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 April 13, Ms. Helen
Winkle will provide opening remarks and will outline the goals and objectives
of the 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, we will present the progress report from the Clinical
Pharmacology Subcommittee for your assessment and recommendations. The subcommittee met on
·
Quantitative analysis using
exposure-response
·
Pediatric bridging studies: pediatric
decision tree
·
Drug interactions
·
Pharmacogenetics: Integration into new drug
development
If
you wish to review the briefing information, presentation slides, and meeting
transcripts, please look at the following internet websites:
http://www.fda.gov/ohrms/dockets/ac/03/briefing/3998B1_01_TOC.htm
http://www.fda.gov/ohrms/dockets/ac/03/questions/3998Q1_Draft.htm
http://www.fda.gov/ohrms/dockets/ac/03/slides/3998s1.htm
http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3998T1.htm
http://www.fda.gov/ohrms/dockets/ac/03/slides/3998s2.htm
http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3998T2.htm
On
1. Parametric Tolerance Interval Test (PTIT)
for Dose Content Uniformity of Aerosol Products
At the
Following this meeting, FDA and the IPAC-RS discussed several approaches for moving forward to efficiently resolve the remaining issues. At this Advisory Committee meeting, we will present the proposal that was developed for moving forward. This proposal recommends the formation of a working group under the ACPS which will consist of key FDA Directors representing the disciplines of statistics (Dr. Robert O’Neil; FDA lead), clinical (Dr. Badrul Chowdhry), new drug chemistry (Dr. Moheb Nasr) and generic drugs (Dr. Lawrence Yu), along with several IPAC-RS nominees. Dr. O'Neil will present the details of this proposal and the IPAC-RS will also provide its perspective.
The presentations and discussions in April will focus primarily on
the proposed process, the goals for the Working Group, and the reporting timeline. We look forward to the ACPS recommendations
on the Working Group's activities and its proposal for resolving the PTIT
issues.
The
ACPS is requested to: 1) evaluate this
proposal for the formation of a working group under ACPS supervision, 2)
recommend improvements necessary for realizing the group's goals and
objectives, and 3) recommend reporting requirements and a timeline for
completing this project.
Following the October 2003 ACPS meeting, I wrote an article (as a
part of my presentation to the XI Respiratory Drug Delivery conference in April
2004) on this topic outlining some of the challenges and opportunities from my
own perspective. This article is
included in the background packet (Attachment #1) for your perusal.
If you
wish to review the ACPS discussions on PTIT from the October and March 2003
meetings, you can find this information on the following websites:
http://www.fda.gov/ohrms/dockets/ac/03/briefing/3996b1.htm
http://www.fda.gov/ohrms/dockets/ac/03/slides/3996s1.htm
http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3998T2.htm
http://www.fda.gov/ohrms/dockets/ac/03/briefing/3926b2.htm
2.
Progress Report and Planned Next Steps for
the Process Analytical Technology (PAT) Initiative
Topics
to be covered include:
·
Status of the training and certification
program for the PAT Review and Inspection Team (Attachment #2)
·
Training on “Rapid Microbial Methods”
(Attachment #3)
·
Process for finalizing the draft PAT
guidance (Attachment #4)
·
Formation and progress of the ASTM’s E55
Committee, Pharmaceutical Applications of PAT (Attachment #5)
·
Perspectives on PAT for your consideration
(review articles, Attachment #6)
·
PAT continuing efforts: Conferences and
Meetings (Attachment #7) and collaborations (Attachment #8)
The ACPS is requested to provide its
assessment of the progress in the PAT initiative and to recommend how we may
improve the impact, effectiveness, and efficiency of this program.
3. PAT Applications for Products in the
Office Of Biotechnology Products in OPS/CDER and in
the Center for Biologics Evaluation and Research (CBER)
The PAT
Initiative, which was launched at the July 2001 ACPS meeting, was developed
through collaboration among CDER, CVM, and ORA.
In October 2003, the Office of Biotechnology (OBP) was formed in
OPS/CDER through a transfer of staff from CBER to CDER. Because staff in this new
office and in CBER were not part of the first PAT training and
certification program, the scope of the draft guidance did not cover the
products regulated by these organizations.
As planned, the final PAT guidance will retain the same scope, and will
exclude OBP/OPS/CDER and CBER products even though the PAT framework outlined
in the draft guidance is broad and applicable to many different manufacturing
environments. This is because the
training of FDA staff is essential to implement this framework. The discussion will include identification of
challenges for implementing the PAT framework in other parts of CDER and in
CBER.
The ACPS is requested to consider the best
way to expand the scope of the PAT framework to include products in OBP and
CBER. In addition, ACPS is requested to
provide input on the following questions:
· What
technologies are available now to evaluate the characteristics of protein
products in real time during manufacturing?
· What
tools would allow us to understand the manufacturing process better?
· What
processes in biological drug manufacturing would benefit the most from
implementation of PAT?
