FOOD AND DRUG ADMINISTRATION

ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE

8:30 a.m.

Wednesday, March 12, 2003

Conference Room

5630 Fishers Lane

Food and Drug Administration

Rockville, Maryland 20857

ATTENDEES

COMMITTEE MEMBERS:

ARTHUR H. KIBBE, PH.D., Acting Chair

Chair and Professor

Department of Pharmaceutical Sciences

Nesbitt School of Pharmacy

Wilkes University

176 Franklin Avenue

Wilkes-Barre, Pennsylvania 18766

KATHLEEN REEDY, R.D.H., M.S., Executive Secretary

Advisors and Consultants Staff

Center for Drug Evaluation and Research

Food and Drug Administration (HFD-21)

5600 Fishers Lane

Rockville, Maryland 20857

JOSEPH BLOOM, PH.D.

University of Puerto Rico

School of Pharmacy

4th Floor, Office 416

P.O. Box 365067

San Juan, Puerto Rico 00935-5067

PATRICK P. DeLUCA, PH.D.

Professor, Faculty of Pharmaceutical Science

University of Kentucky, College of Pharmacy

327-H Pharmacy Building, Rose Street

Lexington, Kentucky 40536-0082

MARVIN C. MEYER, PH.D.

1700 SW 6th Avenue

Boca Raton, Florida 33486

LEMUEL MOYE, M.D., M.D., PH.D.

Associate Professor

University of Texas Health Science Center

at Houston

School of Public Health

1200 Herman Pressler Street, RAS E815

Houston, Texas 77030

ATTENDEES (Continued)

COMMITTEE MEMBERS: (Continued)

NAIR RODRIGUEZ-HORNEDO, PH.D.

Associate Professor of Pharmaceutical Sciences

College of Pharmacy

The University of Michigan

Ann Arbor, Michigan 48109

CONSULTANTS:

(ROBERT) GARY HOLLENBECK, PH.D.

Associate Professor of Ppharmaceutical Science

University of Maryland School of Pharmacy

20 North Pine Stret

Baltimore, Maryland 21201

MERYL H. KAROL, PH.D.

University of Pittsburgh

Department of Environmental and Occupational Health

130 DeSoto Street

Pittsburgh, Pennsylvania 15261

MICHAEL S. KORCZYNSKI, PH.D.

Senior Vice President/General Manager

Mikkor Enterprises, Inc.

P.O. Box 573

Lake Bluff, Illinois 60044

THOMAS LAYLOFF, PH.D.

Principal Program Associate

Center for Ppharmaceutical Management

Management Sciences for Health

5 Thomas Court

Granite City, Illinois 62040-5273

WOLFGANG SADEE, DR.RER.NAT.

Chair, Department of Pharmacology

College of Medicine and Public Health

Ohio State University

5072 Graves Hall, 333 West 10th Avenue

Columbus, Ohio 43210

ATTENDEES (Continued)

CONSULTANTS: (Continued)

CYNTHIA R.D. SELASSIE, PH.D.

Professor of Chemistry

Department of Chemistry

Pomona College

Seaver North, Room 219

645 College Avenue

Claremont, California 91711-6338

MARC SWADENER, ED.D.

2235 Dartmouth Avenue

Boulder, Colorado 80305-5207

JURGEN VENITZ, M.D., PH.D.

Department of Pharmaceutics

School of Pharmacy

Medical College of Virginia Campus

Virginia Commonwealth University

Box 980533, MCV Station

Room 340, R.B. Smith Building

410 North 12th Street

Richmond, Virginia 23298-0533

INDUSTRY REPRESENTATIVES:

LEON SHARGEL, PH.D., R.PH.

Vice President, Biopharmaceutics

Eon Labs Manufacturing, Inc.

227-15 North Conduit Avenue

Laurelton, New York 11413

EFRAIM SHEK, PH.D.

Divisional Vice President

Pharmaceutical and Analytical Research and Development

Abbott Laboratories

Dept. 04R-1, Building NCA4-4

1401 Sheridan Road

North Chicago, Illinois

ATTENDEES (Continued)

GUEST SPEAKER:

HERB CARLIN, D.SC.

6 Abedin Way

Califon, New Jersey 07830-3500

FOOD AND DRUG ADMINISTRATION STAFF:

LUCINDA BUHSE, PH.D.

CHI-WAN CHEN, PH.D.

YUAN-YUAN CHIU, PH.D.

PETER COONEY, PH.D.

DALE CONNER, PHARM.D.

DENA HIXON, M.D.

AJAZ S. HUSSAIN, PH.D.

STEPHEN MOORE, PH.D.

ROBERT OSTERBERG, PH.D.

NANCY SAGER

JONATHAN WILKIN, M.D.

HELEN N. WINKLE

ALSO PRESENT:

THOMAS J. FRANZ, M.D.

Dermtech International

C O N T E N T S

AGENDA ITEM PAGE

MEETING STATEMENT

by Ms. Kathleen Reedy 7

INTRODUCTION TO THE MEETING

by Ms. Helen Winkle 12

SUBCOMMITTEE UPDATES

Process Analytical Technology - by Dr. Tom Layloff 22

Manufacturing - by Dr. Ajaz Hussain 31

Clinical Pharmacology - by Dr. Jurgen Venitz 33

FUTURE SUBCOMMITTEES

Pharmacology-Toxicology - by Dr. Robert Osterberg 38

Microbiology - by Dr. Peter Cooney 44

Biopharmaceutics - by Dr. Ajaz Hussain 47

TOPICAL DERMATOLOGICAL DRUG PRODUCT NOMENCLATURE

by Dr. Yuan-Yuan Chiu 61

by Dr. Jonathan Wilkin 64

by Dr. Lucinda Buhse 79

by Dr. Chi-wan Chen 91

by Dr. Herb Carlin 103

OPEN PUBLIC HEARING PRESENTATION

by Dr. Thomas Franz 149

TOPICAL DERMATOLOGICAL BIOEQUIVALENCE -

METHODS DEVELOPMENT

by Dr. Ajaz Hussain 164

by Dr. Dale Conner 166

by Dr. Dena Hixon 187

by Dr. Jonathan Wilkin 205

COMPARABILITY PROTOCOLS

by Ms. Nancy Sager 221

by Dr. Stephen Moore 227

P R O C E E D I N G S

(8:30 a.m.)

DR. KIBBE: I see by the clock on the wall that we are at 8:30. We have
two days of wonderful presentations, but they\'re all packed together,
which means that you must pay attention continuously for the entire time
frame. No napping.

My name is Art Kibbe and I\'m acting Chair. The agency always let\'s
people act, but never gives them a permanent position. Helen has been
acting Director for three years now. At my school that would allow her
to go up for tenure. I don\'t know what that means.

The first thing we have to do is get Kathleen Reedy to read from a list
of important information about conflict of interest. After that, I will
ask everyone at the table to go around and introduce themselves, and
please use the mike so we can be officially recorded for posterity.

MS. REEDY: Acknowledgement related to general matters waivers, Advisory
Committee for Pharmaceutical Science, March 12, 2003, open session.

The following announcement addresses the issue of conflict of interest
with respect to this meeting and is made a part of the record to
preclude even the appearance of such at this meeting.

The topics of this meeting are issues of broad applicability. Unlike
issues before a committee in which a particular product is discussed,
issues of broader applicability involve many industrial sponsors and
academic institutions.

All special government employees have been screened for their financial
interests as they may apply to the general topics at hand. Because they
have reported interests in pharmaceutical companies, the Food and Drug
Administration has granted general matters waivers to the following SGEs
which permits them to participate in these discussions: Dr. Joseph
Bloom, Dr. Charles Cooney, Dr. Patrick DeLuca, Dr. Gary Hollenbeck, Dr.
Meryl Karol, Dr. Arthur Kibbe, Dr. Michael Korczynski, Dr. Thomas
Layloff, Dr. Marvin Meyer, Dr. Samuel Moye, Dr. Nair Rodriguez-Hornedo,
Dr. Wolfgang Sadee, Dr. Jurgen Venitz.

A copy of the waiver statements may be obtained by submitting a written
request to the agency\'s Freedom of Information Office, room 12A-30 of
the Parklawn Building.

In addition, Drs. Cynthia Selassie and Marc Swadener do not require
general matters waivers because they do not have any personal or imputed
financial interests in any pharmaceutical firms.

Because general topics impact so many institutions, it is not prudent to
recite all potential conflicts of interest as they apply to each member
and consultant.

FDA acknowledges that there may be potential conflicts of interest, but
because of the general nature of the discussion before the committee,
these potential conflicts are mitigated.

With respect to FDA\'s invited guests, Dr. Herb Carlin reports that he
does not have a financial interest in or professional relationship with
any pharmaceutical company.

We would also like to disclose that Dr. Leon Shargel and Dr. Efraim Shek
are participating in this meeting as acting industry representatives,
acting on behalf of regulated industry.

Dr. Shargel reports he is employed full-time by Eon Laboratories,
Incorporated as Vice President, Biopharmaceutics.

Dr. Shek reports holding stock in Abbott Labs and Cephalon,
Incorporated, and that he is employed full-time as Divisional Vice
President for Abbott Labs.

In the event that the discussions involve any other products or firms
not already on the agenda for which FDA participants have a financial
interest, the participants\' involvement and their exclusion will be
noted for the record.

With respect to all other participants, we ask in the interest of
fairness that they address any current or previous financial involvement
with any firm whose product they may wish to comment upon.

DR. KIBBE: Thank you.

And now, if we would start perhaps with Ajaz and introduce everybody.
Thank you.

DR. HUSSAIN: Good morning. Ajaz Hussain, Deputy Director, Office of
Pharmaceutical Science.

MS. WINKLE: Hi. Helen Winkle, acting Director, as Art has already
pointed out, of the Office of Pharmaceutical Science.

DR. VENITZ: I\'m Jurgen Venitz, Virginia Commonwealth University in
Richmond, Virginia, and I\'m here to represent the Clinical Pharmacology
Subcommittee.

DR. KAROL: I\'m Meryl Karol from the University of Pittsburgh, and I\'m
going to be the Chair of the Pharm-Tox Subcommittee.

DR. SADEE: I\'m Wolfgang Sadee. I\'m at the Ohio State University in
pharmacology.

DR. MOYE: Good morning. Lem Moye, University of Texas School of Public
Health. I\'m a physician and biostatistician.

DR. RODRIGUEZ-HORNEDO: Nair Rodriguez-Hornedo from the University of
Michigan, Associate Professor, Pharmaceutical Sciences Department.

DR. SWADENER: Marc Swadener, retired from the University of Colorado,
consumer representative on the committee.

DR. MEYER: I\'m Marvin Meyer, Emeritus Professor, University of
Tennessee.

DR. KORCZYNSKI: Michael Korczynski, consultant.

DR. BLOOM: Joseph Bloom, University of Puerto Rico.

DR. SELASSIE: Cynthia Selassie, Chemistry Department, Pomona College.

DR. HOLLENBECK: Hi. I\'m Gary Hollenbeck, Associate Dean and Professor
of Pharmaceutical Sciences at the University of Maryland.

DR. DeLUCA: Pat DeLuca, University of Kentucky, College of Pharmacy.

DR. SHARGEL: I\'m Leon Shargel, Vice President, Biopharmaceutics, Eon
Labs, a generic manufacturer.

DR. SHEK: Efraim Shek, Abbott Laboratories, industrial representative.

DR. LAYLOFF: Tom Layloff, Management Sciences for Health, a
non-for-profit health sector organization working in developing
countries setting up health systems.

DR. KIBBE: Thank you.

Now, Helen, do you want to introduce us to the meeting?

MS. WINKLE: Good morning, everyone. It\'s really my pleasure to welcome
you all here for this advisory committee meeting on behalf of the whole
Office of Pharmaceutical Science.

I think all of you understand that this advisory committee really
provides an important role to the Office of Pharmaceutical Science in
really helping us vet the significant science that underpins our complex
regulatory processes. This committee continues to provide scientific
evaluation and recommendation on broad scientific issues that really
help us make our day-to-day regulatory decisions in OPS, as well as in
the center. And the committee\'s scientific input has helped us
strengthen and confirm and validate many of our own internal scientific
decisions and our scientific knowledge and expertise. So the committee
is really valuable, and I think this is a thing I want to especially
express today with so many new committee members here, the value that
you all bring to us in the Office of Pharmaceutical Science.

I\'m going to start off this morning just talking a little bit about
what I see as really a significant juncture in the advisory committee.
This committee has been in existence for a number of years, but I think
we\'re starting to change some in structure of the committee and the
focus of the committee. I wanted to talk first about this before I
talked about what we\'re going to do for the next two days.

The first notable change is Dr. Kibbe. Dr. Kibbe said he is acting now
but he will be serving as the full Chair of this committee. Art has
already been very invaluable to us as a committee member. His academic
experience and his knowledge on the complicated regulatory world of FDA
has helped us in clarifying and understanding a number of significant
issues in the past. I think many of you know that Art goes back a long
way with FDA, and that\'s actually how I met him, in his past life with
FDA. He also brings a keen sense of what FDA needs to do in enhancing
its science and technical processes for the 21st century. So we\'re
definitely fortunate to have Art not only as a member of the committee
but as its Chair.

Secondly, as I said, we have a number of new committee members. I really
appreciate your being willing to serve for us here at OPS and being part
of this committee. With new and important questions coming before the
agency at a frenetic rate, I think it\'s really important that the
committee members have the scientific knowledge and expertise to address
the various subject matters that will come before us and provide us with
the wisdom that will help us in serving the public better. We have been
really trying to balance off this committee so we can address issues in
a variety of ways. We feel honored to have each of you as a member of
the committee, and I personally look forward to working with each one of
you.

Thirdly, I think there have been a lot of changes in the advisory
committee structure. I have talked numerous times about the subcommittee
structure, and I think that the structure is going to be extremely
important to us in helping better understand some of the questions and
some of the science that really underpins coming to the right answer to
these questions.

It\'s difficult when we have a committee that has so many various
disciplines on it to really have the knowledge and the expertise to hone
in on a specific answer. So with the subcommittees being able to do some
of the background for the questions, being able to discuss the
questions, and come back with recommendations to the committee, I think
this will help the committee better meet its obligations.

Lastly, I think we are in a time of significant changes in the agency.
All we have to do is step back and look at the cGMP initiative for the
21st century and the consolidation of some of CBER with CDER, and we
know that there are many changes on the horizon for FDA. And these new
and exciting initiatives will affect how we in FDA do our business now
and in the future. I think that you all are an important part of helping
us better understand what our obligations will be as we move to the
future and help us address many of the scientific questions that will
come up. So I think we\'re really looking at a whole new era, and you
all can be a very active part of that.

I hope you all share my enthusiasm in working on these initiatives,
addressing the scientific questions which will arise because of the
changes in our processes and our day-to-day operations, and I hope that
you will share my enthusiasm in taking on the challenges of this
changing regulatory environment. It\'s really an exciting time.

For the next few days, we\'re probably going to overload you, as Art has
already said, with massive amounts of information. We\'ve got a lot
packed into two days, and I sort of want to apologize. But I think the
reason for this is we have a lot of what we will call awareness topics.
I think with the membership of the committee changing, we need to lay
the groundwork of many of the topics that we\'re going to be bringing up
in the future. So it will be fast. Art says you need to listen
carefully, but I think there will be some real good discussions.

This morning we\'re going to start off with a discussion of the
subcommittee structure. We\'ve talked about this in the past. I think
that structure is really pretty much finalized, and we\'re moving and
setting up a number of subcommittee meetings. We\'ve talked about it, as
I have said, in the past. Today we\'re going to give you a little bit of
update on the existing subcommittees and then provide you with where
we\'re going with the future subcommittees. Most of these will be
meeting in the next couple of months. So I want you all to be aware of
where we are and how we\'re developing these particular subcommittees.

I do want to publicly, though, thank all of the people in FDA who have
worked hard on getting these subcommittees up. As you see, when we start
talking about it ‑‑ we have, I think, five, six subcommittees ‑‑
there\'s a lot of work here, a lot looking for membership, getting the
people in. And we\'ve really had to work hard on it. So I really want to
thank the people on my staff and others within the agency for working on
this.

After the subcommittee discussion today, we\'ll discuss topical
dermatological drug product nomenclature. There are a number of
questions which exist regarding the classification of dosage forms,
including definitions of ointments, paste, lotions, creams, and gels.
Dr. Yuan-Yuan Chiu will lead us in a discussion of the issues and the
internal working group\'s recommendations on how to address various
questions.

Dr. Herb Carlin is here representing USP\'s Nomenclature and Labeling
Expert Committee, and he will also present some of his observations and
also present us with the direction USP has been going in this area.

Dr. Jonathan Wilkin, who is the Director of the Division of
Dermatological and Dental Drug Products in the Office of New Drugs in
CDER, will also join OPS\'s staff in this discussion.

After lunch, we want to continue our previous theme of just talking
about topical products, and we\'re going to be discussing topical
dermatological bioequivalence methods development. We\'ve presented
several times to the advisory committee on this topic, specifically
talking about DPK, dermatopharmacokinetics, and we really want to
continue that discussion. At the last meeting we sort of agreed that we
needed to back off of our position on DPK to have it as the only method
for doing BE for topical products. We took the committee\'s
recommendation to withdraw the draft guidance on DPK and determined that
we would take a fresh look at the whole subject of topical
dermatological products and the bioequivalence for those.

So today Dale Conner, who is the Director of the Division of
Bioequivalence in our Office of Generic Drugs, will begin to
reinvigorate the whole topic of BE methods for derm products and will
help enhance the committee\'s understanding of the issues. Dr. Dena
Hixon, who is our Associate Director for Medical Affairs in OGD, and Dr.
Jonathan Wilkin from OND will talk about the clinical perspective on
therapeutic equivalence, and then Dr. Hussain will discuss how we plan
to address the topic in the future and will actually solicit the advice
of the committee on developing a comprehensive research plan for doing
future research in the area of topical bioequivalence.

The next agenda item and the last for the day is on also an awareness
topic. Nancy Sager and Steve Moore will discuss the comparability
protocol process and its specific principles. I think it will be a very
interesting subject for you to hear where we\'re going with
comparability protocols.

Tomorrow we\'re going to start off with an update of the cGMP initiative
for the 21st century. I think all of you are familiar or have at least
seen some information on this initiative. We\'re now starting to call it
the drug product quality initiative for the 21st century. I think it\'s
somewhat misleading to call it GMP because it\'s really focused on the
entire quality process from review through the GMP process.

You\'re probably going to think that we\'re a little schizophrenic or
out of order talking about it tomorrow, but we didn\'t want to squeeze
it on the agenda today because we had so much going on.

We think, though, it\'s really important that you have a better
understanding as the advisory committee of the initiative because I
think there will be a lot of things over the next few years that will
relate to some of the scientific decisions that will come out of the
changes in this whole, entire quality process that we\'ll want to bring
to the committee. So Ajaz and I will talk a little bit about that
tomorrow with you.

