Advisory Committee for Pharmaceutical Science (ACPS)

October 19-20, 2004

This is the final report of the Advisory Committee for Pharmaceutical Science meeting held on October 19-20, 2004. A verbatim transcript will be available in about 2 weeks, sent to the Division and posted on the FDA website at

All external requests should be submitted to the Freedom of Information office.


The Advisory Committee for Pharmaceutical Science of the Food and Drug Administration, Center for Drug Evaluation and Research, met on October 19-20, 2004, at the Advisors and Consultant Staff Conference Room, 5630 Fishers Lane, Rockville, Maryland. Art Kibbe, Ph.D., chaired the meeting.

Advisory Committee for Pharmaceutical Science Members (voting):

Arthur H. Kibbe, Ph.D., Patrick P. DeLuca, Ph.D., Meryl H. Karol, Ph.D., Melvin V. Koch, Ph.D., Michael S. Korczynski, Ph.D., Marvin C. Meyer, Ph.D., Kenneth Morris, 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., Carol Gloff, Ph.D.

Industry Representative (non-voting):

Paul H. Fackler, Ph.D., Gerald Migliaccio, Ph.D.

Guest Speakers:

Shahid Ahmed, M.S.

FDA Guest Speakers:

Lucinda Buhse, Ph.D., Jon Clark, M.S., Jerry Collins, Ph.D., Joseph Contrera, Ph.D., Ajaz Hussain, Ph.D., Monsoor Khan, R.Ph., Ph.D., Steven Kozlowski, M.D., Vincent Lee, Ph.D., Quian Li, Sc.D., Robert Lionberger, Ph.D., Robert O’Neill, Ph.D., Amy Rosenberg, M.D., John Simmons, Ph.D., Keith Webber, Ph.D., Helen Winkle, Lawrence Yu, Ph.D.

FDA Participants:

Gary Buehler, R.Ph.

Open Public Hearing Speakers:

October 19, 2004:

Saul Shiffman, Ph.D.

October 20, 2004: None.


These summary minutes for the October 19 and 20, 2004 of the Advisory Committee for Pharmaceutical Science of the Food and Drug Administration were approved on _____11/16/04___________.

I certify that I attended the October 19 and 20, 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 updates pertaining to the ACPS Manufacturing Subcommittee, the ACPS Parametric Tolerance Interval Test (PTIT) Workgroup, and the Good Manufacturing Practices (GMPs) for the 21st Century initiative. Additionally, the Committee reviewed and discussed: research opportunities under the Critical Path Initiative, the Office of Pharmaceutical Science (OPS) plans and activities designed to take the organization towards the "desired state" of science and risk-based regulatory policies and practices as articulated under the GMPs for the 21st Century Initiative, and specific topics related to pharmaceutical equivalence and bioequivalence of generic drugs.

Art Kibbe, Ph.D. (Committee Chair), called the meeting to order at 8:30 a.m. on October 19, 2004. The Committee members, consultants, and FDA participants introduced themselves. The conflict of interest statement was read into the record by Hilda Scharen, M.S. The agenda proceeded as follows:

Day 1: Tuesday, October 19, 2004

8:30 Call to Order Arthur Kibbe, Ph.D.

Chair, ACPS

Conflict of Interest Statement Hilda Scharen, M.S.

Executive Secretary, ACPS

8:45 Introduction to Meeting Helen Winkle,

OPS Update Director, Office of Pharmaceutical Science,

Pharmaceutical Quality for the 21st Century (OPS), CDER, FDA

9:00 Subcommittee Reports

Manufacturing Subcommittee Judy Boehlert, Ph.D.

Chair, Manufacturing Subcommittee

9:30 Parametric Tolerance Interval Test Robert O'Neill, Ph.D.

for Dose Content Uniformity Director, Office of Biostatistics (OB), Office of

Current update on the Working Group Pharmacoepidemiology and Statistical Science


Committee Discussions and Recommendations

9:45 Break

10:00 The Critical Path Initiative – Challenges and Ajaz Hussain, Ph.D.

Opportunities Deputy Director, OPS, CDER, FDA

Topic Introduction and OPS Perspective

Research Opportunities and Strategic Direction Keith Webber, Ph.D.

