MEMORANDUM
TO: Members,
Advisory Committee for Pharmaceutical Science
FROM: Ajaz
S. Hussain, Ph.D.
Deputy
Director, Office of Pharmaceutical Science, CDER, FDA
DATE:
RE: ACPS
Meeting
Dear ACPS Members and Invited Guests,
We look forward to meeting
with you on
On October 19, Ms. Helen
Winkle will provide opening remarks and will outline the goals and objectives for
this meeting. She will also provide a
brief overview on the progress we've made in the FDA initiative, Pharmaceutical cGMP’s for the 21st
Century.
Following this, Dr. Judy Boehlert will provide a progress report
from the Manufacturing Subcommittee for your assessment and recommendations. The subcommittee met on
· Moving Toward the "
· Developing a Risk-based CMC Review Paradigm in the
Offices of New Drug Chemistry and Generic Drugs: Opportunities, Challenges,
Current Activities, and Next Steps
· Pharmaceutical Communities Research and Training
Needs: The Industrialization Dimension
of the Critical Path Initiative
· cGMPs for the Production of Phase I Investigational New
Drugs (INDs)
·
Pilot Model
for Prioritizing Selection of Manufacturing Sites for GMP Inspection
The briefing
information, presentation slides and meeting transcripts are available at the
following FDA internet websites:
http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4052b1.htm
http://www.fda.gov/ohrms/dockets/ac/04/slides/2004-4052s1.htm
http://www.fda.gov/ohrms/dockets/ac/04/transcripts/2004-4052T1.htm
http://www.fda.gov/ohrms/dockets/ac/04/slides/2004-4052s2.htm
http://www.fda.gov/ohrms/dockets/ac/04/transcripts/2004-4052T2.htm
The following three topics
will be discussed:
1. Parametric Tolerance Interval Test (PTIT)
for Dose Content Uniformity of Aerosol Products.
At the April 2004 ACPS meeting this topic
was discussed. The formation of a joint
FDA-Industry [represented by the International Pharmaceutical Aerosol
Consortium on Regulation and Science (IPAC-RS)] Working group was recommended. This
group was formed to resolve issues to allow FDA to adopt the use of the PTIT
procedure. Dr. Robert O'Neill will
present the group's progress report and seek your recommendation on their
findings, progress, and planned next steps.
For
your reference the information related to the previous ACPS discussion on PTIT
(the April 2004 meeting) can be located at the following websites:
2.
The Critical Path Initiative -- Challenges
and Opportunities.
Attached as part of the background information
is the Agency's white paper entitled "Challenge and
DAY 2
Discussion on the second
day will cover OPS science and policy management plans and selected topics on
bioequivalence assessment. Prior to
these discussions, we have requested Professor Kibbe to share with us his
overview and perspective on his experience as the senior member and outgoing
Chairperson of the ACPS.
1.
OPS Plans and Activities Moving Towards the
"Desired State.
We will
be presenting our thoughts on the following topics:
Organization
Gap Analysis -- Helen Winkle
Scientific
Gap Analysis -- Ajaz Hussain
Policy
Gap Analysis -- Jon Clark
Shortly,
the Agency will be publicly releasing a comprehensive 2-year status report on
the Pharmaceutical cGMPs for the 21
Century initiative. This informative
document will be separately provided to you (by email) as an additional background
piece in preparation for discussions at the meeting.
2. The Concept and Criteria of
BioINequivalence.
This
discussion is intended to further articulate criteria for establishing
bioINequivalence. Such criteria may be
useful to communicate and guide the review of studies intended to establish
bioINequivalence and for companies conducting such studies.
This
continues previous discussion on this topic (April 2004 meeting). If you wish to review the ACPS discussions on
the BioINequivalence topic from the April 2004 meeting, you can find this
information on the following websites:
http://www.fda.gov/ohrms/dockets/ac/04/slides/4034S2_09_Yu_files/frame.htm
http://www.fda.gov/ohrms/dockets/ac/04/slides/4034S2_10_Schuirmann_files/frame.htm
http://www.fda.gov/ohrms/dockets/ac/04/transcripts/4034T2.htm
The Office of Generic Drugs has further refined its proposal for
discussion at the ACPS meeting. This
proposal introduces the concepts and criteria of bioequivalence,
bioINequivalence, failing to demonstrate bioequivalence, and failing to
demonstrate bioINequivalence. It also
explains the statistical criteria used to claim bioINequivalence for one
pharmacokinetic parameter and presents the pros and cons of several strategies
to collectively evaluate the three pharmacokinetic parameters.
ACPS ACTION
ACPS will be requested to discuss the following question:
What is
your preferred method for evaluating the three pharmacokinetic parameters for
bioinequivalence?
·
If bioinequivalence
is demonstrated for any one pharmacokinetic parameter that is prespecified, then
bioinequivalence is demonstrated for the products.
·
Bioinequivalence
must be demonstrated for all three pharmacokinetic parameters for bioinequivalence
to be demonstrated for the products, where the error rate is controlled at 5%.
·
FDA should
allow sponsors of bioinequivalence studies to make their own choice on picking
up strategies; sponsors should prespecify the choice in study protocols before
the study is conducted.
3. Bioequivalence
Testing for Locally Acting Gastrointestinal Drugs.
For
drugs whose site of action is the gastrointestinal (GI) tract, determination of
bioequivalence is more complicated as local drug concentrations cannot be
measured directly. The goal of this
topic is to present to the committee background on some of the scientific issues
involved in developing bioequivalence methods for locally acting drugs that
target the GI tract. In the past FDA has
acted on a case by case basis, but for the future we would like to identify the
key scientific principles for consistent and efficient identification of
bioequivalence methods. We will discuss
and seek ACPS input on the following issues related to bioequivalence of
locally acting GI drugs:
• Role
of pharmacokinetic studies
• Role
of in vitro tests including dissolution and binding assays
• Role
of clinical studies
ACPS ACTION
We would like the committee to comment on
the following questions:
·
For locally acting GI drugs, is PK, if
measurable, an in vivo test sensitive
to formulation performance and useful as a part of a determination of
bioequivalence?
·
Are there any drug specific issues that
would aid FDA in interpreting the results of a PK study on a GI acting drug
with respect to a conclusion about bioequivalence?
·
When is it possible to use dissolution
testing alone to demonstrate bioequivalence of GI acting drugs?
·
When should comparative clinical trial
studies be conducted to demonstrate bioequivalence?
We are looking forward to a
very stimulating discussion with you on the selected topics. Have a safe and
enjoyable journey to