After plowing through this initiative, we\'re going to shift gears.
We\'ll discuss the recommendation from the International Pharmaceutical
Aerosol Consortium on Regulation and Science, IPAC-RS, on dose content
uniformity. IPAC submitted this proposal to us a while back, and
conceptually the agency agrees with the recommendations as presented in
the proposal, but we feel that there are still a number of questions
that need to be answered before we can incorporate that recommendation
into our guidance. So tomorrow we\'d like to make the committee aware of
those questions, have some future discussions at one of the next
advisory committees on the recommendation. So basically what we\'d like
to do is familiarize you with the recommendations, familiarize you with
some of our questions, and then go from there at a future meeting.

Bo Olsson from AstraZeneca will present the recommendation on behalf of
IPAC-RS, and Dr. Walter Hauck, who has been working with FDA for a
number of years and providing statistical support to us as a special
government employee, will provide an assessment of the proposal. So it
should be a very interesting topic. Wally Adams, who is on the OPS
staff, will lead that presentation.

After the open session tomorrow and lunch, we\'ll present another
awareness topic on bioavailability and bioequivalence of endogenous
drugs. Approving such drugs continues to be a challenge here in the
agency because of the different characteristics of endogenous products.
Although we feel that we have made some strong scientific decisions in
the past with respect to these products, we think we can continue to
enhance the science and provide more complete understanding and
information to help better guide the sponsors with regard to what are
the correct bioavailability and bioequivalence studies to do for these
products.

We have two case studies we\'ll present, one on levothyroxine sodium
tablets and one on potassium chloride modified-release tablets and
capsules. In advance I want to thank Abbott Laboratories who has been
willing to work with us and to present some of their study data on
levothyroxine sodium at this meeting relating to the approaches for
baseline corrections.

Dale Conner will lead the overall discussion tomorrow, and Dr. Steven
Johnson and Dr. Barbara Davit will present the case studies. It will be
an interesting discussion and I look forward to your input.

Lastly, we will provide an update on our research program. We\'re
specifically going to focus on the rapid response program. Dr. Nakissa
Sadrieh, who heads up the Rapid Response Team in OPS, will give you an
overview of some of the projects we\'ve been working on under rapid
response. We feel that it\'s really important for the committee to have
an understanding of the research capabilities that we have available in
OPS so as different issues and questions come up before the committee,
you know what we might be able to utilize internally to answer some of
those questions from a research standpoint.

So as I said earlier, it\'s definitely a very packed meeting, but I
think they will be very interesting topics. I thank you for your
participation in advance, and I will turn it back over to Dr. Kibbe.
Thank you.

DR. KIBBE: Thank you, Helen.

A couple of points just for everyone\'s information. There is open
public hearing time on both days. Individuals who wanted to make
presentations had to have gotten their request in by March 3rd. So we
have 1 person on today\'s agenda and 12 on tomorrow\'s. So the hour
tomorrow will be jam-packed and filled with entertaining presentations.

The next speaker will be the beginning of our reports on the
subcommittee updates. Tom Layloff for PAT.

DR. LAYLOFF: Good morning. It\'s a pleasure to be here in front of the
committee again. An unusual event: this is a closing report. The
committee is sunsetting. We have completed our objectives and we\'ll be
moving on.

The interest in process analytical technology goes, I think, all the way
back to the formulation. If we look at formulating a 50 milligram
tablet, we can weigh out the quantities for active diluents and
disintegrants of lubricants, and the only issue after the accurate
weighing is achieving a uniform product. So it\'s relatively
straightforward. You weigh this out very accurately. You throw it in a
bucket, and you get to a uniform, consistent mix. Unfortunately, it\'s
not quite that easy.

Traditionally, the manufacturers follow the active pharmaceutical
ingredient as a measure of uniformity throughout the whole process. So
the univariate handle is applied to a polyvariate process where you have
excipients, diluents, and other materials. And in some cases it is a
poor surrogate marker for many of the components in the process.

Process analytical technology is an optimum application of process
analytical chemistry tools. It\'s a feedback process with control
strategies. It involves information management tools and/or
product/process optimization strategies to manufacture pharmaceuticals.
So pharmaceutical design is a critical factor as is information acquired
during the process.

The 1978 preamble to the GMPs says, \"There is no prohibition in the
regulations against the manufacturing of drug products using better,
more efficient, and innovative methods.\" Further, the USP in the
general notices says, \"Compliance may be determined also by the use of
alternative methods chosen for advantages in accuracy, sensitivity,
precision, selectivity, or adaptability to automation or computerized
data reduction or in other special circumstances.\" So neither the GMPs
nor the USP restrict how you make the assessments of product process
streams or product assessments anywhere.

The charges to the Process Analytical Subcommittee were: What is to be
gained by embracing the technology? What is the state of the art? What
are the problems, hurdles, and solutions? How should the new
technologies be regulated? How should FDA be prepared to adapt to
dealing with the new technologies? And what are the staff educational
issues and how should these competencies be assessed?

Our subcommittee had three meetings. We did applications and benefits.
At those sessions we observed that there were, in fact, assessment tools
which could be adapted for monitoring the process stream on a continuing
basis. Those tools could be validated or qualified, and that there were
chemometric tools which could monitor the process.

We went on in our June 12-13 session. At that session I think we made a
very significant contribution with a group of individuals getting
together and defining the competencies that would be expected for
reviewers and inspectors to deal with process analytical technologies
and to define a curriculum to achieve those competencies. That was done.

Our October meeting was an add-on, and it was added on because of the
perception that there would be problems with the implementation of PAT
technologies with the interpretation at the time of 21 C.F.R. 11.
Because the PAT is inherently computerized very heavily, the concept of
validating software independent of the data acquisition units poses a
very severe burden. CDER has moved 21 C.F.R., part 11 into its
compliance operations to better bring scientific knowledge of PAT to
bear on those assessments.

We also dealt with rapid microbiology testing at that 23rd meeting. How
should the FDA respond? Well, the FDA should develop a general guidance,
a conceptual framework, and establish regulatory positions on this. The
FDA has established ‑‑ I like this ‑‑ PATRIOT. Who came up with this,
Ajaz? Process Analytical Technologies Review and Investigation, Office
of Pharmaceutical Sciences ‑‑ you\'ve got to say that quickly because it
fits in the \"O\" ‑‑ Team.

(Laughter.)

DR. LAYLOFF: And it\'s a science and risk-based approach, integrated
systems approach.

Now, that PATRIOT initiative is probably, I feel, one of the most
important outcomes of the meeting because reviewers and investigators
are trained and work as a team to assess compliance in the industry, and
I think this is going to be a great boon because if you\'re not familiar
with the technologies, it\'s going to be very difficult to review the
material and very difficult to inspect it. It will be eventually stifled
if it\'s not handled well. CDER, Office of Pharmaceutical Science has
moved very quickly and properly to develop the individuals to help deal
with these issues.

There is a proposed draft, a guidance on applications with PAT.

A summary of our observations, tools. The assessment tools, data support
systems, and technologies are available to improve product consistency
and reduce bad production and recalls. We have had many presentations
from individuals in the industry and from academia describing those
tools and their ability to make those measures.

If we look at one of the problem areas that occurs, we look at the USP
content uniformity test issues, the USP allows an RSD of 6 percent. If
we have a normal population at 100 percent, there will be 30 tablets in
a million out of 75 to 125. The USP allows only 1. So statistically no
batch of a million could pass the test because there are more than 1 in
30. There are more than ‑‑ I mean, 1 in 30. We have 30 total. So the PAT
initiative will have to have statistical interpretations science-based
rather than these hard numbers to deal with, but that\'s another issue.

The agency\'s perspective. CDER has assumed a very strong, I think, good
position. They\'re going to use the knowledge, experience, and guidance
from other FDA components, NIST, ASTM, and ANSI and do those by
reference rather than attempting to develop guidances independently.
They will reach out to those existing bodies where many people have put
a lot of effort in developing guidances, such as the Design Control
Guidance for Medical Device Manufacturers.

Also, they will provide a framework to manufacturers with the
flexibility needed to develop design controls to comply with regulations
and also appropriate for their own design and development of processes
and SOPs.

Future issues. These will be left for other committees. Validation of
data and retention of data. In-process endpoint detection and data
acquisition and storage. Documentation and E-sig closure of decision
points. Incoming material stream consistency of robustness assessments.

Regulatory incentives. The FDA has said PAT is not a requirement. It\'s
an option for those that want to implement it. Regulatory support and
flexibility during the development and implementation by meeting with
FDA will eliminate the fear of delayed approval and dispute avoidance
and resolution in the future. So FDA is willing to work with people,
work with the industry.

It\'s a science and risk-based regulatory approach. Low risk
categorization based on a higher level of process understanding.
Continuous monitoring on stream will assure a higher quality product.
There will be a research exemption so that continuous improvement can
occur without fear of being noncompliant. So you can do PAT development
work in parallel with your current process stream as a research tool
rather than an implementation tool and implement it when you\'re
confident in this thing. Until the FDA has approved a new process
approach, the one that is currently approved will stay in force, which
is not unreasonable.

What\'s missing? I believe ‑‑ this is personal ‑‑ industry political
will is missing. I think FDA has bent over backwards to take this
initiative and have these meetings bringing people together. The ball is
now in the industry\'s court. FDA is waiting.

How to move forward. I think the way to move forward is not to try to
eat the elephant in one bite, evolution rather than revolution. Bring on
stream validated or qualified PAT systems piecemeal, incoming materials
ID, wherever they best fit. But piecemeal.

Acknowledgements. I\'d like to acknowledge the leadership of Ajaz
Hussain. He has been a greater leader in this business. And Raj Uppoor
developing guidances. My former colleagues at the DPA, Division of
Pharmaceutical Analysis, and Division of Product Quality Research. The
colleagues on and presenters to the Process Analytical Technology
Subcommittee.

There\'s a compilation of reports on the FDA website, and I\'ve given
that. And comments and suggestions can be sent to: PAT@cder.fda.gov.
Thank you.

DR. KIBBE: Thank you, Tom.

I think we have time for a couple of brief questions, if anyone on the
full committee has any questions of Tom.

DR. HUSSAIN: Just sort of an update to all the recommendations that we
have received on the PAT Subcommittee. I think this committee was
amazingly efficient and effective in getting these recommendations to
us. We have actually progressed quite well.

Tom mentioned the PATRIOT team. It\'s undergoing training and
certification programs as we speak. In fact, next week they will be
going to the University of Washington in Seattle for hands-on lab
experience. That\'s the second session. And within this year, we will
have completed the training program for this team.

So the training program was brought together by three schools, the
School of Pharmacy at Purdue, the School of Process Analytical Chemistry
from Washington in Seattle, and the School of Engineering from the
University of Tennessee. So we brought the three disciplines together to
do this training.

A guidance is floating around inside OPS right now, and I think we will
plan to get the guidance out as soon as possible. The reason we held
back the guidance is we wanted to see the evolution of the drug quality
system for the 21st century, the GMP initiative, and make sure that PAT
becomes a model for that. As that has evolved, the part 11 draft
guidance is out, so I think we are now ready to move the general
guidance forward which will actually provide not only the regulatory
process for implementing PAT, but actually address many of the issues
and concerns that industry has expressed to us. So it removes all
perceived and real regulatory hurdles for bringing innovative technology
into the manufacturing sector.

So I think what was best was, at the final meeting of the subcommittee,
industry representatives at that subcommittee were very clear, saying
that FDA is no longer the hurdle. The hurdle is within the companies. So
I don\'t want to see FDA being blamed as being a hurdle anymore.

I just want to thank Tom and his leadership. In fact, if you really look
at it, the proposal on PAT started in \'93 with what Tom had led, but it
had subsided. What I have done is brought it back and added my
pharmaceutical angle to it. So the FDA initiative actually started in
1993, and I thank Tom for that.

DR. LAYLOFF: I think I\'d like to say the PAT strategy that has been
implemented in OPS is basically a design strategy for a regulatory
action. So it\'s a quality system approach on how do you regulate
because it defines competencies, certification of individuals for
training, and the guidance documents are all converging at once. So
it\'s really an excellent example of a quality system approach to
setting up a regulatory strategy.

DR. KIBBE: Thank you, Tom. And I\'d like to add my congratulations. I
think the subcommittee did excellent work. We were very fortunate to be
able to bring to the table with us some knowledgeable individuals from
industry who came and shared quite openly, and I think that was a good
model for moving forward on things like that. You did a wonderful job.

I understand that there\'s training going on, and I\'m sure there will
be a manual or something that comes from it. And we could call that the
PATRIOT missile?

(Laughter.)

DR. KIBBE: I\'m sorry.

Ajaz now is going to talk about the Manufacturing Subcommittee.

DR. HUSSAIN: Well, I think the credit for naming that goes to Karen
Bernard, and it was her idea to name it that way, so I sort of accepted
that.

I wanted to give you a quick update on the Manufacturing Subcommittee.
On October 22nd when we met at the previous advisory committee, we had
made the proposal on sunsetting the PAT Subcommittee and in its place
establishing a broad, general Manufacturing Subcommittee. The progress I
would like to report back to you is that now we have formed the
committee. Judy Boehlert from this committee will be the chair of that.
The first meeting of this committee is on the 21st of March.

Now, I would like to go back and sort of refresh your memory in terms of
why we wanted this committee and what the goals and objectives are. To a
large degree, we will use this subcommittee to give us advice to move
forward on the drug quality system for the 21st century initiative.

The first meeting of this committee will essentially be to go back and
look at the desired state of manufacturing that we have outlined in our
announcement on February 20th with respect to what that is and how do we
get there and essentially create a framework for the future activities
of the subcommittee.

In addition to that, I think there are a number of issues which have
already started, the aseptic guidance and a draft guidance that we are
working on. Some of that will be discussed here.

Also, I\'ll remind you this is a team effort. We are partnering with our
Office of Compliance and Office of Regulatory Affairs, and we will bring
the combined effort on managing the process of the subcommittee.

So I don\'t have much else to report on this except that now we have
formed the committee and the first meeting is on the 21st of March.

DR. KIBBE: Here?

DR. HUSSAIN: Yes, the same room.

DR. KIBBE: Joe?

DR. HUSSAIN: I\'m speaking for Joe and myself.

DR. KIBBE: Oh, that\'s good. We\'re gaining time. I like it.

(Laughter.)

DR. KIBBE: Thank you, Ajaz.

Jurgen.

DR. VENITZ: Good morning and thank you, Art.

I\'m here to represent the Clinical Pharmacology Subcommittee. As most
of the members of the committee know, this was a committee that was
recommended and endorsed by the parent, the Advisory Committee for
Pharmaceutical Science, about a year or so ago.

The intent of this committee is to provide feedback in three different
areas, feedback to this parent committee, in the areas of: exposure
response, relationship between doses, drug levels, and effect; pediatric
clinical pharmacology; and pharmacogenetics. FDA believes ‑‑ and I think
this committee agreed with that ‑‑ that those are areas where the
science is emerging rather quickly.

We put together the committee membership the second half of last year,
and I\'ve listed the members for you. As I said, three areas,
pharmacometrics, pediatric clinical pharmacology, and pharmacogenomics.
Bill Jusko was kind enough to be the acting chair at our very first
inaugural meeting last year. He at that time was also a member of this
current committee. You see we had two industry representatives, Michael
Hale and Rich Lalonde from Pfizer and Glaxo, respectively, both of them
with very extensive experience in exposure response. Myself, I was not
on the committee at that time since I was on a sabbatical with the FDA.
We have three experts in the area of pediatrics: Ed Capparelli, Greg
Kearns, and Mary Relling. And then we have three individuals, Dave
Flockhart, Howard McCleod, and Wolfgang Sadee, who is a current member
of the parent committee.

We had our first meeting in October of last year, and I\'ve listed for
you the topics that we discussed as part of this meeting. Most of those
are what Helen would call awareness topics. So this was the first
meeting, and we wanted to make sure that the committee members had an
idea of what\'s going to come down the line.

So the first topic was using exposure response information to
individualize dose. How can we use information from premarketing
studies, from clinical pharmacology studies to optimize dosing regimens
and to label new drug products accordingly? What are the data sets that
we can use to make that decision in terms of how to label drugs
appropriately?

Peter Lee, the Associate Director of OCPB, presented an approach that is
currently used that uses kinetic information from usually a special
population or drug-drug interaction studies, combines it with
exposure-response relationships to predict clinical outcomes. For a
given dose, what is the likelihood that we have certain outcomes? And
are those outcomes acceptable? If they are not, well, that would lead to
a dose adjustment.

We had feedback from the committee members. Rich Lalonde and Lew Sheiner
gave an endorsement to the method in general, but discussed specific
potential issues with it. In general, the committee requested to get
specific case examples to get a better sense for how much this approach
could be generalized.

I went on to discuss and introduce a new term called \"utility\" that
deals with linking clinical outcomes to risk where you look not only at
outcomes but also the consequences of those outcomes and you try to
incorporate that in your decision making process.

The second topic, again an awareness topic, was for the committee to be
aware of what the initiatives are within FDA right now in the pediatric
area. Arzu Selen presented an updated on OCPB\'s pediatric database
where they\'re trying to capture on an ongoing basis PK/PD information
from pediatric studies.

Rosemary Roberts discussed what is currently done in terms of the
decision tree that is used to help extrapolate information from adult
studies into the pediatric population.

The final topic was in the pharmacogenetics area. Here the intent again
was to make the committee aware of what are some of the issues that FDA
is facing right now, particularly for drugs that undergo
pharmacogenetically determined either metabolism or other differences in
response. Larry Lesko presented some of those issues, the labeling that
is used that is currently quite inconsistent.

We then specifically discussed TPMT, an enzyme that shows polymorphic
expression, and people that don\'t have that enzyme or that enzyme is
reduced in its activity are at a very high risk of potentially fatal
side effects. So one of the questions that the committee was starting to
address is, is this something that we should incorporate in the label?
Should people be asked to genotype, for example? Dr. Weinshilboum was
the expert that really presented on that topic.

After the meeting, pretty much within a few days after, we were informed
that the committee membership is not allowed to have industry
representatives. So we had to renominate two individuals, Dave
D\'Argenio and Marie Davidian. Both of them are experts in the
pharmacometrics and statistics area.

Our next meeting is next month. You can see it\'s a follow-up meeting,
so the topics look very similar to what I just presented to you. The
first topic is again to look at risk-benefit information gleaned from
exposure- response data. It\'s basically a follow-up to the dose
adjustment approach that Peter Lee presented, and he\'s presumably going
to show us some case examples.

We\'re going to follow up on the pediatric initiative, trying to develop
a template that helps sponsors to collect information in a way that
makes it suitable for FDA to capture it and analyze it appropriately.

We\'re going to follow up on the pharmacogenomics or the
pharmacogenetics topic, look perhaps at different pharmacogenomic issues
as they relate to labeling.

And there\'s a new awareness topic that deals with drug-drug
interactions as it relates to metabolism and drug transport.

That\'s all I have.

DR. KIBBE: Questions?

(No response.)

DR. KIBBE: No questions.

DR. VENITZ: Thank you.

DR. KIBBE: Thank you, Jurgen.

Just something I thought of that I\'d like Ajaz to do. Since Jurgen was
so kind to give us the names of everybody on the committee, maybe we
could do that for the ‑‑ okay.

