October 2-3, 2002
Outline of talk
 Recent ICH meetings and their purpose
 Summary of FDA report on experiences
 Some draft Question and Answers to
clarify E5
 Plans for E5 as a result of Washington
meeting
 Some thoughts on bridging and
prospective planning
Why ?
 Four years of experiences
 Agreement that some clarification is
needed
 The need for more data - how much
Bridging Studies
 When
 Why
 What type
E5 is purposely vague on how to do this
or what their design should be
The Spirit and Intent of E5
 Not intended to request bridging studies every time
 Intended to permit the requesting of one ‘confirmatory’
phase 3 clinical trial (bridge study) in the region (not
specifically defined, nor meant as ‘country’) if needed or
necessary to extrapolate.
 Recognized that there would be a period of time where
experience with foreign clinical studies would be
accumulated and evaluated - not to be confused with
always asking for a new confirmatory trial in local region.
ICH meetings on E5
Implementation
 Brussels: February 6-7, 2002
 Washington, D.C: September 10-11, 2002
E5 Informal Discussion
Group
Brussels discussions
 Acknowledgement that E5 has made a major
contribution towards acceptance of foreign data.
 Each of 6 parties summarized experience
 MHLW has most experience of regulatory
authorities to date with E5 implementation,
described their experience
 Determine strategies for clarification of E5 in view
of experiences
FDA’s experiences based upon:
 An informal survey of medical review divisions
regarding their experiences in asking for
bridging studies and relying on foreign clinical
trial data for regulatory decisions.
 A review of approved applications in calendar
year 2001 with respect to number of clinical
trials all of whose data was foreign, and/or
multi-national in nature
 A summary of the number of domestic and
foreign clinical trials documented in 18 of 30
New Molecular entities approved in 1998
Summary of FDA experience
 Majority of NDA’s contain foreign clinical
trial data, often used as primary evidence
of efficacy and safety - rarely, does the
entire data base on efficacy consist of
foreign clinical data
 Until recently, discussion have rarely been
held with sponsors during IND/NDA
development stages that specifically
consider bridging strategies when relying
on foreign clinical data
Summary of FDA experience
 Some, but not all review divisions, during the
process of evaluation of the clinical efficacy
data examine regional differences in efficacy
and safety. Part of the reason for this is that
sponsors have not, a priori, designed the
clinical trials with this objective in mind -this
may be chaning
 Most multi-national trials have included
patients from Western Europe, U.S., Canada,
New Zealand and Australia. Minimal but
increasing experience with Latin America
Eastern Europe.
Summary of FDA experience
 Few examples of formal bridging studies done in the U.S.
that were performed subsequent to development of a
complete clinical data package, and that were carried out in
response to an FDA request
 Generally, when FDA asks for more data/studies, it is
because the clinical trial evidence in the NDA is not
convincing and other formal phase 3 studies conducted in
the U.S. are needed.
 Despite the inclusion of foreign clinical data in an NDA,
sponsors have anticipated an FDA request by carrying out
U.S. trials without being asked. Sometime these trials are
ongoing at the time of NDA submission
Summary of FDA experience
 As trials come from new regions , it may
become critical to agree in advance on the
sources of data
 There has not often been a prospective
evaluation during the IND of differential
pk, pd or clinical endpoints to treatment
response
 About 7 examples illustrating the types of
issues faced.
Plans from the Brussels
meeting
 MHLW to provide more detailed and comprehensive
description of its experience with E5 implementation,
since MHLW has most experience with bridging
strategies
 Industry to provide more specifics about case studies
 All six parties to specify questions for consideration for
possible Q & A doc.
Washington, D.C
September 10-11, 2002
ICH Meeting
Summary of Discussions at
the Washington meeting
 Evaluation of all written Q and A from 6 parties
 Evaluation of the case studies from MHLW and
EFPIA which illustrate bridging issues and
examples
 Categorization of Q and A in selected topic areas to
reduce redundancy and build consensus
 Discussions on selected Q and A that all parties
agreed to be important
Examples of the type of
Q and A’s that will be
developed
Questions and Answers (Q&A’s)
to clarify intent of E5
Q1. I am planning to develop my new drug globally. Does E5 provide
guidance for this approach?