· For
processes or products that do not currently allow direct product quality
monitoring, what other strategies do you recommend for product quality control
in addition to control of in-process parameters?
· What
additional elements should be incorporated in a training and certification
program for reviewers and inspectors of biotechnology PAT applications?
DAY 2
On
1.
Bioequivalence of Highly Variable Drugs.
The term
“highly variable” in the context of bioequivalence evaluation has been
generally applied in the scientific literature to those drugs or drug products
that exhibit intra-subject variability equal to or greater than 30% CV for
measure of rate (peak drug concentration [Cmax]) or extent of absorption (area
under the drug concentration in blood/plasma - time curve [AUC]). High intra-subject variability poses many
challenges for establishing bioequivalence.
This issue has been discussed for many years and has not been completely
resolved. This discussion will reexamine
the challenges and seek ACPS advice on several questions (Attachments #9 & 10).
ACPS ACTION
ACPS is
requested to provide advice on the following issues:
· That
“highly variable drugs or drug products can be defined as those exhibiting
intra-subject variability of 30% CV or greater in AUC or Cmax.”
· Comment
and recommendations on two approaches for addressing the challenges:
·
Expand bioequivalence limits from 80-125%,
and restrict the mean T/R difference, e.g., ± 20? What information is necessary to properly set
these new confidence interval limits?
·
Reference Scaling: Scale current
bioequivalence criterion based on the reference variability
in each study and restrict the mean T/R difference as above.
2. The Concept and Criteria of BioINequivalence
At
first glance, this may appear to be an odd topic; however, FDA sometimes
receives submissions containing studies intended to show bioINequivalence
between two drug products. Often these
are from innovator companies that conduct studies to challenge FDA’s approval
of generic versions of innovator drug products.
This discussion is intended to 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.
The Office of Generic Drugs has developed a proposal for
discussion at the ACPS meeting (Attachment #11). 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. The document
also provides thoughts on several statistical issues.
ACPS
ACTION
ACPS will be requested to discuss the following questions:
·
Does the ACPS agree with the distinction
between demonstrating bioINequivalence and failure to demonstrate
bioequivalence?
·
Does the ACPS recommend a preferred method
for evaluating the three pharmacokinetic parameters for bioINequivalence?
1. If
bioINequivalence is demonstrated for any one pharmacokinetic parameter, then
bioINequivalence is demonstrated for the products.
2. BioINequivalence
must be demonstrated for all three pharmacokinetic parameters for
bioINequivalence to be demonstrated for the products.
3. There
should be one pre-selected pharmacokinetic parameter used for bioINequivalence
testing. If so, which one?
4. The
three pharmacokinetic parameters should be evaluated for bioINequivalence with
statistical corrections to the level of significance for each parameter in
order to maintain an overall significance level of 0.05.
3. Update on Topical Bioequivalence Method
Development
Following
the October 2003 ACPS meeting, FDA staff developed a scientific paper that
reviews the challenges for establishing pharmaceutical and bioequivalence
(hence, therapeutic equivalence) of topical products. The attached manuscript (Attachment #12) was
developed in collaboration with Dr. Jonathan Wilkin and it further develops the
"Q3" concept that was introduced to ACPS in October 2003. At this ACPS meeting we will provide a brief
overview of the proposal outlined in this manuscript to seek your general
impressions and thoughts -- for example, are we on the right track? We plan to publish this manuscript to
initiate scientific dialog before we bring the concept to the ACPS as a formal
proposal.
4.
Nanotechnology: An Awareness Topic
(Attachment #13)
Nanotechnology
is a very rapidly growing area of science and technology. It is expected to lead to the development of
many novel and sophisticated applications in drug delivery. Historically, nanometer-sized materials
(e.g., silver and gold colloids) have been used in medicine. Additionally, many current pharmaceutical
materials and drug delivery systems (e.g., particles, micro-emulsions, and
liposomes) can have materials with dimensions in the nanometer range.
The safety
and efficacy of these products are currently being addressed adequately within
the established regulatory system.
However, the extensive research and development activities in
nanotechnology are expected to lead to the development of more complex drug
delivery systems, drug-device combination products, and other products
regulated by the FDA. To ensure that FDA
is ready to meet this responsibility, a multi-disciplinary discussion group has
been assembled at the Agency level in the Office of Commissioner. This group is proactively gauging the growth
of nanotechnology in anticipation of the complexity of future submissions to
the FDA. As such, the Agency needs
adequate regulatory procedures in place to deal with the challenges of the
nascent technology.
The purpose of the brief discussion at the April 2004 Advisory
Committee is to share information on CDER/FDA activities and emerging plans to
address the regulatory needs of nanotechnology-based products. At a future meeting of the Advisory
Committee, we will discuss and seek advice on our approach to address
nanotechnology-based products.
We are looking forward to
a very stimulating discussion with you on the selected topics. Have a safe and enjoyable journey to