This brings us to committees that are in the \"let\'s get started\"
phase, the future committees. We should start with Bob Osterberg.

DR. OSTERBERG: Good morning. I\'m Bob Osterberg, the acting, as Dr.
Kibbe pointed out many times, Associate Director of Pharmacology and
Toxicology in the Office of New Drugs. I think our interaction here
indicates that both the Office of Pharmaceutical Science and the Office
of New Drugs can work together very effectively to resolve scientific
problems that perhaps individually we couldn\'t do.

I\'d like to point out to you that the Office of New Drugs pharm-tox
group does not have an advisory committee that we can go to and ask
specific questions, and we don\'t have a research laboratory that we can
ask to develop data that we can use to make regulatory decisions.

But we do have a Pharm-Tox Coordinating Committee and a Research
Subcommittee of that. Interestingly, Dr. Frank Sistare, who runs the
Division of Pharm-Tox in OPS at the laboratories, is my co-chair on this
Research Subcommittee. Together we have been asked to develop this
particular Pharm-Tox Subcommittee of the OPS.

When Mrs. Winkle told me about this particular activity that she had in
mind, I saw the merit of it and I immediately said, yes, I think this is
a very good idea. My predecessor in this position also said likewise,
I\'m told. Of course, when we briefed our Office of New Drugs Division
Director, he was also very supportive of this activity.

What I\'d like to do is to tell you a few things that we\'re doing
within the subcommittee with respect to its development and this morning
I\'d like to mention some of the things about the committee with respect
to background, its objectives, its mission, and its membership, and a
few other things.

Now, the Pharm-Tox Subcommittee is an advisory committee. We pay
particular attention to the advice given because it\'s valuable
information. The people on the subcommittee will be experts in their
field. They\'ll be well-recognized scientists and we can rely heavily on
what they suggest to us. But their advice, like all advisory committee
statements, is not binding on the agency. But as you know, we mostly do
agree to accept their opinions.

The subcommittee is expected to provide feedback to the Pharm-Tox
Coordinating Committee and to facilitate activities down at the National
Center for Toxicology Research\'s Non-Clinical Studies Subcommittee in
meeting not only this subcommittee\'s research needs but Pharm-Tox\'s
research needs because, as I mentioned, we don\'t have our own
laboratories.

Now, the objective of this subcommittee is to provide expert advisory
feedback to the Pharm-Tox Coordinating Committee and the nonclinical
pharm-tox research disciplines in targeting cross-cutting areas of
pharm-tox, the big problems that we see not specific to any division but
across the agency, where integration of new scientific knowledge or
methodology could be helpful in drug development and in helping to
identify laboratory-based research priorities to address what we
perceive to be data gaps as identified by the Pharm-Tox Research
Subcommittee.

We also anticipate that the committee will provide input to the National
Center for Toxicology Research\'s NCSS ‑‑ that\'s the Non-Clinical
Studies Subcommittee ‑‑ to address CDER\'s identified data gaps.

We also expect the committee to advise the Pharm-Tox Coordinating
Committee in the evaluation of research data related to pharm-tox
activities.

Now, meetings of the Pharm-Tox Subcommittee of OPS will occur on an
as-needed basis. There\'s no point in having a meeting if there\'s
nothing to discuss, but we anticipate at least that two meetings per
year will occur, especially in the early phases of getting this activity
together and focused on a common concern.

The agendas and topics that will be presented to this Pharm-Tox
Subcommittee will come from the Research Subcommittee of the Pharm-Tox
Coordinating Committee because that coordinating committee is the major
Office of New Drugs pharm-tox group.

Also, activities and recommendations of this subcommittee will be given
to this advisory committee and to CDER\'s Pharm-Tox Coordinating
Committee and on an as-needed basis to NCTR\'s committee.

A member of this subcommittee will serve on NCTR\'s Non-Clinical Studies
Subcommittee and that will probably be Dr. Frank Sistare.

Now, the first topic that we think we\'d like to have this subcommittee
address is pharmacogenomics. It will be a trial run because, in any new
committee, you want to make sure that ground rules are laid down and
certain activities are ongoing without any problem. It\'s a shakedown
cruise, if you will.

We chose pharmacogenomics because this is a very interesting and useful
area, we think, that because of being able to observe a chemical or a
potential drug\'s effect at the molecular level on human genes, we may
see a pattern emerge of up and down regulation perhaps of some genes
which, if we can correlate that change in the gene expressions, we might
be able to see or predict what the human toxicities may be during the
initial phases of drug review or drug development. So we really think
this is a pretty hot topic and we\'re very interested in getting as many
experts on this subcommittee as possible.

Now, we\'ve already recognized that we have two members already on the
committee, Dr. Meryl Karol, who is going to be our chairperson, and our
consumer rep, Dr. Marc Swadener. Now, we will be selecting other people,
another generalist and several specialists in this area of
pharmacogenomics and genetics in general, and we hope that they\'ll be
able to help us in this endeavor.

We anticipate that the first meeting of the subcommittee will occur in
the early portion of June, and hopefully by that time, we\'ll have a
series of proposals to offer the subcommittee to help us.

Thank you.

DR. KIBBE: Thank you, Bob.

Are there any questions from the members? Marv?

DR. MEYER: Do you think there will be any overlap with the clinical
pharmacology group, the subcommittee, in terms of their pharmacogenetic
interests and activities?

DR. OSTERBERG: I would say yes to that. I can\'t tell you the extent
because the Commissioner of FDA has asked the pharm-tox folks in the
agency not only to address the nonclinical aspects of pharmacogenomics,
but also the clinical aspects. So I would think at some point in time,
after we get our committee ongoing and we start getting data coming in
from industry ‑‑ as a matter of fact, we\'ve had several meetings with
industry in the past year where we have discussed this particular area.
But we just know what to make of it. But when we think we do know what
to make of it, since we\'re using a human genomic expression platform,
we think this will bear on the clinical aspects of it. Certainly we\'ll
avail ourselves of the subcommittee.

DR. KIBBE: Dr. Karol, do you have anything to add?

DR. KAROL: No, other than that I\'m really looking forward to working
with this committee.

DR. KIBBE: Well, thank you.

Our next future subcommittee is on microbiology. Peter Cooney.

DR. COONEY: Good morning. I\'m Peter Cooney. I\'m the Associate Director
for New Drug Microbiology in the Office of Pharmaceutical Science.

Product quality microbiology issues, including sterilization, sterility
assurance, and microbial quality of nonsterile pharmaceuticals, are of
critical importance in the assessment of the safety of drug products.
Now, somewhere between 20 and 25 percent drug products are marketed as
sterile, and the quantity and type of microorganisms associated with the
majority of products which are not sterile can also be of critical
importance to patient safety.

The center, therefore, believes that the formation of a subcommittee
specializing in microbiology can be of great benefit in providing advice
for the regulatory and scientific approaches taken in the regulation of
a great number of products that we regulate. We believe a subcommittee
composed of approximately eight members with diverse backgrounds in
microbiological science can help the agency in making scientific and
regulatory decisions related to microbiology issues.

Now, what are some of the potential subcommittee topics that might come
up in the future? These might include both regulatory and technical
issues, and some of them are as follows.

Parametric release of sterile products. Should the center create a
guidance and should everybody use this type of methodology?

Development of vapor phase hydrogen peroxide decontamination cycles for
decontamination of isolators used in aseptic processing.

Interaction of the field and center function in microbiology relative to
sterility microbial limits, endotoxins, preservatives, et cetera.

The appropriateness of microbiology review for safety and risk
assessment.

The appropriateness of monitoring adverse event reports for microbiology
risk assessment and determination of risks which may or may not be
related to specific manufacturing processes.

The appropriate use of subject matter experts in risk analysis following
event reporting.

Decision criteria for risk management in microbiology and in
manufacturing processes for sterile products.

And discussions and identification of critical processes, tests, and
criteria to ensure microbiological quality.

There are many new sterilization technologies being developed. Pulse
beam light, for example. Closed aseptic filling systems where the
container closure system is closed and then penetrated with a needle to
fill it.

Product and process compatibility issues can be discussed, and combining
terminal sterilization and aseptic filling processing in the same
manufacturing operation.

A critical issue that\'s come up now, of course, is the PAT initiative,
the rapid microbial methods for detecting, counting, and identification
of microorganisms associated with manufacturing processes and products.
What kind of filing strategies in terms of applications for instituting
rapid methods should be developed?

Experimental evaluation and/or validation of rapid methods in
microbiology versus parallel testing of old versus new methods. Which
approach has the most scientific validity? And is it always the same or
does it depend on the specific test or process being evaluated?

And finally, what is FDA\'s role in harmonization of standard
microbiological tests? And can future rapid methods and new technologies
be harmonized?

There\'s a plethora of issues that we believe can be discussed in the
future, and as those arise, there would be a need to have the
Microbiology Subcommittee. So, therefore, we look forward to working
with and receiving advice from a microbiology subcommittee.

And I\'ll entertain any questions anybody might have.

DR. KIBBE: Questions anybody?

(No response.)

DR. KIBBE: Thank you.

I don\'t want anybody lulled into a sense of false security. We\'re
moving too quickly. This will change.

(Laughter.)

DR. KIBBE: Ajaz on biopharmaceutics.

DR. HUSSAIN: I have one observation that listening to some of the
updates and presentations, I think we have a wonderful opportunity in
this advisory committee to bring all aspects together and actually
connect the dots. We can look at pharmacogenomics, pharm-tox,
clin-pharm, the risk from clinical, from quality perspectives. So I hope
you see the opportunity here to connect the dots with all disciplines
and sort of come up with more cohesive policies and procedures that not
only are specific to a particular discipline but bring across the
generality that sort of underpins all these activities.

The origin of the Advisory Committee for Pharmaceutical Science was in
the Generic Drug Advisory Committee. That\'s how we started. At some
point we were looking at issues and topics for discussion that went
beyond generic. As a result the Generic Drug Advisory Committee became
the Advisory Committee for Pharmaceutical Science.

As we grow, in terms of the complexity, in terms of the topics that we
have to cover, I think biopharmaceutics becomes an important topic to
keep our focus on. Especially in the next several years, we plan to have
a significant research initiative in the area of the generic drug
program, essentially develop methodologies for approving generic drugs
based on pharmaceutical equivalence, bioequivalence. So there is a need
to essentially come back and establish a biopharmaceutics committee that
will focus on these aspects.

So that\'s the proposal that we have for you, that we would like to move
forward putting this committee together and would like to develop the
charter for this committee with the help of Professor Marv Meyer, who
has graciously agreed to be a chair of this committee, with the help of
Art Kibbe, and develop this subcommittee to focus on certain areas.

But let me take a step back and try to outline what are the issues in
biopharmaceutics. I think I\'m looking at biopharmaceutics as a
discipline more in terms of a critical link between quality and clinical
performance. So there are many topic areas that need to be addressed in
this.

If I take a step back and use the test methods that we use to assess
some of these or to link quality to the clinical aspect, you\'re looking
at drug release methodologies. How do you establish a meaningful
specification for, say, dissolution tests? For the last 30 years, we
have talked in terms of dissolution testing, but as we go to more
complicated dosage forms and release mechanisms and so forth, what are
the strategies for developing more meaningful release specifications
that not only relate to quality but also provide a meaningful link to
the clinical performance of these dosage forms.

For example, we are looking at several liposomal drug delivery systems
that have been approved. Now, how does one establish meaningful release
and quality specifications for these products or for parenterally
administered microspheres, implants, and so forth that have a very long
duration in human use? How does one develop a meaningful quality control
test as well as establish in vitro/in vivo correlation for some of these
products?

So that\'s sort of the tip of the iceberg in terms of what we can start
thinking about, but I think the major issues also are in methodologies
for bioavailability and bioequivalence.

We have for discussion, for example, tomorrow afternoon an issue on
endogenous drug substances, and that probably will become a topic for
discussion in the subcommittee as we progress. What are the challenges
in establishing bioavailability and bioequivalence? More so, I think
what are the challenges in establishing pharmaceutical equivalence? Keep
in mind I think pharmaceutical equivalence is the foundation on which we
base a lot of our decisions. Bioequivalence/bioavailability comes from
that in some regard. And I\'ll, in a minute, try to explain that process
to you.

But in addition, I think the ultimate goal here is to have therapeutic
equivalence for both new drugs and generic drugs in the event of
post-approval changes and for approval of generic drugs.

So these are sort of the major areas or broad areas for discussion.

I think immediate needs that we have in terms of seeking help from this
committee is to seek advice in terms of developing methodologies for
bioavailability, bioequivalence, challenges such as endogenous drug
substances.

But moving on, I think locally acting drug products would be the major
focus for discussion. You also have a topic that we\'ll present to you
this afternoon on bioavailability/bioequivalence of topical drug
products. We have struggled for the last 12 years trying to develop a
method for assessing bioequivalence of drugs applied to skin and we have
not been successful in trying to move that decision forward in a
consensus way. There are many issues and you\'ll get a flavor of some of
those issues this afternoon. So how does one establish bioequivalence
for locally acting drug products where blood levels may not be a
surrogate or may not be an indicator of rate and extent of absorption at
the site of action? So that would probably be the starting point for a
number of discussions.

We would also like to use the committee to guide us as we develop our
research programs. We have an announcement coming out soon for
recruiting a director-level position for a research leader. I think as
we go through and recruit that person, the biopharmaceutics research
program will sort of reemerge under his leadership or her leadership,
whoever that person might be. I think that would be also a very
important link to this committee and the subcommittee also.

So there are many broad topics. I think we are ready to start moving in
that direction from a methodological perspective in terms of
specifications and so forth, but that\'s not all.

I would like to bring another topic for discussion at some point. At the
training some of you heard about the TIACC committee, Therapeutic
Inequivalence Action Coordinating Committee. And what is that? It is
essentially a quality system where we respond to complaints from
consumers to physicians to citizens petitions where there is a claim
that a generic was not found to be therapeutically equivalent to a brand
name product. How does one respond to that? What are the mechanisms we
have used?

This is a fairly established, old committee, but I think we are taking a
fresh look at that committee to see how do we integrate that into a
quality system perspective. What are the most appropriate procedures to
investigate some of these cases, and how can this committee be more
proactive? So I think that also will provide a number of very
interesting situations and very interesting problems that need to be
addressed. We would probably address those in-house, but I think at some
point there are general issues that come from that investigation that I
think would be appropriate for discussion at the subcommittee.

But let me take a step back. I think the challenges that we see in the
future in this area also deal with misinterpretation or lack of
understanding of our bioequivalence, pharmaceutical equivalence, and
therapeutic equivalence standards. At some point I think this committee
will also be useful in articulating the right message to explain our
standards because many times what we see is our standards are either
misinterpreted or not even understood by the practicing community, the
pharmacists or physicians. So how do we get over that hump and bring
some of this discussion to explain the scientific rationale for that?

What I\'m proposing here is, as we start putting the goals and
objectives of this committee and the charter for this subcommittee, what
we\'ll do is work with Professor Marv Meyer, and when we come back next,
sort of develop this with his help, and then start moving towards
putting the subcommittee together.

I would like to step back and share with you the general approach to
approval of generic drugs per se, essentially establishing therapeutic
equivalence. In sort of a systems thinking way, I think we need to go
back to the statute, go back to the 1986 bioequivalence hearing where
Marv Meyer spoke and sort of reexamine where we are what we have
accomplished and where we need to go in the future.

In terms of systems thinking, I go back and look at our Orange Book and
how we define therapeutic equivalence. So if you go back to the Orange
Book, which is available on our website, U.S. FDA System to Ensure
Therapeutic Equivalence, drug products are considered to be therapeutic
equivalents only if they are pharmaceutical equivalents and if they can
be expected to have the same clinical effect and safety profile when
administered to patients under conditions specified in the labeling.

The key phrase here is \"pharmaceutical equivalence.\" Often, especially
the practicing community forgets the pharmaceutical equivalence part of
our analysis. That is the foundation of approval of generic drugs. It
does not get the attention or the recognition as the bioequivalence part
does, and many times all the discussion is focused on bioequivalence and
people have forgotten that part of that equation.

If you really look at the definition, therapeutic equivalents are
pharmaceutical equivalents first and then if you put this in sort of a
systems criteria, what the subsystems for this program?

First, to be a generic drug you need to have an approved safe and
effective new drug application. The generic has to be pharmaceutically
equivalent to be that. They have to contain identical amounts of the
same active drug ingredient in the same dosage form and route of
administration, meet compendial or other applicable standards of
strength, quality, purity and identity.

Then bioequivalent with the caveat that they do not present a known or
potential bioequivalence problem and they meet an acceptable in vitro
standard. So in vivo bioequivalence is not an automatic need, and in
many cases we don\'t even need that. If they do present such a known or
potential problem, they\'re shown to meet an appropriate bioequivalence
standard. So that part is often not discussed.

They have to be adequately labeled, and they have to be manufactured in
compliance with the current good manufacturing practice regulations.

So you can see, as we move in a systems thinking, the link between
manufacturing, the link between pharmaceutical equivalence,
bioequivalence, therapeutic equivalence, everything is starting to come
together. I think it will be an exciting area as we move forward. We
have much more complex dosage forms coming down the pike, and how do we
deal with bioequivalence of, say, liposomal drug products where now you
have a target oriented drug delivery system and there are many, many
challenges.

So with that sort of a background, what I will propose is I think as we
move with the Microbiology and Biopharmaceutics Subcommittee, this
subcommittee would essentially link back to our established
biopharmaceutics coordinating committee within the center. So the
aspects are all there right away. I think what this does is it gives a
much more focused discussion on this important topic.

So with that, I\'ll stop.

DR. KIBBE: Thank you, Ajaz. Are there any questions?

DR. HOLLENBECK: I have a question.

DR. KIBBE: Good. Thank you.

DR. HOLLENBECK: I thought I\'d break the ice.

Ajaz, I have a process question. I suppose I could direct it to anybody,
but you\'re up there right now. We begin to see subcommittees formed
under the advisory committee. I guess my question is, do you have a
vision of the parent committee serving more of a role as a coordinating
committee and a strategic planning committee than it has in the past?

DR. HUSSAIN: I think the parent advisory committee is an extremely
multi-disciplinary committee. I think we would like to maintain that. I
think that will bring the connectivity between the different
disciplines, different topic areas that need to come about. But at the
same time, I think you do need more in-depth discussions in certain
disciplinary areas, and that\'s the reason for the subcommittees.

The process simply is these subcommittees report back to the main
advisory committee, and in that regard, I think you have an opportunity
to take all that information back because we take advice directly from
you. The subcommittee reports to you. I think from that perspective you
will have to be the conduit for the main advice that we seek. Whether
that\'s a coordination function or whether that is an integration
function or much beyond, I think it will be up to you and the chair of
this committee to decide. So I\'ll throw that to Art.

DR. KIBBE: Is that okay, Gary?

DR. HOLLENBECK: Yes. I guess my question is, is the committee going to
be more prospective than retrospective? My experience on this committee
is we basically hear reports from these working groups, and I certainly
think that\'s an appropriate philosophy. But my question is, how will
you know when you have enough subcommittees? Do you anticipate using
this committee maybe to help you identify needs that are out there and
future strategic direction?