Q2. I have developed my drug in one region, addressing safety,
efficacy, dosing, etc., as well as use in special populations such as
patients with renal/hepatic impairment, the elderly, children, and
pregnant and lactating women. If I can successfully demonstrate
(e.g., through a bridging study), that my safety, efficacy, and dosing
information in the general population are relevant to the new
region, will I also need to further address the extrapolatability of the
special populations data?
Questions and Answers (Q&A’s)
to clarify intent of E5
Q3. My drug is sensitive to ethnic factors and the medical settings
in which it is used may vary between regions. Does that mean
that my efficacy study in one region is of no value in support
of my application in another?
Q4. My drug is insensitive to ethnic factors and there are no
significant, relevant differences in extrinsic factors, including
the practice of medicine, among the regions. The
pharmacokinetics of the drug are insensitive to intrinsic and
extrinsic factors. The diagnosis and therapy of the condition
in the indication do not significantly vary among regions.
Nonetheless, the regulatory authority of the new region is
requiring an additional study of safety and efficacy for
bridging. Is that requirement inconsistent with E5?
Questions and Answers
(Q&A’s) to clarify intent of E5
Q5. My drug has been approved in 2 ICH regions and I am about
to meet with regulatory authorities in the third region to
discuss an application for marketing. I believe that the present
data should be accepted by the new regulatory authority and
that little or no additional data should be required by that
regulatory authority. What information should I submit to
support my case that additional data are not needed?
Q6. My drug is insensitive to ethnic factors and drugs in its class
have similar activity in all regions. However, the endpoints I
studied (or control group I used) were acceptable to regions in
which the studies were conducted but not to the new region.
Does E5 indicate that the new region should accept those data
as evidence of efficacy?
Q and A Summary Topics
 Need for Safety Data
 Considerations on Special Populations
 Multiple Indications
 Global Development Strategy/Global
Study (Study Design Issues)
 Medical Practice
 Requesting One More Study
 Responsibility to Justify Bridging
Plans for the next year
 An Implementation Working Group will
be constituted under ICH auspices to
complete the Q and A’s and to collect new
issues as experience accrues
 Final Q and A’s need to be consistent with
intent of E5 and with regulatory policy in
each region
 Timeframe: Feb 2003, Tokyo or July 2003,
Brussels
Some thoughts on bridging
studies and strategies
 Many different bridging strategies, depending
upon data, disease and individual circumstances
of studies
 There are clinical study design issues which need
to be addressed at the planning stage to facilitate
extrapolation and interpretability for both
 Multi-regional studies
 Simultaneous global drug development
 Similar designed studies in two different
regions (1 year vs. 2 year endpoints)
Issues to consider at the
planning stage
 Definition and diagnoses of disease and patient
 Variation in frequency or rarity of clinical
endpoint -impacts benefit risk evaluation
(Number needed to treat)
 Medical practice, concomitant medications
 Prospectively, planning to examine a regional
subgroup in a manner that may be different than
overall treatment effect [e.g. more emphasis on
one of the endpoints, certain entrance criteria]
Issues to consider
 Same or different endpoints in each region
 Same or different comparator treatments in
different regions
 Difficult issue; implications for interpretation
in superiority and non-inferiority trials
 Size of regional component of multi-regional
study to evaluate similarity of response
 Dose response
 Benefit/risk (efficacy and safety data)
Concluding Remarks
 The intent of the updated Q and A’s is to
clarify some areas of perceived
misunderstanding
 More dialogue with regulators on study
design strategies will continue and
experiences with completed studies and
bridging approaches shared
 My talk is primarily intended to be an
update on the informal working group
ICH meetings