The
Advisory Committee for Pharmaceutical Science of the Food and Drug
Administration, Center for Drug Evaluation and Research met on
Advisory Committee for Pharmaceutical Science Members (voting):
Arthur H. Kibbe, Ph.D., Charles L. Cooney, Ph.D., Patrick P. DeLuca, Ph.D., Melvin V. Koch, Ph.D., Meryl H. Karol, Ph.D. (April 13 only), Marvin C. Meyer, Ph.D., Cynthia R.D. Selassie, Ph.D, Marc Swadener, Ed.D., Nozer Singpurwalla, Ph. D., Jürgen Venitz, M.D., Ph.D.
Advisory Committee for Pharmaceutical Science Consultants (voting):
Gordon Amidon, Ph.D., M.A., Judy Boehlert, Ph.D., Thomas Layloff, Ph.D. (April 13 only)
Acting Industry Representative (non-voting):
Paul H. Fackler, Ph.D.
Industry Representative
(non-voting):
Gerald Migliaccio
Guest Speakers:
Leslie Benet, Ph.D., Laszlo Endrenyi, Ph.D., Charles DiLiberti, M.S.
FDA Guest Speakers:
Ali Afnan, Ph.D., Dale Conner, Pharm.D., Barbara Davit, Ph.D., Sam Haidar, Ph.D., Ajaz Hussain, Ph.D., Chris Joneckis, Ph.D., Robert Lionberger, Ph.D., Robert O’Neill, Ph.D., Brian Riley, Ph.D., Nakissa Sadrieh, Ph.D., Donald Schuirmann, M.S., Chris Watts, Ph.D., Keith Webber, Ph.D., Helen Winkle, Lawrence Yu, Ph.D.
FDA Participants:
Gary Buehler, R.Ph.
Open Public Hearing Speakers:
April 13, 2004:
Parrish M. Galliher, Troy J. Logan, Leo Lucisano, Robert Mattes
Dr. Jeffrey A. Staffa, Consillium, LLC (paper submission only)
These summary minutes for the April 13 and 14, 2004 of the Advisory Committee for Pharmaceutical Science of the Food and Drug Administration were approved on ________________.
I certify that I attended the April 13 and 14, 2004, meeting of the Advisory Committee for Pharmaceutical Science of the Food and Drug Administration meeting and that these minutes accurately reflect what transpired.
______//S//______________________ _____//S//_______________________
Hilda F. Scharen, M.S. Art Kibbe, Ph.D.
Executive Secretary Chair
The
Committee received an update from the Clinical Pharmacology Subcommittee, and
on the formation of a Working Group for Parametric Tolerance Interval Test for
Dose Content Uniformity, and discussed the following: Process Analytical
Technology (PAT) – Next Steps, PAT Applications for products in the Office of
Biotechnology Products (OBP), Bioequivalence of Highly Variable Drugs, Bioinequivalence,
Topical Bioequivalence. A topic awareness presentation
was made on Nanotechnology. The members and the invited consultants were
provided the background material from the FDA prior to the meeting.
Art
Kibbe, Ph.D. (Committee Chair), called the meeting to order at
Day 1:
Introduction to Meeting Helen Winkle
OPS Update Director, Office of Pharmaceutical Science
Pharmaceutical Quality for the 21st Century (OPS), CDER, FDA
Subcommittee Reports
Clinical Pharmacology Jürgen Venitz, M.D., Ph.D.
Chair, Clinical Pharmacology Subcommittee
Parametric Tolerance Interval Test Ajaz Hussain, Ph.D.
for Dose Content Uniformity Deputy Director, OPS, CDER, FDA
Moving Forward -- An Approach for Resolution Robert O'Neill, Ph.D., FDA
Committee Discussions and Recommendations
Break
Process Analytical Technology (PAT) – Ajaz Hussain, Ph.D.
Next Steps
Finalizing PAT Guidance Chris Watts, Ph.D., FDA
Standards Development Ali Afnan, Ph.D., FDA
Rapid Microbial Methods Bryan Riley, Ph.D., FDA
Committee Discussions and Recommendations
Lunch
Open Public Hearing
Leo Lucisano, Regional Director, CMC Regulatory Affairs, GlaxoSmithKline
Parrish M. Galliher, Founder, President and CEO, Xcellerex, LLC
Robert
Mattes, Laboratory Instrumentation Scientist, Foss-NIR Systems
PAT Applications for products in the Office of Biotechnology Products Keith Webber, Ph.D., FDA
Overview and Issues
Christopher
Joneckis, Ph.D., FDA
Charles Cooney, Ph.D.
Massachusetts Institute of Technology
Melvin Koch, Ph.D.
Tom Layloff, Ph.D.
Principal Program Associate
Management Sciences for Health
Break
The meeting was
adjourned at approximately
Art Kibbe, Ph.D. (Committee Chair), called the
meeting to order at
Day 2:
Bioequivalence of Highly Variable Drugs
Why Bioequivalence of Highly Variable Drugs Charles DiLiberti, M.S., Barr Labs, Inc.
is an Issue? .