DR. HUSSAIN: Definitely, but I think with respect to the subcommittee,
for example, for the PAT, that was such a specific one, we did want to
continue that because that job was done. So we sunsetted that. But now
if you look at the key disciplines that we are responsible for,
microbiology is a discipline, biopharmaceutics is one. CMC is a broader
discipline, so we took the manufacturing part. Clinical pharmacology. So
all the disciplines that are the key disciplines have been addressed,
and if there is a need for a future subcommittee, it might be a
transient, ad hoc, process-specific or topic-specific committee. I think
you are there to advise us if there\'s a need for that.

DR. KIBBE: I think the workload of this committee ebbs and flows around
issues and how well developed they are. Staff inside the FDA have to
develop the issue to a point where advice is even worthwhile. The
subcommittees are charged with looking at specific areas for that
purpose. But you\'ll notice in our agenda even, we\'re going to deal
with a terminology issue that would never be fruitful to send to a
subcommittee. There\'s a limit to how many of those we want to do.

I think PAT really set the stage for me in understanding how really
effective a subcommittee can be because when you have two days focused
on one topic with integrated industry input, you really get good
conclusions. You bring them back here for one more think-through and
then make recommendations for the agency. So it seemed to work well.

Anything else for Ajaz? Go ahead.

DR. MOYE: Ajaz, I may have gotten myself a little turned around in your
conversations about bioequivalence and pharmaceutical equivalence. I
thought I heard you say ‑‑ and please correct me if I\'m wrong ‑‑ that
bioequivalence is not necessary. Did I hear you correctly?

DR. HUSSAIN: For some products, yes.

DR. MOYE: All right. But you don\'t mean to suggest, do you, that
bioequivalence is a second-tier consideration?

DR. HUSSAIN: No. I think it\'s part of the system. You have to look at
that as a part of one system. For example, just to give you ana example,
if you have an oral solution like elixir or syrup which is a solution,
then the bioequivalence essentially has been waived for it. We don\'t
require an in vivo assessment of bioequivalence. It is simply the
pharmaceutical equivalence, and the quality attributes, the CMC review
part of it, is essentially sufficient. For such a product, we would say
bioavailability is self-evident.

DR. MOYE: So essentially what you mean to do then is to re-illuminate
the concept of pharmaceutical equivalence.

DR. HUSSAIN: Yes.

DR. MOYE: Thank you.

DR. KIBBE: Anybody else?

(No response.)

DR. KIBBE: Thank you, Ajaz. This gets us way ahead of the game. I can\'t
believe that we are this far ahead. As a result, we are scurrying around
to get our other presenters here, and we are at our 10:25 break at 9:45.
You guys are not into it yet. I can see you need more coffee.

A couple of things I suggest we try to do first. Is there a reason for
us not to go out of order with the presenters on the next topic? If
Yuan-Yuan is not here, could we ‑‑ oh, she is. Okay, great.

The second thing is we\'ll take a small break now just to keep things in
order.

(Recess.)

DR. KIBBE: I see by the clock on the wall that you should have gotten
your coffee, moved back to your seat, and then prepared for the next
presentation.

We will now hear presentations on the topic of dermatological drug
product nomenclature. The first presenter is Yuan-Yuan Chiu and she is
ready to go.

DR. CHIU: Good morning. We\'re very pleased to present this topic to the
committee members, and we are looking forward to listening to your
comments, your advice.

The objective of this project we put together since last year is to
develop a clear, concise, and science-based classification, or
nomenclature system for topical dosage forms where the existing system
is not adequate.

Right now, there are two existing systems. One is the USP system.
Everybody is familiar from the book. And the other one is the FDA data
standards. Copies of those nomenclature definitions are in your package.
You could see some of the nomenclatures are very ill-defined, sort of
not very concise.

So we decided that we should limit our scope to only dermatological
topical administration. To make the job easier, we decided that we do
not want to go into mucus administration dosage forms. We only want to
discuss dosage forms which are not quite clearly defined and those are
the ones including liquid emulsion, semi-solid emulsion, and semi-solid
suspension. Specifically those dosage forms are lotion, cream, ointment,
paste, and gel.

If one uses the current definition, either the FDA or USP, you will see
the definitions are quite broad, and it creates a gray area. So two
different products with similar physical characteristics could be called
the same name. And two products with similar characteristics may be
called different names. So when you see a product called a lotion,
actually it may be called a cream by another company. Therefore, it
creates some confusion to the patients and to the physicians.

As well, it has a regulatory impact because as Ajaz said, generic drugs
need to be pharmaceutically equivalent. So you have a different name.
Actually it\'s considered a different dosage form, but they may have the
same physical characteristics. They should be considered the same dosage
form. So, therefore, it does have economic and regulatory impact.

We are not going to discuss solution, liquid suspension, powder,
aerosol, including foams, because those definitions would be quite clear
and it doesn\'t really need further investigation.

So we have taken all the following steps. We identified current
practices in labeling and also specifications establishment at FDA and
at USP. We reviewed the properties and the formulations of more than 50
approved NDA/ANDA drugs. Then we also discussed with our medical staff
any efficacy significance associated with definitions of topical dosage
forms. We also reviewed the literature, textbooks, and most importantly,
we also evaluated many OTC products, as well as the NDA/ANDA drugs for
their physical properties in our own laboratory.

With all this in place, we came up with a proposal we\'re going to
discuss with you today. We would like to get your input and then we will
revise our proposal as needed. After that, we would like to publish our
proposal for public comments. We also would like to forward our proposal
to USP for their adoption.

So today\'s agenda is after my talk, Dr. Jonathan Wilkin ‑‑ many of you
are familiar with him. He\'s the Director of the Dermatologic Products
in CDER. He will make some remarks from a medical perspective.

Then we will have the Deputy Director of the Drug Product Analysis, Dr.
Cindy Buhse, discuss the laboratory findings.

After that, Dr. Chi-wan Chen, the Director of the Division of New Drug
Chemistry III, will present our proposal, the definitions, and the
decision tree.

Then Dr. Herb Carlin from USP will give you an overview of USP
nomenclature for topical dosage forms.

After that, I\'ll come back to present the questions. Then we will
discuss the questions.

I\'d also like to inform you this project involved collaboration of our
review chemists, our research chemists, as well as our medical staff. So
it\'s really a true collaborative study.

Now I would like to bring Dr. Wilkin.

DR. WILKIN: Thank you, Dr. Chiu.

I would like to think about this in terms of what the issues are today
and where we can be in the future.

Many know the old saw about dermatologic therapeutics. If it\'s dry, wet
it, and if it\'s wet, dry it. What you may not realize is how old the
old saw really is. It\'s lost in antiquity. There\'s very clear evidence
in the ancient Chinese, ancient Indian, ancient Egyptian, and ancient
Greek writings that already topicals were being used for their physical
and sensory aspects to improve skin disease.

So originally there were no active ingredients. The therapeutic choice
was based on the physical and sensory properties.

In the 1800s, there were active ingredients that began to be added to
these preparations. Also in the 1800s, there became sort of a recognized
list of usual terms for different types of these dosage forms. So late
in the 1800s ‑‑ I collected these from a variety of medical textbooks ‑‑
colloidal baths, shake lotions, creams, ointments were defined in the
textbooks. Pastes, solutions, tinctures, varnishes, powders all had
their specific place in dermatologic therapeutics.

Later in the 1900s, gels, foams, and the latest, the emollient creams
have been added to the lexicon.

As Dr. Chiu pointed out, the FDA and USP dosage forms are insufficiently
defined. Actually they are somewhat acceptably defined at the epicenter
of what is creamness or ointmentness, but when you get out to the
periphery where an ointment might become a cream if you modify it ever
so slightly, it\'s those boundaries that are really not separated very
clearly. And manufacturers produce dosage form intergrades that are very
distracting to our chemistry group trying to figure out exactly whether
they are, say, creams or lotions.

So what we\'d like to see is a creation of mutually exclusive
definitions for dosage forms and a consistent terminology. I think in
addition to that, there would be the potential for relevant vehicle
properties being listed in the description section of product labeling.

Why would this benefit the public health? It would allow clinicians to
use the dosage form which would be a rough guide to what the vehicle
properties would be in selecting a product for their patients, and if we
had some extra material in the description section on more specific
vehicle properties, that could even be additive.

Examples of potential relevant vehicle properties. I have to say that
this is early in my own thinking. I just looked through some papers to
see what we might consider. I\'m not sure yet that these would be
relevant. It looks like there\'s a lot of overlap to me.

But viscosity may be a useful thing, maybe not actually listed out in
centipoise. I\'m not sure how many dermatologists would appreciate that.
But maybe we could take the range of viscosity for the semi-solids and
we could break it into three categories, which might even been nonlinear
because there may be a psychometric appreciation of greater differences
at lower viscosities and less so at higher viscosities.

Spreadability. I know the industry works with spreadability for some of
their products.

Wash and rub resistance.

Skin smoothness, time curve.

Usual appearance, including color.

Odor is important to patients.

Permanence on the skin. What\'s the residue at 10 minutes? That can be a
positive. If it\'s a dry skin disease, that could be a negative if it\'s
thought to be sticky in a moist skin disease.

Moisturization, the transepidermal water loss time curve.

Volatilization. How long does it take for the volatile components to
actually leave and leave this residue?

This is from an article by Barry Salka, and I\'ll give that reference on
one of the slides. This is not really talking about vehicles. This is
talking about individual oil components of vehicles. I just would point
out that he has this way of looking at it, spreading value millimeter
squared in 10 minutes. That might be something that you could actually
do with vehicles, and that could be helpful information for
dermatologists.

This is also from his paper. The point of this slide is you have time on
the x axis and smoothness on the y axis. If you have a rapidly spreading
preparation, one gets skin smoothness early on, but it rapidly
dissipates. If you have a slowly spreading emollient, then that skin
smoothness persists over time. And different aspects could be
advantageous in different skin diseases.

So Barry Salka, Choosing Emollients. It\'s in Cosmetics and Toiletries.

So the vehicle choice is an important factor in patient compliance.
There is a huge dermatologic literature that supports this. Often the
prescribing physician today finds out about which vehicle to use simply
by squirting it out on their own hand and letting their patients do
this. Our thought is that we could better define the dosage forms so
that they could know this up front, and we probably could capture some
relevant vehicle properties to put in the description section.

Now, what will be the impact on stakeholders, especially with putting
some specific pieces into the description section on relevant vehicle
attributes? The innovators may find that they have just an absolutely
superior proprietary manufacturing process that could reduce generic
competition. I mean, that\'s one plausible outcome.

On the other hand, the generics have been incredibly good at reverse
engineering, and if they have these specific attributes of viscosity or
spreadability, they\'re going to have targets to achieve so that the
generic product is actually going to have greater sameness with the
innovator. Right now, one of the disturbing things one hears from
dermatologists is you can take the innovator, squirt it in one hand,
take the generic, squirt in another hand, and they may work the same in
terms of reducing the psoriasis, but they have a very different feel,
and patients may like the one better than the other.

Health care providers. This would be a more informed choice among
products if they have really good dosage form definitions and if they
have some additional attributes listed in the description section. Of
course, the patients are the ultimate winners. If they end up with a
product that they really like and are going to use, then they\'re going
to have better control of their skin disease.

So looking ahead and breaking this down into the two parts, one is the
dosage form part. I think USP and FDA have a really nice way of thinking
about this process. Ultimately it will need industry, academia, and the
professional societies to buy into this, but I think this already has a
very good start.

The second part, whether we want to add something to the description
section of labeling that describes relevant vehicle properties, relevant
in the patient care setting, I think the innovator and possibly the
generic industry already have the methods and the terminology. I think
they actually develop their vehicles with this in mind. But it\'s
something that doesn\'t come to FDA in the IND or NDA review process. We
just simply don\'t see this kind of optimization of the vehicle.

So I think industry is going to have to lead this. I think that\'s where
the storehouse of all this innovative information would be, and if
industry decides that this is desirable, to use a phrase we heard in the
last section, if there\'s the \"political will,\" then I think industry
must be leaders in this effort.

Thank you.

DR. KIBBE: Do you want to take questions or do we want to go through all
of them before questions?

DR. SHEK: Just a general question. I think we talked here about
medicated topicals. What about the whole cosmetic industry? If I go and
buy a wrinkle-free liposome cream formulation, will that also apply to
those products?

DR. WILKIN: So the question is, would the discussion we\'re having today
also apply to cosmetics as well as to ‑‑ you know, I think if we start
out with drugs and can get the topical drug products sort of in order,
the cosmetics may decide to adopt the same sort of terminology. As you
know, a lot of the cosmetics is, if you will, regulated by industry.
It\'s sort of a different philosophy. FDA becomes involved when there
are problems with a product. But I think if we have a compellingly
logical system, it may be something that they would want to adopt.

DR. SHEK: Just looking at the consumers being confused out there when
they buy topicals, whether it\'s medicated or nonmedicated, if they\'ll
start defining differently ‑‑ I don\'t know. Maybe the cosmetic industry
does it that way because they are so consumer oriented.

DR. CHIU: The cosmetic industry is not regulated as closely as drugs. In
terms of whether they can make certain claims, if they make a drug
claim, then it would be regulated as an OTC product. But if they don\'t
make a drug claim, then they can market it as cosmetics. Like wrinkles,
it\'s sort of borderline. Some of the wrinkle creams are actually
prescription drugs and some are cosmetics.

DR. WILKIN: Well, I could add to that. I think if you look at the
wrinkle products that are cosmetics, they say, \"improves the appearance
of.\" If you look at the drug products, it actually says, \"to treat.\"
That\'s one of the distinctions. It\'s subtle. I realize that.

And the other aspect in DDMAC, we have a group that looks at advertising
for all of the prescription preparations, but it falls pretty much to
the FTC for over-the-counter products and for cosmetics.

DR. SHEK: Just if I may as a follow-up, one concern I\'m looking at here
is that we will draw or distract the attention from the therapeutical
optimization of the dosage form or the formulation. I know when you
develop this product, you are trying to optimize their penetration
through the skin or whatever the purpose is when you design the vehicle.
And now, we are going somehow maybe to distract their attention from
just appearance or description and not looking at their therapeutic
efficacy of the two preparations.

DR. WILKIN: I think that\'s an excellent point. That\'s something that
we don\'t want to lose track of that piece. We know that the vehicle
contributes to the success of the topical preparation in a variety of
ways. One, of course, the vehicle participates in several of the main
components of what controls passage across the barrier, the stratum
corneum. Clearly the solubility in the vehicle provides for the actual
concentration of dissolved drug, and it\'s only dissolved drug that acts
in the concentration gradient. If you have some that\'s not dissolved,
it\'s not participating in the gradient. Likewise, the vehicle plays a
role in the partition coefficient. The vehicle can actually have
independent effects on the stratum corneum and can modify what is the
apparent diffusion coefficient.

And then in addition to that, it has some of these other aspects that
may somehow be different and they may be smoothness, let\'s say, over
time, but that might be one of the pieces that a psoriasis patient
actually appreciates having that smoothness. They\'re more likely to use
the product. They\'re more likely then to get the corticosteroid that\'s
in that product into the psoriasis lesion. So at the end of the day,
it\'s not something that is involved in the thermodynamic aspect of
getting active in, but I think it still contributes.

We have the saying in our division that the vehicle is composed of
inactive ingredients, but it\'s not inactive and it really isn\'t. It
contributes some very positive things. I think we haven\'t recognized
that as much in the past.

DR. HOLLENBECK: I ask this question out of ignorance. Does a generic
topical have to have exactly the same name? For instance, if I have a 2
percent hydrocortisone ointment, if I want a generic product, would it
be called exactly the same thing?

DR. WILKIN: It might have a different brand name, but it would still
have to have that same technical name of hydrocortisone 2 percent. Dr.
Hussain actually mentioned earlier that identical labeling is a key
piece. There must be identical labeling in all those relevant areas
between the innovator and the generic.

DR. HOLLENBECK: And that\'s my question. The label would have to
include, for instance in this example, ointment.

DR. WILKIN: Yes, that\'s correct.

DR. CHIU: Yes. We discussed this in our working group. We had OGD
representatives. They told us they have to be exactly the same. The name
must be exactly the same.

DR. HOLLENBECK: And I guess my question comes from trying to get my
hands around the real issue here. This is one of the real issues. You
would have two products that could have the same name, yet be
substantially different in their formulation.

DR. WILKIN: I wouldn\'t make that an innovator versus generic issue. I
would submit that\'s plausible even in the innovator versus innovator
issue. You could have one innovator with the same corticosteroid and
another and they\'re both called lotions, and yet there would be
substantial differences between the lotion qualities, if you will.

DR. KIBBE: Go right ahead.

DR. KAROL: It seems to me the objective here is to develop science-based
classification and descriptions, and I\'m wondering whether that can be
done with such issues as smoothness and spreadability. Is there any
scientific basis for describing something as smooth or less smooth and
so on?

DR. WILKIN: A good question. I think there are actually two separate
aspects to this. One is defining dosage forms. I think the group is
taking great pains to not have such subjective pieces go into the
definition of the dosage forms. There may be some temporary things in
there, but we\'re really sensitive to that and we\'d like to make it as
objective and something that one does with a physical experiment to the
extent possible.

On the other hand, I think there are some subjective things that might
be permissible, if they can be documented to be clinically relevant and
vehicle-dependent, that could go into the description section.

So I see sort of the rough guide as getting the dosage forms defined
appropriately and exclusively so that you don\'t have the problem we
have now where some things look pretty much the same but one is called a
lotion and one is called a cream.

And then the other part is thinking about ‑‑ and this is much further
into the future ‑‑ can we do something with the description section that
will be informative.

DR. KIBBE: Marv, go ahead.

DR. MEYER: The CDER Data Standards Manual that was in the backgrounder
has some definitions. Are these the ones that are currently in use or
proposed?

DR. WILKIN: We\'re actually going to have another speaker to that.

DR. CHIU: Those are actually for our database. So they\'re very rough
standards. Basically we use the USP standards, and now we are proposing
different definitions for some of the dosage forms or maybe some
modified definitions.

DR. MEYER: I thought it was interesting that this list really shows the
difficulty inherent in this topic. For example, under salve, it says,
somewhere between an ointment and a plaster, but doesn\'t define what a
plaster is. So now you need another definition.

DR. CHIU: That\'s right.

DR. MEYER: Under tincture, alcoholic. It doesn\'t say what kind of
alcohol.

DR. CHIU: But tincture actually is defined in USP.

DR. MEYER: Okay. Hydro-alcoholic is also defined?

DR. CHIU: Yes.

DR. MEYER: Not in terms of percentage, though, or does it? It is? Okay.

DR. CHIU: Those are USP definitions.

DR. KIBBE: Is there anyone else?

DR. RODRIGUEZ-HORNEDO: Briefly one comment. Is your initiative similar
to what went with the process analytical technology initiative from
industry where you\'re inviting industry leaders to come forward? Has
there been an answer to that invitation?