Acting Director, Office of Biotechnology

Products (OBP), OPS, CDER, FDA

Informatics and Computational Safety Analysis Joseph Contrera, Ph.D.

Staff (ICSAS) Director, Informatics and Computational Safety

Analysis Staff(ICSAS), OPS, CDER, FDA

Office of New Drug Chemistry (ONDC) John Simmons, Ph.D.

Director, Division of New Drug Chemistry I, ONDC, OPS, CDER, FDA

Office of Generic Drugs (OGD) Lawrence Yu, Ph. D.

Director for Science, Office of Generic Drugs (OGD), OPS, CDER, FDA

12:00 Lunch

1:00 Open Public Hearing

2:00 Office of Biotechnology Products Amy Rosenberg, M.D.

Current research and future plans Director, Division of Therapeutic Proteins,OBP,OPS,CDER,FDA

Steven Kozlowski, M.D.

Director, Division of Monoclonal Antibodies, OBP, OPS, CDER, FDA

Office of Testing and Research Jerry Collins, Ph.D.

Current research and future plans Director, Laboratory of Clinical Pharmacology,

Office of Testing and Research (OTR), OPS, CDER, FDA

Lucinda Buhse, Ph.D.

Director, Division of Pharmaceutical Analysis,


Mansoor Khan, R.Ph., Ph.D.

Director, Division of Product Quality Research, OTR, OPS, CDER, FDA

3:30 Break

Wrap-up and Integration Jerry Collins, Ph.D.

Challenges and Implications Vincent Lee, Ph.D.

Senior Pharmacist, OPS, CDER, FDA

Committee Discussion and Recommendations

5:00 Adjourn

The meeting was adjourned at approximately 5:35 p.m. on October 19, 2004.


Day 2: Wednesday, October 20, 2004

8:30 Call to Order Arthur Kibbe, Ph.D.

Conflict of Interest Statement Hilda Scharen, M.S., FDA

8:45 Science in Regulation -- Visionary Overview Arthur Kibbe, Ph.D.

9:15 The "Desired State" of Science- and Ajaz Hussain, Ph.D., FDA

Risk-based Regulatory Policies

(1) Organization Gap Analysis Helen Winkle

(2) Scientific Gap Analysis Ajaz Hussain, Ph.D.

(3) Policy Gap Analysis Jon Clark, M.S.

Associate Director for Policy Development, OPS, CDER, FDA

10:30 Break

    1. Generic Pharmaceutical Association (GPhA) Shahid Ahmed, M.S.
    2. Perspective Vice Presdient, Regulatory Affairs

      American Pharmaceutical Partners (representing GPhA)

    3. Pharmaceutical Research and Manufacturers Gerry Migliaccio, Ph.D.

of America (PhRMA) Perspective Vice President, Global Quality Operations,

Pfizer, Inc. (representing PhRMA)

Committee Discussion and Recommendations

12:00 Lunch

1:00 Open Public Hearing

2:00 Pharmaceutical Equivalence and Bioequivalence

of Generic Drugs

(1) The Concept and Criteria of BioINequivalence

Concept of BioINequivalence Lawrence Yu, Ph.D.,

Director for Science, Office of Generic Drugs (OGD), OPS, CDER, FDA

Criteria of BioINequivalence Qian Li, Sc.D.

Mathematical Statistician, OB, OPaSS, CDER, FDA

Committee Discussion and Recommendations

3:00 Break

(2) Bioequivalence Testing for Locally Acting

Gastrointestinal Drugs

Topic Introduction Lawrence Yu, Ph.D.

Scientific Principles Gordon Amidon, Ph.D. Professor of Pharmacy and Professor of Pharmaceutical Sciences, College of Pharmacy, University of Michigan

Regulatory Implications and Case Studies Robert Lionberger, Ph.D.

Chemist, OGD, OPS, CDER, FDA

Committee Discussion and Recommendations

4:30 Conclusion and Summary Remarks Ajaz Hussain, Ph.D.