Highly
Variable Drugs: Sources of Variability Gordon L. Amidon, Ph.D.,
Clinical
Implications of Highly Variable Drugs Leslie
Benet, Ph.D.,
Bioequivalence Methods for
Highly Variable Drugs Laszlo
Endrenyi, Ph.D.,
Break
Bioequivalence of Highly Variable Drugs: Case Studies Barbara Davit, Ph.D., FDA
FDA Perspectives Sam
Haidar, Ph.D., FDA
Bioequivalence of Highly Variable Drugs Q & A Dale Conner, Pharm.D., FDA
Committee Discussion and Recommendations
Lunch
Open Public Hearing: No speakers
BioINequivalence – Concept and Definition
Statistical Demonstrations of BioINequivalence Donald Schuirmann, M.S., FDA
Break
BioINequivalence Q & A
Committee Discussion and Recommendations
Update -- Topical Bioequivalence
Establishing Bioequivalence of Topical Dermatological Products Robert Lionberger, Ph.D., FDA
Future Topics - Nanotechnology Nakissa Sadrieh, Ph.D., FDA
Conclusion and Summary Remarks Ajaz Hussain, Ph.D., FDA
Questions to the Committee:
Topic #1: Parametric
Tolerance Interval Test (PTIT) for Dose Content Uniformity of Aerosol Products
Evaluate this proposal for the formation of a working group under ACPS
supervision
Recommend improvements necessary for realizing the group's goals and
objectives
Recommend reporting requirements and a timeline for completing this
project
The Committee agreed on the proposal for the
formation of a working group under the supervision of the Advisory Committee
for Pharmaceutical Science. The Committee accepted the outlined process for how
the working group will function and the proposed timelines. The committee emphasized the importance of
clinical representation on this working group, as this is the essence of risk
based management.
Topic #2: PAT Applications for Products in the Office Of Biotechnology Products in OPS/CDER and in the Center for Biologics Evaluation and Research (CBER)
1.
What
technologies are available now to evaluate the characteristics of protein
products in real time during manufacturing?
The Committee agreed it is difficult to judge how well the developed
tools are applied. The members felt that this was an important question, as it
relates what is being made to its therapeutic efficacy and safety. The
Committee argued that asking the right questions and understanding what is to
be known will drive the creation of new technologies.
2.
What tools
would allow us to understand the manufacturing process better?
The Committee emphasized that data
collection/mining is important. However, the members felt that a correlation of
cause/effect and critical thinking about the analytical data are crucial.
3.
What
processes in biological drug manufacturing would benefit the most from
implementation of PAT?
The members recognized that variability
control is key. The committee suggested that the goal
is to identify how much variation is allowed at each critical step, while still
maintaining a good product.
4.
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?
The Committee agreed that critical thinking
needs to be applied to understanding what needs to be measured and what we know
about the product. The members added that can be measured may not be helpful
and it is important to find the technology to measure what is needed.
5.
What
additional elements should be incorporated in a training and certification
program for reviewers and inspectors of biotechnology PAT applications?
The Committee felt
there is a need to emphasize critical thinking and problem solving in the
training. In addition, the members felt it was important to incorporate the
science of uncertainty and its quantification in the training programs. Also,
the committee agreed that the PAT Guidance is a framework, applicable to any
manufacturing and will apply to the Office of Biotechnology Products; not
originally part of the initial training and certification activities.
Topic #3: Bioequivalence of Highly Variable Drugs
1. 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.”
The Committee suggested the need to understand where the variability
originated. The members added that prior knowledge of all biostudies may help
set more appropriate specifications to make decisions.
2. Comment and recommendations
on two approaches for addressing the challenges:
The Committee emphasized that Highly Variable (HV) drugs focus on HV drug product. The
members emphasized there is an undue reliance on the use of confidence
intervals to make decisions, thus a paradigm shift is in order.
The
members agreed that the use of reference scaling and good scientific methods
could reduce the variability in the short term. However, in the long term, the
Committee felt a Decision Tree would be useful in understanding what the
problem is, as well as the real fundamentals i.e. physical and chemical
parameters. The Committee added that the role of decision trees is not merely
an understanding of a problem, but a necessary step for making coherent,
science based decisions. In conclusion, the Committee agreed that a limit on
the point estimate should also be used along with reference scaling.
Topic #4: The Concept and Criteria of
BioINequivalence
1.
Does the ACPS agree with the
distinction between demonstrating bioINequivalence and failure to demonstrate
bioequivalence?
The Committee felt that there was a need to
separately define bioINequivalence, not just as failure of the bioequivalence
test. The members argued it was important to focus on the clinical relevance with
the therapeutic index. The Committee discussed both Area under the Curve (AUC)
and Cmax as metrics important for bioequivalence and bioINequivalence.
2.
Does the ACPS recommend a preferred
method for evaluating the three pharmacokinetic parameters for bioINequivalence?
·
If bioINequivalence is demonstrated
for any one pharmacokinetic parameter, then bioINequivalence is demonstrated
for the products.
·
BioINequivalence must be demonstrated
for all three pharmacokinetic parameters for bioINequivalence to be demonstrated
for the products.
·
There should be one pre-selected
pharmacokinetic parameter used for bioINequivalence testing. If so, which one?
·
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.
The Committee agreed on a general understanding of bioINequivalence to
move forward recognizing it is not a simple matter. In addition, the members
felt this is an important concept, especially how it applies to the entire
regulatory scenario. There was no consensus at this point as to a final
criteria pertaining to the three pharmacokinetic parameters.
In addition, the members’ felt that the criteria used for approving
bioequivalence is very good. However, the Committee felt that the criteria used
to define bioINequivalence is very difficult, with the criteria and confidence
interval both needing to be outside the boundary.
In conclusion, the committee agreed that these discussions will force
people to ask questions of why a product is bioequivalent and will lead to
mechanistic understanding.
The meeting was
adjourned at approximately