And secondly, to what extent can some of these maybe subjective measures
of the feeling of the formulations can be correlated to some chemometric
measurements or something along those lines?

DR. WILKIN: Well, if you\'re talking about the dosage form definition
part, I think this is the meeting where this is the invitation to get
everyone thinking about this. And likely there will be a draft FR notice
at some point. There will be some way of getting input, I would think.

DR. CHIU: Yes. When we discuss the questions, we actually are looking
for other technologies or methodologies which can measure certain
parameters which we have not included if you consider them essential.

DR. DeLUCA: I guess I certainly applaud the efforts to try to
standardize the nomenclature here. I guess in your slides here, you
certainly have gone back as long as maybe folklore for this and the time
when there wasn\'t really any of the sophisticated analytical techniques
to make measurements.

It seems that if you\'re going to come up with nomenclature, it has to
be science-based. These different dosage forms, it seems to me, have
different thermodynamic activity, different physico-chemical properties,
the structure, the morphology. There are differences here, and I think
we have to look at what types of equipment and analytical techniques for
characterization are available now, like atomic force measurements and
that sort of thing, that have to be, I think, part of this to be able to
define these dosage forms. What makes something a lotion as opposed to a
cream by virtue of some physical measurement or some property that can
be actually defined?

DR. WILKIN: So you\'re actually describing then two stages. The first is
figure out what you really think are the relevant essential properties
of, say, a lotion or a cream, and then figure out what the assay
technology would be to document that those properties are within the
certain specs for that.

DR. CHIU: We come with the proposal based on our own laboratory data
which we use science criteria. Actually we did an empirical experiment.
Our laboratory prepared placebo ointment and cream and then passed it
around to everybody on the working group. It actually made several
preparations, four or six, and asked people to identify which one would
feel like an ointment, which one felt like a cream. And based on the
criteria we have established, we had consensus. Everybody figured it
right. So, therefore, we believe our data supports our proposal based on
this empirical experiment.

DR. KIBBE: Thank you. I think we probably could move on and come back to
a whole slew of potential questions.

I would just like to comment that the creation of mutually exclusive
definitions for dosage forms and consistent terminology is a wonderful
goal.

DR. BUHSE: If not a difficult one, right?

Hello. I\'m Cindy Buhse, and as Dr. Chiu said, I\'m the Deputy Director
for the Division of Pharmaceutical Analysis, and we actually do collect
data in our lab. So I want to go through some of the data we collected
to try to help distinguish between creams and lotions, et cetera.

I\'ve just thrown up here some of the definitions that are included in
your packet in the CDER standards manual. You can see they\'re fairly
broad: creams, a semi-solid dosage form. A lotion is used to describe
any topical solution intended for application to the skin. You can see
there\'s really no distinguishing between any of these definitions. So
we tried to use some data to see if we could figure this out.

We looked at a lot of different things for about 50 different topical
dosage forms. We looked at basically what\'s their base composition,
what are they made of. We looked at some of the physical properties that
I think we\'ve talked about here. You really can\'t get away from, even
though you\'d like to, things like appearance and feel which tend to be
very subjective.

And then we tried rely, as much as we could, on the physico-chemical
properties, so those things you could actually measure with an
analytical instrument, and here\'s a list of some of the properties that
we looked at.

I just wanted to briefly go over what we did with appearance and feel,
in addition to passing samples around. One of the things we obviously
tried to look at in appearance is, is it clear, is it opaque. You can
imagine that there are some trends. Gels tend to be clear or
translucent. Creams are opaque. We also looked at does it seem viscous,
does it seem liquidy. We put a drop on a microscope slide and basically
looked at does it form a stiff peak, does the peak fall over, is it soft
or does it spread out and form no peak. So we tried to look at some
things that are still subjective but maybe could be a little bit more
nailed down.

In terms of feel, there\'s greasy versus non-greasy, and there\'s a
cooling sensation. As something evaporates from your skin, you get that
cooling sensation. So we tried to capture that as well for all these
formulations that we looked at.

We also looked at microscopy at 400 times, looking for two phases, one
phase, particles suspended, not suspended, that type of thing.

I\'m going to start with creams and lotions. We started with a variety
of creams and lotions, and we did a multivariate analysis looking at
viscosity, surface tension, specific gravity, and loss on drying.
Viscosity was done using a Brookfield viscometer at 5 rpms at 25 degrees
C, so we took it as a single point since most of these obviously are
non-newtonian. Loss on drying was done at 105 degrees in an oven for 24
hours or to constant weight.

You can see in the upper left the scores plot. This puts the different
formulations and clusters them together based on their different
properties. You can see that using these variables, lotions are kind of
clustered together and creams are kind of clustered together. So this
analysis did separate lotions from creams, but the main separating
parameter was actually viscosity. So viscosity was the most significant
variable that we found that separated lotions from creams.

So we then took a broader range of lotions and creams than just this and
took a look just at viscosity. Here\'s an example of some of our data.
You can see that lotions do have a lower viscosity than creams on
average, but there was some overlap between around 30,000 centipoise up
to just under 100,000 centipoise.

So we went back and took a look at those lotions and creams that seemed
to overlap and tried to determine what separated them. One thing we
wanted to say about lotions was that creams are semi-solids and lotions
are not. We wanted lotions to be a liquid. So, therefore, we wanted a
lotion to be pourable.

So we went back to these creams and lotions and determined which ones
were pourable and which ones were not. We found that the ones under
30,000 centipoise were in fact still pourable even though right at
30,000 you\'re kind of more like ketchup. So it\'s very slowly pourable,
but they were still pourable.

So one of the criteria we put down on lotions is that they need to be
pourable, and for us that meant a viscosity of less 30,000 centipoise at
the conditions I mentioned earlier.

We also then took a look at viscosity when trying to separate creams
from ointments. There are still some trends here. Ointments tend to be
fairly viscous. If you feel them, they seem viscous, and we see that
even in viscosity. You can see for all the ointments we tested there,
viscosity was greater than 500,000 centipoise.

But there is a huge overlap between creams and ointments. You can see
it\'s about a 300,000 centipoise overlap. So we didn\'t want viscosity
to be a determining factor between creams and ointments.

What we did find between creams and ointments was loss on drying or the
volatility of the vehicle. Some of this goes back to, I think, what Dr.
Wilkin was talking about. How long does it stay on your skin? What are
you expecting it to do once you put it on your skin?

What we found was that, for the most part, the ointments had LODs less
than 20 percent, and so they weren\'t losing very much weight over the
time spent in the oven, and that all the lotions we looked at had
greater than 50 percent LOD.

We did have one ointment, you can see there at the end, that was above
the 20 percent. This is where we came down to feel and appearance. This
is one of the borderline cases which we took and passed around the table
and asked people to put it on. Do you think it\'s an ointment? Do you
think it\'s a cream? And everyone unanimously thought it was a cream
based on what they felt in putting it on their skin and just feeling it.
So we stuck with the 20 percent LOD for ointments.

The other thing that obviously is very important is the chemical
composition. We looked at the percent of hydrocarbon or polyethylene
glycol content in the vehicle. Once again, we saw some trends. Ointments
tend to have very high hydrocarbon content or polyethylene glycol
content, typically above 80 percent, and lotions and creams tend to be
more water-based although not always. So we did also decide the
criteria, that ointments need to have a percent hydrocarbon or
polyethylene glycol of greater than 50 percent.

You can see there\'s one ointment on this graph that does not meet that
criteria and that is the exact same sample that you saw in the previous
slide that had the LOD of greater than 20 percent.

Not surprisingly, there is a trend between the chemical composition and
the loss on drying. I just put this slide in to show you that as you
have more hydrocarbon or polyethylene glycol content, you have less loss
on drying.

So we have some scientific criteria that are separating creams from
lotions and creams from ointments.

We also took a look at quite a few gels and gels are tricky. We looked
at a lot of the same parameters. Gels usually go across a fairly low
viscosity range; 10,000 to 70,000 centipoise is what we found in our
lab. They have a very high loss on drying. They\'re usually water- or
alcohol-based. They tend to be water soluble but not always. If you put
them in a high humidity environment, they sometimes will absorb water;
sometimes they won\'t. If you dry them, they\'ll sometimes dry in a thin
film and sometimes they won\'t.

We also did thermogravimetric analysis on them, and I\'ll show you an
example of that in a minute. We did note that gels seemed to have fewer
transitions than creams or lotions.

They always contain a gelling agent. Most of the ones that are available
on the market contain carbomer.

As I mentioned earlier, they tend to be clear or translucent but not
always. There are quite a few gels on the market that are still opaque,
and if you looked at it, you wouldn\'t necessarily know it was a gel
versus a cream if you were just to look at it.

They tend to be non-greasy and cooling.

We also found no specific trend in microscopy. We tried to see if we
could see something there, but we couldn\'t really.

I just wanted to show you the TGA data because it is kind of interesting
and we are pursuing it further. This is an example of two different
drugs that have several different formulations and manufacturers on the
market. You can see drug B. There are four different creams currently on
the market and two different gels for the same active drug. You can see
that the gels tend to have a single transition for water. That\'s the
light blue and the light green line. Whereas, the cream, you can kind of
see some multi-transitions. If you read the literature about that, it\'s
often described that creams have two kinds of water in them. They have
what you call free water and then you have water that\'s bound up in the
emulsion which may have a different transition temperature. A true gel,
where you have a three-dimensional structure with a solvent in it, you
would expect the solvent itself maybe to just have one environment that
it\'s in. So we kind of are seeing some of that with this TGA data, and
we are pursuing this further. You see the same trend over with the drug
C which comes as a lotion, a cream, and a gel.

Just to summarize a little some of the data we\'ve done in the lab. I
think, as Dr. Chiu indicated earlier, we would like your input as to
further techniques we could use to distinguish between these different
dosage forms.

We found that lotions were pourable with the viscosity of less than
30,000 centipoise and they had a very high loss on drying as they were
mostly aqueous based.

Ointments have a very low loss on drying because of their hydrocarbon or
polyethylene glycol content.

Gels. We did see that they have quite a bit of gelling agent, but we
would like advice on further determining how to separate gels out,
especially from creams.

And then Dr. Chen will give you more details on the definitions we came
up with based on this data.

DR. KIBBE: Questions? Gary, do you want to jump in or do you want to
wait?

DR. HOLLENBECK: Let me ask a couple then. Stop me when you want me to
stop, Art.

First of all, your viscosity testing. Why did you decide on 5 rpms?

DR. BUHSE: We wanted a low sheer, so we chose 5 rpms. And we chose room
temperature. There was a lot of discussion about whether to choose the
temperature the drug is actually at, the temperature of the skin. You
could make arguments every which way. What we did for this work was room
temperature and the low sheer, 5 rpms. If you look at the literature,
there\'s a variety of different ‑‑

DR. HOLLENBECK: Sure. I understand it\'s a challenge.

Did you shake things up before you measured it?

DR. BUHSE: What we did is we equilibrated everything. None of the
formulations we used separated. I\'ll just say that first. They were all
well emulsified or gelled. And we equilibrated them at 25 degrees for 24
hours before we measured viscosity on them.

DR. HOLLENBECK: 24 hours, okay.

I guess my other sort of analytical question is, why didn\'t you measure
moisture content or water content instead of doing LOD?

DR. BUHSE: We had moisture content. We had the formulation, so we knew
how much water had been put in already just based on the applications to
the agency.

We looked at LOD because we wanted to pick up everything that was
volatile in the formulation, not just the water. There are alcohol or
other agents in there that may be volatile but you wouldn\'t pick up in
a moisture analysis.

DR. KIBBE: Does anybody else want to chime in? Do you have a question,
Wolfgang?

DR. SADEE: Yes. I just have a very minor comment here on the definition
of a cream. It\'s a semi-solid dosage form containing one or more drugs.
So if it doesn\'t contain any drugs, it\'s not a cream?

DR. BUHSE: I think that\'s from the Data Standards Manual. I don\'t know
if you want to address that.

DR. CHIU: Well, we\'re not going to use that. You will hear our proposal
later.

DR. SADEE: And then viscosity is done, you say, at room temperature. Do
you specify that? What temperature are you actually talking about?

DR. BUHSE: 25 degrees C was what we considered. We wanted to make sure
everything was at the exact same temperature, so that\'s what we chose.

DR. MEYER: In the case where you\'re comparing viscosity or loss on
drying for the various products, these are actually marketed products?
Is it possible then that where there was overlap or they weren\'t
classified in a distinctive way, that they were just mislabeled?

DR. BUHSE: Yes, there were several. I mentioned the one product that was
labeled as an ointment that we felt was more a cream. There were several
lotions you saw that were above the 30,000 centipoise. So with these new
definitions, we would consider those to be creams rather than lotions,
yes. So we did look at over 50 different drugs, but we did not make the
assumption that they were labeled correctly. We just tried to look for
trends, and then some of them ended up not being labeled the way we
would necessarily want to label them in the future if our definitions
are adopted.

DR. DeLUCA: There\'s quite a bit of information in the literature on
rheological behavior of these forms. I\'m just wondering whether you
looked at that aspect of it.

DR. BUHSE: Yes. We did a lot of literature reading and looking at the
rheological behavior. All of these are non-newtonian and they\'re all
different in terms of what kind of behavior they have.

We thought about looking closer at the rheological properties of
everything. For our first cut here, we tried to keep it simple. We just
picked a single point, but that would certainly be one area we could go
into in the future.

DR. KIBBE: Ajaz.

DR. HUSSAIN: I think Pat makes a very good point, and I think as we go
towards the complexity of the flow behavior, I think you might see
certain other attributes that fall off. In fact, from a use perspective,
I think the rheology, whether it\'s thixotropic and so forth, will also
be linked to possibly how effective its use on the skin itself. So I
think that\'s a very good point.

I had another question. I think Cindy showed on her first slide a figure
where you\'re looking at a multivariate approach to classifying and
looking at these attributes to see whether we can cluster and we can do
this. She didn\'t mention that was a principal component analysis, the
study that she has done.

DR. KIBBE: Anybody else?

(No response.)

DR. KIBBE: I think you\'re off the hook for a few minutes.

DR. BUHSE: You can ask later.

DR. KIBBE: Don\'t worry. I\'ll ask you why you didn\'t look at magmas.

(Laughter.)

DR. CHEN: Good morning. I\'m Chi-wan Chen, Director for the New Drug
Chemistry III Division in the Office of New Drug Chemistry in OPS.

I think Dr. Buhse has the work cut out for me for my presentation. What
I would like to present is our proposal on how to better define these
problematic dosage forms for topical drugs.

As Dr. Chiu mentioned in her introduction, our task is focused mainly on
the topical dosage forms that are for dermatological application. That
is not to say that the same kind of approach, with or without any
modification to some of these dosage forms, can be applied to topical
dosage forms that are not applied to skin, in other words, mucous
membranes.

Also, as alluded to earlier, our focus is on five particular dosage
forms for which the currently existing system or definitions in either
the USP or the FDA standards manual or in the literature are less than
adequate and cannot distinguish among some of the dosage forms, namely
between lotion and cream, gel and cream, or gel and lotion, cream and
ointment, ointment and paste. That will be our focus.

You will see that the system we are proposing to define these dosage
forms consists of roughly four parts.

One is a broad classification: liquid, semi-solid emulsion, suspension.
That is the first component of our system.

The second part of the definition has to do with chemical composition
and/or physico-chemical properties.

The third one is the appearance, the feel.

And the fourth one is perhaps loosely linked to the spreadability that
Dr. Wilkin mentioned earlier, the feel when applied rather than just how
it looks.

So to start out, gel. We felt it was easy when we started out. It always
contains a gelling agent in sufficient quantity that it will form a
three-dimensional cross-linked matrix.

But then as we looked a little bit closer, we found some difficulties.
How do you define \"sufficient\"? Now, although this is mentioned in
some literature articles, we don\'t know whether we can actually quote
those numbers. As you know, these numbers certainly will vary. The
absolute amount or even the relative amount may vary from one gelling
agent to another or from one preparation to another.

The next question is the three-dimensional, cross-linked matrix. Do we
have to have some easy physical measurement to be part of this
definition so that there is another tool that can be used to distinguish
this dosage form from any other overlapping dosage form, namely cream
and lotion, as I\'ll get into when I get to those two dosage forms?

It\'s usually translucent or clear and is not greasy. It provides a
cooling sensation when it\'s applied to the skin.

A paste ‑‑ we thought we could easily tease this one out too ‑‑ as a
broad category is a suspension semi-solid. In terms of composition, it
contains a large proportion, i.e., 20 to 50 percent, of solids dispersed
in a vehicle that\'s either aqueous or fatty. It\'s opaque. It\'s
viscous. It\'s greasy to mildly greasy. In terms of application, it
adheres well to the skin and forms a physical barrier, a protective
layer.

A lotion is a liquid. As far as we can tell, I don\'t think we will find
a lotion that\'s a suspension. I think a liquid suspension clearly
belongs to a suspension. So right now we\'re proposing that a lotion is
an emulsion liquid. It generally contains a water-based vehicle with
more than 50 percent of volatiles, as measured by loss on drying.

The next feature is the viscosity. It has sufficiently low viscosity. We
consider a lotion a liquid and this viscosity should be sufficiently low
that it can be poured. We find that cutoff to be 30,000 centipoise, as
Dr. Buhse mentioned earlier. And this sets apart a lotion from cream. We
will visit that briefly again when we get to cream.

It\'s opaque and non-greasy, and it tends to evaporate rapidly with a
cooling sensation when applied to the skin.

Ointment is an emulsion or suspension semi-solid. In terms of chemical
composition, it generally contains more than 50 percent of hydrocarbons
or polyethylene glycol as the vehicle and ‑‑ and this is a capital
\"and\" ‑‑ less than 20 percent of volatiles as measured by LOD. It is
translucent or opaque, and it\'s viscous and it\'s greasy. It tends not
to evaporate or be absorbed when applied to the skin.

Cream as a category gave us the most difficulty and it\'s most
challenging. As you probably can agree, we almost have to say cream is a
default. When it\'s not an ointment, not a gel, not a lotion, it\'s a
cream.

(Laughter.)

DR. CHEN: Basically that\'s what it boils down to.

Chemical composition-wise, unlike an ointment it doesn\'t contain more
than 50 percent of hydrocarbons or PEG. It does not contain less than 20
percent volatiles. In other words, it generally contains less than 50
percent of hydrocarbons or PEG or more than 20 percent of volatiles or
both. That\'s in terms of chemical composition what a cream would be.

It\'s viscous compared to lotion, as I mentioned earlier, and it\'s not
pourable as compared to lotion.

In terms of appearance, it\'s generally opaque. It\'s viscous and it\'s
non-greasy to mildly greasy, but not extremely greasy.

It tends to mostly evaporate or be absorbed when rubbed onto the skin.

In terms of comparison to gel, we know some creams seem to contain a
gelling agent, and I think that the TGA data show that these creams,
though containing a gelling agent, do have multiple transitions. So we
are inclined to still keep them as creams, and perhaps the role of the
gelling agents present in these creams is as a thickening agent.