Helen Winkle

5:00 Adjourn


Questions to the Committee:

Topic #1: Critical Path Initiative

Are we focusing on the appropriate Critical Path topics? Are there others that we should be addressing through our research programs? How should we identify Critical Path issues in the future and how should we prioritize them?

The Committee thanked the presenters for their in-depth presentations. The Committee agreed that FDA is focusing on the right Critical Path topics to improve drug development and processing. The members felt that the FDA knowledge base puts the Agency in a unique position to identify some of the problems. However, they added that since FDA does not have all the information, collaboration with Industry and Academia is necessary in order to achieve the critical pathway.

In addition, the members highlighted that a science-based approach is necessary to define the metrics and the desired state. The committee discussed several metrics, which are helpful to measure effectiveness of the program, such as the multiple review cycle and tracking of FDA personnel turnover. Also, the members suggested that a Bayesian approach may be the best way to reduce the review cycle time for drug approval.

The members underlined that collaboration and trust are essential for a science-based approach to the regulatory arena and commended FDA on their research efforts and collaboration with NIH. The members emphasized that it is a challenge for Industry to contribute to the knowledge base due to the legal pressure placed on them; intellectual property rights and trust complicate the collaboration effort. Also, the members underlined that better communication between FDA and Industry can help make the approval process more predictable for the sponsor. The members added there is an acute need for fundamental research and public funding. The members underlined that manufacturing has been a neglected area in the United States, compared to Europe.

In addition, the committee felt that Academia would be the best group to pursue the continued research projects needed to contribute to the science-based approach and be hypothesis driven, in order to achieve the Critical Path issues of the future. In conclusion, the committee felt a reduction in risk with knowledge sharing is necessary in achieving scientific truth, as well as, compliance not to be a barrier to the scientific knowledge. Finally, the members stressed that as the rate of technology advancement increases, an internal committee needs to also be considering the questions of the future, in order to handle the prospective paradigm shifts.

Topic #2: The Concept and Criteria of BioINequivalence

Please comment on the following recommendations:

The committee recognized the difficulty of a developing a science-based response to this problem. The members recommended that the existence of prior information must be included in the determination of bioinequivalence.

In addition, the members argued that if the area under the curve (AUC) is picked, this gives no information about the rate; the Cmax captures both the rate and extent of absorption. Some suggested that the criteria for establishing bioinequivalence must include all three metrics of Cmax, AUCt and AUCµ , while the others recommended that one metric be sufficient.

In conclusion, the Committee highlighted that it is a hurdle to prove bioinequivalence, as the bounds used have to disapprove all three metrics. The committee agreed that bioinequivalence is a challenge for FDA, in the light of diminished Agency resources, but prior information such as failed biostudies could answer some of these questions.

Topic #3: Bioequivalence Testing for Locally Acting Gastrointestinal Drugs.

Please comment on the following recommendations:

The Committee discussed the use of dissolution testing to establish bioequivalence for drugs that act in the GI tract. The members added that in vitro testing is good if there is control over the test. The members emphasized that dissolution tests are needed early on in the process, in order to narrow down the variables. Further, pharmacokinetics studies are useful to assure safety of the test product.

In addition, the members stressed that dissolution tests are formulation tests, and can be a surrogate for clinical tests. The Committee discussed that dissolution tests can be very discriminating if the study is designed well. Although the committee felt that the Agency had all the data necessary to do dissolution testing for the products being discussed, dissolution test procedures can be simple for some drugs, but complicated for others. The Committee argued that when a lot of background information is available, the dissolution test could be used. However, the members added that when doing dissolution testing, careful attention needs to be paid to the calibrator.

The members emphasized that as local acting products, such as GI, nasal, or topical are part of the Critical Path Initiative, they could contribute to the timely approval of generic drugs.

In conclusion, the Committee agreed it was difficult to reach a consensus, but that in order to prove bioequivalence in vitro dissolution along with pharmacokinetics should be acceptable.

The outgoing Chair praised the committee and the FDA staff for the great work that has been accomplished over the last three years. He especially recognized Ms. Winkle and Dr. Hussain for their leadership of these efforts.


The meeting was adjourned at approximately 4:35 p.m. on October 20, 2004.