On the other hand, some gels are opaque because of the presence of an
emulsifier, and I don\'t know if we will leave them. I think we probably
will leave them as a gel if we can show that it has the
three-dimensional structure by way of TGA, or maybe there\'s a better
method than TGA.

Then lastly as far as cream, we wonder if it may be useful to separate
the creams into two categories, hydrophilic versus lipophilic, for the
benefit of the clinicians and patients. Perhaps it will be useful for
them to know one versus the other. But that\'s one of the questions that
we will present to you.

Next I will just present a decision tree not necessarily as part of a
proposal, but as a tool to aid the thinking process when you are given a
topical dosage form. This may be a good exercise or thought process to
get you to where it belongs. This really is a parallel to our proposed
definitions and it\'s based on the data from the lab on the select
products and chemical composition data from NDAs and ANDA products
approved in recent years.

Again, we are limiting this exercise or this decision tree to
dermatological applications, and the goal of the first test is to tease
out those dosage forms that we are now focusing on.

So the question we ask is, is it a liquid emulsion or a semi-solid
emulsion or suspension? If it\'s none of the above, it has to be a
solution, which is clearly defined in the standards and literature, an
aerosol, a powder, or a suspension. I think both USP and the FDA
standards manual have clear definitions of suspension, which is defined
as a liquid preparation containing solids dispersed in a liquid phase.

Now, if the answer to this test is yes, then you go to all the branches
down in the tree.

The first test after that is whether the preparation contains a gelling
agent in sufficient quantity to form a three-dimensional, cross-linked
matrix. Again, we\'re not sure how to define sufficient and we\'re still
exploring what the best method is to clearly demonstrate that there is a
3D matrix.

But if the answer is yes, it\'s a gel. It goes to the left in the green
box. And if the answer is no, then you continue the exercise.

Test 3 asks the question whether the preparation contains a large
proportion of solids dispersed in the vehicle. And if the answer is yes,
it\'s a paste. We actually haven\'t come across very many pastes in the
FDA-approved products. There is an over-the-counter zinc oxide and maybe
a couple of others. But we thought this is a clear feature that can
separate paste from the rest. If the answer is no, then you go to test
4.

Test 4 asks the question whether it contains more than 50 percent of
volatiles as measured by LOD. You branch out from this point on. If the
answer is yes, you go to 5a underneath. If the answer is no, then you go
to the right to 5b.

5a is a test that asks the question whether the preparation is a
pourable liquid with viscosity less than 30,000 centipoise. If the
answer is yes, it\'s a lotion. If the answer is no, it\'s a cream. You
can see how we view cream as a default. It\'s a no, no, no. Then you end
up with cream.

Test 5b, where you end up on the right-hand side after test 4, asks the
question whether the formulation contains more than 50 percent of
hydrocarbons or PEG as the vehicle and less than 20 percent of
volatiles. If the answer is yes to both, then it\'s an ointment. If the
answer to either is no, then you end up with a cream. Again, it\'s
another indication that it\'s a default compared to ointment.

So I hope our proposal is a step in the right direction. Hopefully we
have put some boundaries to better define these dosage forms and not to
stifle future innovations.

DR. KIBBE: Any specific questions? Gary?

DR. HOLLENBECK: Do you want to entertain questions on the decision tree
now or do you want to wait until we get to the end?

DR. CHIU: I think we could do it later at the end when we do the
discussion.

DR. SELASSIE: I have a question.

DR. KIBBE: Over here then.

DR. SELASSIE: You know the way you delineate what\'s a cream it\'s based
on whether it\'s hydrophilic or lipophilic. That\'s based on the
continuous phase. What happens, for example, when your continuous phase
is a fatty ester, often alcohol and acid? Then doesn\'t that change?
Does it change hydrophilicity?

DR. CHEN: I think it\'s the vehicle that defines whether it\'s
lipophilic or hydrophilic.

DR. SELASSIE: Right, but I\'m talking about the oil in water. Sometimes
you use these fatty acids and fatty alcohols and use the esters.

DR. CHEN: And the vehicle is aqueous.

DR. SELASSIE: Right. It doesn\'t have a great impact on the overall
hydrophilicity?

DR. CHEN: I think when we say hydrophilic, we mean it\'s oil in water.

DR. SELASSIE: You\'re strictly basing it on what the continuous phase
is.

DR. CHEN: That\'s right, yes.

DR. SELASSIE: Okay.

DR. KIBBE: Leon?

DR. SHARGEL: I was curious about the exclusion of suspensions as
lotions. As I recall in the USP, there\'s a white lotion, a calamine
lotion. At least there were older articles. And those are suspensions.
There are several products that are suspensions that are considered by
the public in its use as lotions. Is there any thought process in that?

DR. CHEN: We feel the definition of suspension as it currently exists is
fairly clear, and the solids are dispersed in the liquid and it needs to
be shaken before use. It separates, while lotion doesn\'t separate.

DR. SHARGEL: From the concept of the consumer, the consumer would think
calamine lotion is a lotion, not necessarily a suspension. And how would
we then distinguish if a manufacturer makes a suspension to be used as a
lotion?

DR. CHEN: Hopefully this definition we\'re providing will clearly
separate suspension from lotion.

DR. HUSSAIN: I think the point being made is, in a sense, we already
call a suspension lotion, and that is well established, well recognized.
Calamine lotion, for example. So that falls out from this decision.
That\'s the point I think Leon is making.

DR. CHEN: Yes. I think the products that FDA oversees and approves may
have to be revisited ‑‑ some of them ‑‑ if our proposed definition is to
be adopted. But some of the products that are truly OTC or are
cosmetics, we wouldn\'t be able to touch them.

DR. KIBBE: I have Marv and then Pat I think had his light on.

DR. DeLUCA: Well, I wanted just to follow up.

DR. KIBBE: Why don\'t we get Marv and then you and then Leon goes, and
Wolfgang, you\'ve got your light on or off? Do you want to speak or not?

DR. SADEE: It\'s off.

DR. KIBBE: Okay. Marv.

DR. MEYER: Is there, from a regulatory point of view, a problem with a
formal definition that could change terms like \"generally,\" \"tends
to,\" \"mostly\" ‑‑ that appears in numerous cases ‑‑ \"usually.\" That
gets a waffle in there. Is that a problem from a regulatory point of
view?

DR. CHEN: We hope it won\'t be a problem because we\'d like to provide
clear enough distinction without being too strict. So there could be
borderline cases that would be exceptions. But perhaps as we refine
these definitions or gather more data, we might be able to better define
them. I don\'t know if we necessarily want to lose some of the words
that are sort of vague or general. I guess our fear is there may always
be an exception, and that\'s the reason for choosing those words,
\"generally,\" \"usually.\"

DR. CHIU: May I add to this? Although we have some loose description of
the appearance or the feel, however we also have other criteria in terms
of composition, in terms of viscosity, and the loss on drying. So we
believe in the totality of the criteria, we would be able to define a
cream from a lotion and others in most of the cases. We cannot say there
would be no exception, but we believe it will cover a lot of cases also.

DR. DeLUCA: I just wanted to follow up what Leon had. He gave the
example of white lotion, which is a suspension. But also to come in with
the process of making white lotion. So, in other words, just because you
have a composition, if you don\'t add these in the right manner and
under the right conditions, you won\'t get the same product. Aside from
the water and the hydrocarbon, I\'m wondering how much importance you
put on composition.

To me property is the way because we may have a new surfactant or
gelling agent or something we don\'t even know about right now that
comes down the pike. It seems to me that it\'s important to be able to
base these definitions on property on some physical measurement or some
thermodynamic activity, not even therapeutic performance because
something may have the property of being a cream or gel but maybe not be
effective. So I think that I just wanted to kind of stress that some
property or measurement or thermodynamic activity, structural behavior,
or morphology should be the criteria for the definition rather than
composition.

DR. CHEN: And I think we can continue that discussion in our questions
and answers.

DR. KIBBE: Yes. One more and then we\'ll go to the next speaker. Then we
can come back. I think all of the speakers are still here, so we can go
back to individuals.

Did you have some, Efraim?

DR. SHEK: Yes, just a comment. We have systems which are thixotropic
systems and sometimes you purposely use it. They might be in the
container as very viscous, and when you pour them or when you agitate
the system, they become liquids. We have to find a way to handle those
because what the customer feels is maybe it\'s a cream. When it\'s in
the container, maybe it\'s close to an ointment.

DR. KIBBE: Thank you.

Herb. You have plenty of time, Herb.

DR. CARLIN: Thank you. Well, it\'s a pleasure to be here today and to
meet some of my old friends that I haven\'t seen in a number of years.

The USP has not devoted much time to topical dosage forms in the past.
We are in the process of coming up with a new taxonomy and a glossary,
and this is a very timely meeting because the definition of lotion is
something we\'ll discuss in a few minutes.

I\'m going to give you a little history lesson. You\'ve had some
science. You\'ve had some other types of information today, but I\'m
going to give you a little history on topical dosage forms for the USP.

I went back to USP XII because before that, the titles were all in
Latin. I\'ve forgotten everything I learned in high school, and that was
a long time ago. And I followed through up until the recent. We\'ll just
do this quickly.

From I through XII was titles in Latin. Nomenclature within the USP was
assigned to a Committee on Scope of the Executive Committee. Attention
in naming products was paid to existing monograph titles for tradition
and at that time coordination with the NF because that was owned by the
American Pharmaceutical Association.

Beginning with number XII, the titles changed to English, stayed with
the Committee on Scope, and synonyms were deleted from the USP. That was
a significant thing, and that was part of one of the Food, Drug and
Cosmetic Acts that said there could only be one name for an item. It
caused a little difficulty, but we got rid of them. Lime water became
calcium hydroxide solution, a very hot, competitive item. Silver nitrate
pencils disappeared and became toughened silver nitrate. Zinc gelatin
boot became zinc gelatin. And it was the first time that routes of
administration were added to titles. Prior to this time, an ophthalmic
solution was a solution. Now it became an ophthalmic solution. The same
with otic solution and suspension.

We were talking about zinc oxide, and it\'s funny how things pop back
into your head. All I can remember is P into the Z. Or what is it?

DR. DeLUCA: \[Inaudible.\]

DR. CARLIN: If you did it the right way, you got white lotion. If you
did it the wrong way, you got black lotion.

(Laughter.)

DR. CARLIN: It was always on the boards of pharmacy. I think the last
time I did it was in 1954 making powder papers for the Board of Pharmacy
in Rhode Island. Or making suppositories in August when you put the
cocoa butter on the platter, it just melted by itself. You didn\'t have
to insert it anywhere.

(Laughter.)

DR. CARLIN: In 1980, the USP purchased the NF. It should make things
simpler. There still was a Committee on Scope, and there was some
revision to the topical titles trying to get these things working
together. There was topical aerosols, aerosol solutions, solutions,
solutions for irrigation and powders. And there was addition of two new
topicals, emulsions and magmas. So, Arthur, we got your magma in there.

In 1985, finally the USP created a Drug Nomenclature Committee. It
reviewed past decisions and recommended many changes to make the titles
more user friendly for health care providers. It added drug topical
solutions, drug gel, drug topical suspension, drug ointment, drug cream,
and made the recommendation to get rid of lotions. Maybe if we had
gotten rid of lotions in 1985, we wouldn\'t have all the scientific work
that\'s going on today. These recommendations were passed on to the next
committee.

Oh, I should give you the definitions that we had in 1985.

Drug topical solution and drug topical suspension is the general format
for monograph titles of topical liquid dosage forms. This nomenclature
is intended to displace lotion terminology because lotion has been
criticized as difficult to define with no physical meaning. I guess
since 1985 we\'re finally coming to the point of defining lotions.

I think they made a typographical error back then. They should have
talked about topical emulsions and topical suspensions, but it\'s too
many years ago.

Drug ointment is a preparation of one or more therapeutic agents in any
of the various classes of bases described in chapter 1151 of
Pharmaceutical Dosage Forms. So you\'ve got to go read another section
of the book.

Drug cream is a topical preparation that is formulated in an emulsion
base. The term \"cream\" preferably pertains to semi-solid preparations
in water-removable bases that are oil-in-water emulsions. 1985.

They had one for gel. Drug gel is a formulation in a water-soluble base
and may be regarded as a greaseless ointment.

The committee from 1985 to \'90 and \'90 to \'95 got together and sort
of ratified what the previous committee had suggested and published a
stimulus article, a multi-page article in Pharmacopoeia Forum,
January-February 1991, entitled Nomenclature Policies and
Recommendations: Review and Current Proposals and Decisions. And if
you\'re interested in this nomenclature subject, that would be a nice
one to go back to and read.

They came up with a new title, new dosage form ‑‑ and I\'m confining
myself now just to topicals ‑‑ of pledget. It\'s a vehicle carrying a
topical solution.

In the \'90s, we got into a lot of veterinary products and they added
soluble powder, intramammary infusion, and topical gel.

There were three powder titles changed. They called them topical powders
instead of just powders. And one water was changed to witch hazel. For
any pharmacists present, you\'ll remember it was hamamelis water. It was
too long for the label I guess, and they made it witch hazel. But now
it\'s very difficult when you got into a taxonomy, where do you put
witch hazel? Where do you stick paregoric? That was all part of getting
rid of synonyms. The synonyms were more popular than the official
titles, and maybe white lotion is going the same way.

There were two new veterinary products added in the topical area in
2000: concentrate for dip and uterine infusion.

In 2002, we formed a new committee called Nomenclature and Labeling
Expert Committee. It became very obvious you can\'t separate the title
of an item from its labeling. If you\'re going to get very specific in
the title, then you\'ll have a title that\'s too long for the label. So
you need to tie in certain labeling aspects.

And revisions to current monographs began to relate to packaging, like
mineral oil enema became mineral oil rectal when suitably packaged, and
light mineral oil to topical light mineral oil when suitably packaged.

I\'m going to spend a few minutes with you on the USP as it stands
today. It\'s published every year now. So it\'s USP 26, 2003.

There are 310 topicals in the USP. As liquids, there are 108. One is an
emulsion. Three are suspensions and 78 are solutions. And if you add
those up, it doesn\'t come out to be 108 because there are 23 or 22
lotions, but I\'ll talk about that in a second because we\'re finally
getting around to getting rid of lotions. Maybe. Semi-solids, there are
170: 3 collodions, 70 creams, 1 foam, 12 gels, 72 ointments, and 6
pastes. Most of the pastes are very old. They must be pre \'38.

Solids. There\'s 1 gauze, 3 patches, 24 powders, 1 tape, and 3 tablets.
The tablets are those that you dissolve in liquid before you add it to
the skin.

You might want to know what the one emulsion is. It\'s called drug
cleansing emulsion.

There are 23 lotions that may be changed to drug topical emulsions, drug
topical solutions, or drug topical suspensions. But I doubt you\'ll see
any drug topical solutions because it doesn\'t meet the criteria.

Topical solutions. There\'s a cleansing solution, 1; 6 irrigating, 1
liquid soap, 2 oral/topical solutions; 4 solutions; 6 tinctures, which
will become topical solutions.

I\'ll tell you why we did some of these things with solutions. The
old-time pharmacists know that elixirs are supposed to contain alcohol
until Tylenol Elixir was marketed with a big headline, \"contains no
alcohol.\" And they did such a good job with their promotion that the
American public now doesn\'t relate elixirs to alcohol, so we decided to
get rid of elixirs and call them topical solutions.

And we did the same with syrups. We found there was some syrups that had
a lot of alcohol in them. We found some syrups with no sugar in them,
and they\'ve become oral solutions or oral suspensions.

There\'s 1 topical oil, and there are 44 topical solutions.

In suspensions, there\'s 1 drug and it\'s a shampoo, and there are 5
topical suspensions, many of which are veterinary.

For semi-solids ‑‑ well, we just did that.

Powders. There are 12 topical aerosols, 2 topical solutions, 1 dusting
powder, 1 just called topical, and topical powders.

Patches. There\'s 1 film. There\'s 1 plaster, and there\'s 1 pledget.

And there\'s one gauze. You wonder if it\'s worth the time.

Solids. These are tablets for topical solutions, and tapes, there\'s 1
drug tape.

Now that I\'ve bored you, that\'s the section of the USP that we have
not looked at for a long time. The Nomenclature Committee spent most of
their time on things we felt more important to patient care which was
injectables. If you\'ll recall, any of you who are manufacturers of
injectables, all the title changes that went on in the last few years.
Then we went to oral liquids, and that\'s when the syrups and elixirs
were changed. And now we decided to look at topicals, and it becomes an
important subject.

There are three committees at USP right now working on a taxonomy and
glossary for dosage forms. So this is very timely. We have the Dosage
Form Committee, which is chaired by Keith Marshal who was going to be
here today but couldn\'t make it for other reasons. The Biopharmaceutics
Committee with Tom Foster from Kentucky because we go into a third tier
in the taxonomy. And the Nomenclature and Labeling Committee.

A stimulus article is in draft form and should be published in PF very
soon. What I\'m going to show you is some of the draft things for the
taxonomy. It may change. Things change rapidly.

There are three tiers. The first tier delineates the tissues to which
the active is first delivered by the dosage form. The second tier is the
criterion for this group is based on the general type of dosage form
involved. And the third tier is the individual dosage form grouping
depends on the release pattern from the active.

Here\'s an example of the first tier. You can see gastrointestinal,
tissues of body fluids by injection, mucous membrane, skin surface, and
lung. What we\'re talking about here today is the topicals. You see skin
surface breaks down into topical and transdermal.

You go to the second tier, and you see we break it down: skin surface,
topical, liquid, semi-solids, solids. Liquids are broken down into
emulsions, water in oil, oil in water, suspensions and solutions. The
semi-solids are collodions, foams, ointments, pastes, creams, gels. And
the solids are powders, which include aerosols, patches, plasters,
films, gauze, tapes, and this slide was official last week. It\'s
already changed. The sticks have been changed to tablets because we
don\'t have any sticks. They went out with silver nitrate.

And the third level, which is still working very hard at the USP, breaks
it down into conventional release or modified release. And modified
release breaks down into a variety of ways: extended release, which are
very common; delayed release, which used to be enteric coated; targeted
release, which we don\'t have any in the USP yet; pulsatile release;
orally disintegrating we don\'t have any but that\'s where it will fit;
and orally dispersing. I\'m not too sure what that is. The first time I
saw it was when this slide was given to me the other day.

So you see we\'re having a taxonomy, and then there will be a glossary.
And that\'s changing day by day but will be part of the stimulus article
that will be published in the Pharmacopoeia Forum.

So you can see over the years, USP has converted official titles of
dosage forms ‑‑ converted from those that indicated a formulation or a
method of manufacture to describing the finished product in terms
believed to be most useful to the prescriber, dispenser, and patient,
also by adding the route of administration to the title ‑‑ example,
ophthalmic, otic, nasal, vaginal, rectal, topical. It should be noted
that the type of packaging and labeling may become more significant
players in designing dosage form titles.

Now, to the one thing that\'s of interest to this committee. In 1985 it
was decided to get rid of the term \"lotion.\" We\'re now getting it to
be on the top of the plate. So we made a decision a year ago to delete
lotions and convert them to topical suspensions or topical emulsions. We
then had a meeting with FDA and realized that FDA was now beginning to
look at this situation. So at our next meeting, we tabled the motion,
waiting to see what will come out of your activity and the USP activity.
So really what\'s going on in this committee is very important to us
because we were just ready to kill \"lotion,\" part of it because there
are lotions that are suspensions and there are lotions that are
emulsions. And it is vague. And thixotropic is another problem that
comes in here.

So, we\'re very pleased to be here with you today to listen to the
deliberations, and I thank you for your patience of listening to this
history of non-activity. Thank you.

(Laughter.)

DR. KIBBE: Thank you, Herb. Stick around. There might be questions.
Don\'t go wandering off.

Does anybody have questions directly for Dr. Carlin?

(No response.)

DR. KIBBE: I guess not.

DR. CHIU: I would like to present our questions. We also welcome
comments outside the scope defined by the questions. When you look at
the question, please also refer to this table in your package.

The first question is the appearance and the feel of the topical dosage
form is part of the proposed definitions. In conversations with
practitioners and evaluation of the literature, words such as
\"greasy,\" \"non-greasy,\" and \"cooling\" are often used when
describing these dosage forms. Is there any value in including these
attributes in the definitions?

DR. SHARGEL: I just have sort of a question. In terms of if you label a
product a cream or an ointment, and the manufacturer then in its
labeling says this is non-greasy, it\'s smooth, it\'s whatever
attributes, how does that work together in terms of the labeling saying
this is nice, smooth thing, whereas you may title it in USP as an
official name?

DR. CHIU: The labeling has two parts. One is the name of the product,
the established name, and the other part is the description section. So
certain properties may be included in the description section. However,
it must meet all the definitions for that name. So that\'s how it works.

DR. SHARGEL: Just to follow it up, if the manufacturer then gives an
attribute in its labeling, how would that be in terms of quantifying
that attribute, or is there any need to do that if it\'s already
quantified as a suspension?

DR. CHIU: Could you elaborate?

DR. SHARGEL: If a manufacturer said it has a nice, smooth feel or
non-sticky or something, that\'s sort of a sell point.

DR. CHIU: That would not be sufficient to say this is a cream or this is
a suspension because there are other properties they have to meet in the
definition. So if this preparation is a liquid suspension, which we
would not consider as a lotion or a cream or anything, we would just say
you have a liquid suspension even though it feels not greasy or greasy.

DR. SHARGEL: The reason why I asked is because the consumer may want to
know that or a physician may want to know something about the
attributes.

DR. CHIU: Right. Those attributes then will be described in the
description section of the package insert.

DR. HOLLENBECK: Yes. I guess I would follow up on that. You\'re not
proposing that we label a product really smooth hydrocortisone ointment.

(Laughter.)

DR. CHIU: No, no, no. We would just say hydrocortisone ointment. But in
the description section, the firm may want to say this is not greasy or
greasy or something like that.

DR. HOLLENBECK: Yes. I think this could be useful in the description
section, but it isn\'t really part of your criteria to identify what is
a gel, what is a lotion, what is a suspension. Right?

DR. CHIU: It is not a sufficient criteria. It may be just part of it
because usually a lotion is not greasy and an ointment is greasy.

DR. KAROL: In looking at the definitions and the four broad categories
you gave us in the beginning, you said that the first thing we would
look at would be the broad definition. Then would be physico-chemical
characteristics, and then the appearance and feel, and the fourth one
would be spreadability. It seems that the definitions are clear based on
the first two, the broad category and the physico-chemical
characteristics, and there really is no need to include the appearance
and feel or the spreadability in any of the definitions. Your decision
tree distinguishes all of these various forms based upon
physico-chemical characteristics and chemical emulsions and so on. So I
don\'t think including greasy or non-greasy and spreadability in the
definition is necessary.

DR. CHIU: Okay.

Jonathan, would you like to address that?

DR. WILKIN: Well, I would agree with that sentiment. I think there are
two places where we think about the attributes of a vehicle. One is in
the decision tree to define what particular dosage form it would be,
say, an ointment or a cream, and then the other is where we might list
some other relevant properties in the description section. I would hope
that in the end all of the attributes of the vehicle that help determine
its lotionness or ointmentness could ultimately be physical, tested
properties, recognizing that there are some pieces that when one is
looking at viscosity, for example, it\'s technique dependent. So I think
it\'s more than just simply saying we need viscosity. We would need to
define the technique where one is actually looking at viscosity. But I
think in the end, the dosage forms ideally should be rooted in very
specific physical measurements often defining the assay technique.

On the other hand, getting into the description section of the labeling,
I think there would be an advantage if we could take these psychometric
sorts of senses of really greasy, not very greasy, and sort of the
intermediate things, and if we could somehow find a device that would
help us with that, that would make it more predictable so we\'re not
relying on 20 or 40 human subjects to tell us about the greasiness feel,
I think that would be better even also for the description section. So I
think in the end, the more we rely physics, really the better we\'re
going to have consistency from one description section, one dosage form
definition to the next.

DR. KAROL: I think we also run into trouble with these subjective
measurements because we\'re really interested in the patient\'s
description of whether this is greasy or spreadable and so on. Are these
materials going to be tried on patients to get their reaction as to how
greasy they are, you know, patients with eczema and so on, or is this a
control panel that\'s going to decide on these descriptions?

DR. CHIU: I don\'t think we had planned to do that. But, Jonathan, in
your clinical trials, do you include an element to have patients to
report back?

DR. WILKIN: I think there may be patients or human subjects for some of
these. For example, we may find that moisturization is best defined as
sort of the time curve for transepidermal water loss. There are nice
devices that one can put on the skin after applying some topical product
and look over time at the amount ‑‑ I mean, all of us right now are
losing a lot of water through our skin. And topical products can shut
that off. In diseased skin, it\'s even higher. So that might be
something where you actually need live human beings who have skin that
one is going to look at.

But once again, I think to the extent that these things can be made into
physical assays, we\'re going to have much better consistency from one
label to the next in what they mean.

DR. RODRIGUEZ-HORNEDO: Along the same lines, it appears that in your
definitions perhaps there could be inconsistency with the feel or this
greasy or non-greasy or cooling effects. You might have ointments that
do not feel greasy or gels that do not have a cooling effect. So what
are you going to do under conditions such as those? It concerns me that
then it may create some level of ambiguity that may be unnecessary even
if you had the physical measures. So I\'d like to know how would you
address that.

DR. CHIU: If you look at a formulation with the definition together, you
will see based on the composition you could determine ointment is more
lipophilic. So lipophilic usually is more greasy. So we just don\'t have
technology or methodology to measure the greasiness, but it\'s sort of
coupled with the composition.

And the same thing with the cooling effect. It is coupled with the
volatiles present in the formulation.

That being said, is it important to put the sort of subjective language
in the definition? That\'s the question.

DR. KIBBE: Ajaz?

DR. HUSSAIN: I don\'t remember. Going back to the report that Cindy
presented, we did look at some surface tension, interfacial tension, and
so forth. Does that have any link here with the issue of something that
happens on interface and something that is related to interfacial
tension and possibly other attributes?

DR. BUHSE: We looked at surface tension and we didn\'t find that it
correlated to anything really. We could certainly look at it deeper.

DR. HUSSAIN: You didn\'t look at it from a greasiness perspective, the
correlation from that perspective?

DR. BUHSE: No, we did not. In fact, we did most of our surface tensions
on creams and lotions and not, in fact, on ointments.

DR. KIBBE: Gary, and then I think I\'m going to take the privilege of
the chair and say something myself.

DR. HOLLENBECK: It seems that there\'s agreement that the decision for
calling it a lotion or a cream or an ointment should be based on
objective physical testing as much as possible.

But Jonathan\'s comments earlier about a prescriber wanting to know the
general characteristics of these systems I think adds a reason for us to
have within the description, this usually has a cooling effect, this is
water washable, this is normally a greasy kind of product. I think that
kind of general information helps you make a choice in terms of which
one of these forms you might want to use for a particular application.

DR. KIBBE: I teach pharmaceutics and pharmaceutical dosage forms. We
teach heterogeneous systems. A lot of the definitions that you put out
here, if my students wrote them down, I\'d take off full or half credit.
They\'d get it wrong.

(Laughter.)

DR. KIBBE: We have criteria for establishing what these things are based
on the composition of them, and then we assume that the physical
characteristics will be a result of the composition. We define them
based on the base or the vehicle and not on the active ingredient.

For us, gels are clear. They\'re either molecular or colloidal
dispersions in water. If they happen to become opaque, it\'s because
we\'ve added an active ingredient to it. But if you make a semi-solid
which is clear, whether it\'s colored or not, it\'s a gel.

Ointments. We have four categories of ointments depending on what we use
as an ointment base. It\'s clear what they are. They are in gradations
greasy, starting with hydrocarbon bases going to absorption bases, which
are usually compared, if you will to lanolin, which can absorb water and
it\'s a byproduct of the wool industry. I always like to tell my
students that lanolin is on wool on sheep so that when they get caught
in the rain, they don\'t shrink.

(Laughter.)

DR. KIBBE: But it\'s that greasy material that covers it.

We go from absorption bases to water-washable bases and then to
water-soluble bases. So if you have ointment on the label, if you say
that it is a hydrocarbon base, absorption base, water-washable base, or
water-soluble base, then I know exactly how it\'s going to feel or
behave on the surface of the skin.

A paste is an ointment with lots of solids. We know what happens when we
add solids to any heterogeneous system. It makes it more viscous and it
makes it more occlusive.

Ointments and suspensions can be lotions. Lotions is a terrible term,
but we use it all the time.

I would throw out there that a magma is a suspension whose viscosity is
such that it acts as a semi-solid rather than a liquid.

There is another term that we throw around a lot called insufflation.
Those of you who are interested in insufflation, that\'s a powder
that\'s blown into a body orifice.

Liniments, which haven\'t been mentioned, are liquid solutions intended
for external use with certain kinds of characteristics.

I wonder if our level of scientific sophistication is getting us away
from the basic understanding of some of the classic definitions and how
they help us understand things. If we could establish these classic
definitions and then say, if people are so interested, how does the
active ingredient change the characteristic of that base and how does
that base affect the characteristic of the active ingredient, we might
not need to do a lot more defining.

I read all of this stuff and I wonder what we\'re gaining and what
we\'re losing. I think I\'m reluctant to ‑‑ clearly question 3 says loss
on drying and that\'s because creams are emulsions and there are only
two kinds. And if we said that this was a cream and it was an oil in
water, it would have certain characteristics. If it was water in oil, it
would have another. Cold creams and vanishing creams are different
because of exactly how they\'re made. And those are the classic bases
from which everything else is relatively derived.

I think we might be overdoing it here.

DR. HOLLENBECK: Well, I\'ll jump in and respond to that first. I sort of
felt the same way as I read my backgrounder. I was trying to figure out
what is the problem we\'re actually trying to solve. And yet, as I\'ve
listened to presentations, a few things really have resonated with me.

Art described a system that isn\'t working. The confusion that you
currently have I think is evidence that the system isn\'t working. Maybe
that\'s our fault as teachers of pharmaceutics.

The idea that some clear guidance to prescribers might help them make
better choices in terms of pharmaceutical care I found to be a strong
reason for maybe clarifying these categories.

The generic drug product issue I find as maybe a reason for greater
clarity too, that you would like to approve a generic product if it\'s a
paste that is really a paste according to your definition.

So I think I\'ve come to the feeling that there is benefit to provide
some clarity in a system like this.

Having said that, I feel that you\'re quite a ways away from it. You\'ve
got a series of laboratory tests and some primary criteria which might
help you do that. But I have a lot of problems with the decision tree.
Like Art, I can\'t even get to gel because I don\'t see the word colloid
on your decision tree anywhere. So I think there\'s a lot of work to do
there.

But I would speak in favor of perhaps five or six categories here that
might provide some clarity.

DR. KIBBE: I\'m not saying that we couldn\'t improve the system, and I
think one of the problems we have is that only a small percentage of the
people who deal with these things actually know the classic definition
well enough and know the reasons for it to make sense out of it. Clearly
that doesn\'t include the physicians unless they happen to be
dermatologists who were once pharmacists and then became dermatologists.
I think that\'s part of what we have to address.

DR. CHIU: This is exactly the kind of comments we would like to hear. If
we are not on the right track or if we are overdoing it or undergoing
it, we\'d like to know, and we would welcome specifics. Gary, you\'re
talking about there may be other attributes or other things, like gel
should include colloidal, and we agree. We are here to listen. So we
really would like to hear a lot more specific recommendations so we can
move forward.

DR. MEYER: I think Gary asked an interesting question. What problem are
we solving here? Is it a bioequivalence Orange Book problem in that you
don\'t want to approve a cream as an ointment and vice versa? Or is it
directions or a description in the labeling that you want to be expanded
and appropriate ways to test that? Just what are we solving here by the
decision tree or definitions or what have you?

DR. CHIU: The problems are multiple. For example, one company has made a
lotion and then they want a line extension. They made some minor
modification of the formulation, but it hasn\'t changed the
characteristics. And they said, now, I have a cream. So then you have
two products because the definition is not clear enough. Then if the
generics need to copy it, then they have to copy the lotion from cream,
actually lotion, cream, that could be a product called the same name.

Then when you have products of a different characteristic, one company
calls this hydrocortisone lotion, the other company calls it
hydrocortisone cream. Actually they have the same physical
characteristics.

So, therefore, it is important to clearly define the different terms so
we know what dosage forms we are talking about.

DR. HUSSAIN: I think there are two ways of thinking about this problem.
One is I think there\'s a need for reexamining the naming system itself,
and I think there is a lot of confusion. So I think one of the aspects
is I think we want to float the proposal of identifying the problem that
needs to be addressed and what is the solution to that, I think you\'re
looking at that as the start to a proposal. So consider that as you
discuss this because FDA alone cannot handle this. Industry has to be
part of this discussion. Academia has to be part of the discussion.

Clearly I think this is just the tip of the iceberg. This problem is not
unique to topicals. It is inherent in every dosage form. I\'m struggling
with one dosage form right now. What is an orally disintegrating tablet.
So I think it\'s time to rethink and provide a much firmer foundation to
this issue.

DR. KIBBE: One of the problems that seemed to be coming out is that we
want a product that\'s called a cream to be exactly the same every time
it\'s called a cream, which means that we need to maybe subset some
creams, or there are creams which are oil-in-water emulsions and creams
which are water-in-oil emulsions. So that\'s two subsets. And if you
want the industry to follow along, you almost have to have the
equivalent of a USAN Committee for naming products when you\'re dealing
with heterogeneous systems.

It would be reasonably easy for me to say, okay, you are claiming an
ointment. Which one of these four categories of ointments have you made?
Tell me what the components of your base is and I\'ll tell you which one
you fit. And you can say you\'re a hydrocarbon ointment. You can say
you\'re absorption. You can say a wash and so on.

If you want to continue to keep lotion, you can say that this is a
suspension or an emulsion lotion. The problem comes when you have both
in the same combination and those things.

But do you want an acceptable nomenclature committee at FDA for topicals
that when the companies come forward and they want to call it X, you
say, well, your base doesn\'t allow you to call it X? Your base is
really this kind of a base. You have to call it Y.

Go ahead.

DR. WILKIN: Well, I was going to respond in part to the query about what
are we trying to fix. I think we had definitions in the past for these
different dosage forms at a time when there weren\'t many other examples
within a class.

If you look at the literature on taxonomy or systematics, just sort of
the general way one approaches trying to divide things up and making
order out of chaos, some sense, some structure, one of the ways of
thinking about definitions is called a typology, and it\'s saying in
general this would be lotionness. And then you\'d list some categories.
So what you\'ve done is you have a definition of a lotion that\'s pretty
good at the epicenter of lotionness, but we know that there are
intergrades between lotions and creams. So as one marches out towards
the border, then we at FDA have these difficulties when products come in
deciding whether we\'re going to call it a lotion or a cream. So I would
say that\'s one issue.

The second issue is the part about the intergrade. We had an example.
And I don\'t think I\'m divulging any proprietary information here. It
was a topical that was a cream, and the sponsor wanted to have a line
extension. So they were going to keep the active ingredient at the same
concentration. They were going to keep the inactive ingredients in the
same ratio to each other, but they were going to add a substantial
amount of water. If you just think of the problem between what is a
lotion and a cream, technically at some point there\'s going to be a
drop of water added to this that\'s going to then convert it from a
cream to a lotion.

Now, I don\'t know that we have to precise the boundaries quite to that
extreme, but the boundaries are so soft right now that we have things
that I think have more lotion-type properties that we call creams and
other things with more cream-like properties called lotions. I think
that\'s part of the confusion. I\'m not going to say this is a
horrendous public health issue. I just think it could be made better. It
could be made more relevant.

Then the second part is it seems like we\'re focusing an awful lot on
the composition. It\'s absolutely true that the properties of the
vehicle are critically dependent upon the list of ingredients and also
the quantitative aspect, how much each one is there. But I would say
that the manufacturing process adds a lot of emergent properties that
you can take the same, literally, mix and manufacture it in different
ways, and you can end up with different viscosities. So I think there
does need to be something beyond just simply basing this on what is the
dominant ingredient. I think we may need some more physical measurements
to add to it.

DR. KIBBE: I agree about the difficulty of putting a line between
lotions and creams. I think your work using 30,000 ‑‑ oh, and by the
way, generally accepted, we are now using millipascals instead of
centipoise. It\'s the same unit value; 1 centipoise is equal to 1
millipascal. But internationally if you\'re publishing, you want to
publish in millipascals.

That being said, I think making a decision as an agency on where the
delineation is is, of course, difficult and worth doing. But you can
still define the lotion as either an emulsion-based lotion or a
suspension-based lotion with viscosity less than 30,000 millipascals. I
don\'t think you have to do an as extensive a redefinition as it sounded
like we were going down.

DR. CHIU: We can easily do that. During our discussion, we thought a
liquid suspension is clearly defined. Maybe we don\'t need to say that
some of them could be a lotion. But we can relook at that element and
then include this.

With respect to the subclasses, which is hydrophilic cream, hydrophobic
cream, we have a question there later. Our thinking is the subclass
information could be put in the description section of the package
insert rather than use them to define the name. So, therefore, the name
would be a cream and then a cream is a cream that either is hydrophilic
or hydrophobic. But that the information would be important.

But we have that question later. We want to ask you whether that\'s the
right approach.

Could we go on to the next question?

DR. KIBBE: Anybody else?

(No response.)

DR. CHIU: The next question is about viscosity. Laboratory work found
viscosity to be the most discriminating property that separated lotions
from creams. In addition, most literature sources describe lotion as
liquids and creams as semi-solids. In the proposed definitions, lotion
is distinguished from cream based on pourability which we found in the
lab to be a viscosity less than 30,000 millipascals.

(Laughter.)

DR. CHIU: I got it.

(Laughter.)

DR. CHIU: Using the Brookfield viscometer at 25 degrees and 5 rpm. Is
this reasonable?

DR. HOLLENBECK: Well, I would like to congratulate us on harmonizing the
units for viscosity today.

I\'d say fine as a screening tool, but we all know that rheological
characterization is a very complex process. Somewhat arbitrarily
choosing 5 rpms and 25 maybe is as good as any other choice.

I\'d make a couple of comments there. I do think you ought to sheer the
system first. Usually if you\'re trying to assess pourability, you\'re
pouring it out of something. Normally we shake these things. So I would
sheer the system and then measure its viscosity.

The second thing I would say is this is perhaps one of the most powerful
tools that you have to somehow identify this three-dimensional abstract
network for gels. You can look at time-dependent, sheer-dependent
behavior here, and maybe that\'s a tool that you can use to help
discriminate gels from other systems.

DR. CHIU: Any other comments?

(No response.)

DR. CHIU: Number 3. Laboratory work found loss on drying to be a
discriminating property that separated ointments from creams. In
addition, a review of the current submissions to the agency found that
ointments had a large percentage of hydrocarbons or PEGs in their bases.
In the proposed definitions, ointment is distinguished from cream based
on the proportions of volatiles, less than 20 percent LOD, and
composition, hydrocarbons or PEGs greater than 50 percent. Is this
reasonable?

DR. KIBBE: That fits directly with the common definitions that we give
all the time. The four classes of ointment bases all contain none or low
amounts of water, the water-soluble one being PEG, and then creams are
always emulsions and in most cases greater than 20 percent water.

DR. SHEK: Well, if that\'s the case, why not just talk about water and
say ointments don\'t contain water, and if it contains water, now it\'s
a cream?

DR. KIBBE: Some ointments have some water. Absorption ointments can
contain small amounts of water. If you take an active ingredient that\'s
water-soluble and you want to incorporate it in an emollient, which
creams are not as good at, you can take it up in a water-absorption
base. It still would be an ointment because it\'s below a certain amount
of water. But you\'re right.

DR. SHEK: I\'m just saying you can change the definition and just decide
anything which is water it\'s not an ointment, it\'s a cream, the way it
feels.

DR. CHIU: We will look into that.

Other comments?

(No response.)

DR. CHIU: Question number 4. The distinction between hydrophilic and
lipophilic creams is made based on the composition of the continuous
phase. Is there any value in including these two types of creams in the
definitions?

As I mentioned earlier, our original thought is to put this kind of
information in the description section of the package insert, not use it
to define creams. So both hydrophilic and lipophilic creams will have
the same name. Drug cream, like that. So we can add this into the
discussion as well.

DR. KIBBE: I\'m so used to using the emulsion type rather than saying
hydrophilic and lipophilic. It\'s either an oil-in-water emulsion type
or a water in oil, and it carries the general characteristics of the
external phase when it\'s applied. So you can use that.

When we start talking about hydrophilic-lipophilic, my mind immediately
goes to hydrophilic-lipophilic balance, the HLB nature of the
surfactants, which surfactants are in there.

DR. SHEK: I\'ll support and agree because I think the oil in water,
water in oil is very, very important fact in the way you design the
dosage form, the way it really acts. So I think this part is important.
I agree with you that a definition of whether it\'s lipophilic or
hydrophilic might be confusing.

DR. CHIU: The next question has three parts about gel. Gel is
distinguished from cream based on the presence of sufficient quantities
of a gelling agent to form a three-dimensional, cross-linked matrix. Is
this reasonable? Should \"sufficient quantities\" be defined? Which
literature sources should be used as references?

DR. HOLLENBECK: I don\'t know what to do with this one. I don\'t know
how to analytically discover the three-dimensional, cross-linked matrix
on a regular basis.

DR. CHIU: When you make a gelatin or gel, actually the entire container
contains a long cross-link to one molecule. So this is how we got the
idea it should be a three-dimensional, cross-linked. However, we do not
really know how to actually do this. What is the minimum gelling factor
that should be there so therefore you always get a three-dimensional,
cross-linked matrix?

DR. HOLLENBECK: I know we\'re mixing physical tests with composition all
through this system. But this is one that I would resolve based on
composition. I think you know the things that form gels, hydrophilic
colloids, celluloses, carbapols. If those things are in there, you have
a gel. You may end up with a paste later on because you added a lot of
solid or an emulsion if you put something else in there. But it seems to
me the first kind of screening criteria for a gel might be based on
composition more effectively than this more difficult thing.

DR. CHIU: The question is how much is the minimum amount to be present
because if you add a little bit, it could be an emulsion factor rather
than a gelling factor.

DR. HOLLENBECK: Yes. Again, depending on which hydrophilic colloid you
use, very small concentrations can give you large viscosities and large
concentrations can give you small viscosities. I think in a screening
sense, if those materials are in there, you have a gel. Then you can
look at your other criteria later to maybe separate it into subsequent
categories.

DR. KIBBE: I have a small concern with that, and that is that there are
things that are gelling agents when you use them to make a gel, which
are emulsifying agents when you use them to make an emulsion, which are
thickening agents to stabilize suspensions when you\'re making a
suspension. And to say that you have to have X of an ingredient isn\'t
defining the result. The result is that gels are semi-solid systems with
dispersion of small or large molecules and predominantly aqueous, and
when the base is made, the base is clear.

DR. HUSSAIN: Just to go back to that, I think the 3D structure ‑‑ the
point you had made earlier. You get to the rheology, and I think the
rheology will provide that information because it\'s the yield point
there, and that\'s where it comes from. That probably would be a better
approach to that.

DR. HOLLENBECK: But we know that you can have that kind of behavior for
creams as well. So I would argue that you can\'t have a gel without the
hydrophilic colloid.

DR. KIBBE: That\'s the definition of a gel.

DR. HOLLENBECK: Yes. So that would help you in terms of your screening
characteristics to get to a gel.

DR. KIBBE: But I wouldn\'t worry about sufficient quantities.

DR. HOLLENBECK: That\'s right. I agree with that.

DR. CHIU: So you don\'t think we need to worry about whether it contains
sufficient quantities. Just the presence of gelling agents and then look
at the physical characteristics.

DR. HOLLENBECK: Yes.

DR. CHIU: 5b. Some currently marketed gels contain an emulsifier that
gives the dosage form an opaque appearance. Should the presence of an
emulsifier in a formulation preclude a dosage form from being classified
as a gel? Should it then be considered a cream instead of gel?

DR. KIBBE: You\'re going to leave me with this one. Right, Gary?

DR. HOLLENBECK: Yes.

DR. KIBBE: This is so good.

(Laughter.)

DR. KIBBE: This is why have scientists working years and years to come
up with esoteric definitions that take 40,000 words.

If the base is a gel, then it\'s a gel. If the active ingredient, in
order to be able to be uniformly incorporated into a gel base must be
emulsified because it\'s oleaginous in nature and you need an
emulsifying agent, then I think you\'re really on the horns of making a
call. Do you have a micro-emulsion, which is a colloidal dispersion and
therefore makes the gel cloudier than it would normally be? Do you have
an oil-in-water emulsion where the external phase has been gelled to
make it a semi-solid? Or have you solubilized the active ingredient in a
gel?

Enjoy yourselves.

DR. BLOOM: Do you have any TGA data that will provide any information to
make this distinction?

DR. CHIU: Cindy?

DR. BUHSE: We have some data which I showed you. We\'re collecting more
now. So we don\'t have a complete conclusion yet on TGA, but based on
our initial data, we have collected additional samples of gels and
creams that contain gelling agents whether they\'re used as gelling
agents or emulsifiers. We went out and specifically looked for some of
those materials and we have those in the lab currently.

DR. BLOOM: Maybe that will be useful too maybe in the \"sufficient
quantities\" part of the last question that we were looking at.

DR. SHEK: Yes. It\'s interesting whether we start with a cream and made
it a gel or we start with a gel and made it a cream because if you start
with a gel, my question is, if you have an emulsifier, what are we
emulsifying there? There has to be now another phase, I would assume,
there which is now lipid and we add water. Otherwise what are the
emulsifiers doing there? Right? So that\'s why I\'m asking the question,
what did we start with.

DR. BUHSE: I think one of the things we\'ve really seen with our
committee is that the formulations that manufacturers are coming up with
are very complex. They have not been to Art\'s class and learned what
they should be doing.

(Laughter.)

DR. BUHSE: And they have everything in there that you could possibly
imagine.

DR. HOLLENBECK: I guess I think an emulsion trumps a gel.

(Laughter.)

DR. HOLLENBECK: So if you\'ve got oil, if you\'ve got surfactants, if
you\'re creating this multiple-phase system, then your gel actually
becomes a thickening agent, a term that Art used earlier. I believe as
you move from the more sort of homogeneous colloidal system, the gel, to
the heterogeneous emulsion system, I\'d rather call that a cream because
then I want to know what the external phase is, and the properties of
that system really depend more intrinsically on its emulsion
characteristics than the gel characteristics.

DR. KIBBE: I think we have the same problem, though, here as we had with
differentiating cream and lotion and using 30,000 millipascals is useful
in that case. In this case if the oil phase, quote/unquote, that we put
into our gel represents 1 or 2 percent of the weight and it\'s only the
active, have I really gone all the way to making a cream? That\'s why I
was throwing out the possibility that we might have added enough
surfactant to actually solubilize. Or have we made a micro-emulsion
which is really distinctly different than a standard emulsion that you
make? Or have we really gone to an emulsion? I think the agency is going
to have to try to think through when does it cross that line.

I agree with you that suspensions trump solutions every time. Emulsions
trump ‑‑ and we go from there because as soon as you have an emulsion,
you can define it, oil in water, water in oil. You know a lot of the
characteristics. Along with the viscosity, you\'ve defined your system.
You either have an emulsion that\'s a liquid and pourable or you have an
emulsion that\'s a semi-solid and unpourable. The characteristics of the
feel of that emulsion on you is directly related to whether it\'s oil in
water or water in oil. One cools, the other doesn\'t.

So I agree with you. Emulsions trump. But when have you gotten there?

DR. CHIU: 5c. What is the most appropriate analytical technique that can
be used to identify the three-dimensional structure of a gel?

DR. KIBBE: Nair, this one is yours.

DR. RODRIGUEZ-HORNEDO: I deal with solids, not semi-solids.

(Laughter.)

DR. RODRIGUEZ-HORNEDO: I can\'t answer this one.

DR. HOLLENBECK: Just to repeat, I think rheological characterization is
the only way I know to do it. To look at the extent of hysteresis in a
full-blown rheological study might help guide you in that direction.

DR. CHIU: The last question. Is the overall approach taken in the
proposed definitions appropriate? I think we have some comments, and if
there are further comments, we\'d like to know.

DR. SADEE: I just have a general question. I didn\'t take Art\'s
classes.

(Laughter.)

DR. SADEE: So I do not know about these things.

What are the implications if we design very firm guidelines that
distinguish one from the other? And also, what is the implication if
certain definitions or certain terms are left out? Are those no longer
usable? For instance, salves and liniments and concoctions or milks or
however you might label a product.

DR. KIBBE: Yes. Don\'t forget collodions.

DR. SADEE: That\'s right. So are these then no longer usable if it were
to be a drug because it doesn\'t fit into the definition?

DR. CHIU: If this becomes a formal policy at the FDA, it will only apply
to future products, not retroactive. Once this becomes a USP policy and
published, then USP usually lets companies phase in existing marketed
products to change their names. So sometimes it could be 10 years to
phase it in. But for the agency, we do not retroactively ask companies
to change their current labeling.

DR. SADEE: But proactively then it would mean that those are the only
terms that should be used in the future.

DR. CHIU: If today\'s proposal, say, is accepted by everybody, then for
liquid emulsion, semi-solid emulsion, and semi-solid suspension dosage
forms will then use these five terminologies for topicals for skin use.

DR. SADEE: I\'m just wondering also about some international issues
whether products imported or exported, for that matter, would fall under
these definitions.

DR. CHIU: Products marketed in the United States will need to follow the
new definitions, but the products exported to other countries will have
to follow the definitions the other countries adopt.

DR. DeLUCA: What are some of the legal implications here with regards to
these definitions and intellectual property and patent infringement
cases and stuff like that? Has anybody thought about that? When you
starting putting definitions, is this going to be a factor also?

DR. CHIU: In the agency if we propose and then finally adopt a new
policy, it will go through our Office of Chief Counsel. So the legal
aspect will be reviewed by them. If the approach is not considered legal
under the FD&C Act, then it won\'t be finalized.

DR. KIBBE: Marv?

DR. MEYER: Specific to your question, I think the overall approach seems
appropriate. I really like the decision tree because it causes you to
focus in on your decisions along the way, and it\'s also helpful in
coming up with a classification.

What would be the down side of just eliminating gel from your
nomenclature? Because that seemed to be the one with the iffiest
definition and no perfect physico-chemical test. In other words, it
looks like gel would fold into either ointment, cream, or lotion. And
that couldn\'t be, according to Art.

Part of the problem is that we\'re dealing with an historical thing, and
we\'re trying to make it fit contemporary attributes. Why couldn\'t you?

DR. KIBBE: A gel is a solution that has become a semi-solid. A
suspension, which is a heterogeneous system as opposed to a homogeneous
system of a gel, when it becomes a semi-solid, becomes a paste or an
ointment. An emulsion becomes a cream. Okay? And that\'s where the
difference is. While you might think it\'s subtle, those of us who have
been involved with this stuff don\'t necessarily think it\'s that subtle
a difference.

Gary?

DR. HOLLENBECK: I like the decision tree idea too, but I know this is
not the place to go into great detail. But this is really going to be a
challenge. As I look at your decision tree, the first thing I notice
over on the right is an aerosol. Well, an aerosol is inherently an
emulsion. So I can\'t get to that box by going through your ‑‑

DR. KIBBE: Some of them are solutions.

DR. HOLLENBECK: Some of them are solutions. Well, okay, proving my
point.

(Laughter.)

DR. CHIU: We removed aerosol because of the way it is administered.

DR. HOLLENBECK: I understand.

DR. CHIU: It needs to be under pressure. So it\'s quite different from
other semi-solids.

DR. HOLLENBECK: Yes, I understand that, but you\'d need a yes to get
over to that box for many aerosol products.

As I told you before, I can\'t get to a gel with your current decision
tree because it\'s not a suspension or an emulsion.

And one other thing. If you mixed calamine with propylene glycol or
glycerine or something like that, I\'d call that a lotion, and my sense
is that you\'re not going to see much loss on drying if you study that.
So you really do have a challenge I think facing you in terms of making
the decision tree work.

DR. KAROL: I guess my only comment about the decision tree ‑‑ I think
it\'s very good and very effective ‑‑ is the definition of a cream.
It\'s a negative definition, and it\'s like saying if something is not
black or white, then it\'s red, but of course, it could also be green or
blue or something else. So I think eventually you\'re going to run into
problems with the definition of cream.

DR. KIBBE: Have we run out of things? Are we all hungry enough for
lunch? Are there any closing remarks?

DR. CHIU: I would like to thank everybody for very constructive input.

DR. KIBBE: I enjoyed it. It was fun.

DR. HOLLENBECK: I think you and I did, Art. I\'m not sure about
everybody else.

DR. KIBBE: Well, I\'ve got an exam being given tomorrow by a colleague
in my class that covers this issue, and if I lost all of these
definitions, I\'d have to go back and give them all 100s because none of
the definitions that I ask them for would be right.

We are now officially adjourned for lunch. We will return for the open
public hearing at 1:30. The individual who is speaking, Thomas Franz, is
he here? Good.

(Whereupon, at 12:30 p.m., the committee was recessed, to reconvene at
1:30 p.m., this same day.)

AFTERNOON SESSION

(1:27 p.m.)

DR. KIBBE: Well, folks, I hope you have enjoyed your lunch and
camaraderie with your colleagues and you are prepared to work diligently
through the afternoon.

We are lucky today that we will probably end on time. Remember, that if
we get out of here early today, we will make up for it by getting out of
here late tomorrow.

Good news and bad news about tomorrow. We have one hour for an open
public hearing. We started out with 17 people. We\'re down to 12. So we
have a chance of actually getting through the one in two, instead of
three. So, we\'re getting better.

After lunch, we start with our open public hearing. We have an
individual, Dr. Thomas Franz, from Dermtech. Is Dr. Franz ready to go?
He looks ready.

DR. FRANZ: I\'m Dr. Franz. I\'m the Chief Medical Officer for Dermtech
International, which is a contract research organization in San Diego.

I have no vested interest in the material I\'m going to present because
as a contract research organization, we do work for all the
pharmaceutical and cosmetic companies, and whatever method the agency
chooses to promulgate for proof of bioequivalence, we will do. So we
make money no matter which direction the agency goes.

What I\'m going to talk about today for consideration is the use of the
cadaver skin model as an in vitro way to assess the bioequivalence of
topical drugs. This model has been around for a long time, widely used
in the pharmaceutical industry, the new drug part of it, in terms of
developing topical formulations. I\'m really not aware of any
pharmaceutical company in developing a new topical drug that doesn\'t
use this particular model system to optimize formulations and thereby
maximize bioavailability. So there is a great deal of use of this
particular model.

Through this model, which uses cadaver skin in an in vitro chamber type
setup, one can very easily measure the rate and extent of absorption of
any topical drug through the skin. So it\'s measuring parameters that
are by definition those that we use to define bioequivalence.

As I mentioned, there\'s long experience with this. It\'s not only
widely used now, but if one goes back to the literature of 30 to 40
years ago, one will find lots of articles on this particular model as it
was evolving in its infancy. And particularly 30 years ago, classic work
by Katz and Paulsen and others at Syntex pretty much developed the
procedures that are now used by most pharmaceutical companies when
Syntex developed the first of the high potency topical steroids, Lidex.
So there\'s a long history of use.

Even today what we\'re finding is many generic companies have found it
necessary to resort to this model as a means of screening their
formulations prior to going to some expensive clinical tests because
sometimes reverse engineering gets them in the ball park but doesn\'t
necessarily define the innovator formulation precisely. And more
critically, given the variation in innovator lots from lot to lot, it\'s
even become popular to screen innovators and choose that innovator lot
which best fits your generic lot. So there\'s tremendous background in
the use of this model.

There\'s also good in vitro/in vivo correlation, and I\'m not here
talking about clinical in vitro/in vivo correlation, but just if you
take the data that one gets in this in vitro model and then do a similar
test of bioavailability in living man, usually using radioisotopes, but
not necessarily always using radioisotopes, there\'s very good in
vitro/in vivo correlation. In our hands ‑‑ and I\'ve been working at
this over 30 years now ‑‑ I\'ve never found a situation where the in
vitro and in vivo did not correlate.

Well, what I\'m proposing is use of this model to screen topical generic
drugs for proof of bioequivalence. For those of you who have followed
the tape stripping procedure that was proposed a number of years ago,
loosely characterized as DPK, it\'s clear that the agency would like to
see two sets of data presented in order to validate any model.

One would be to take a situation where one has a generic and an
innovator drug that have been shown to be bioequivalent by clinical
testing and then show that whatever model system you use can come to the
same conclusion.

Then, of course, the reverse would also be nice to have. Take a generic
and innovator that were shown to be not bioequivalent by clinical
testing and show them not to be bioequivalent through use of the model.

Unfortunately, it\'s hard to come across that type of data because
generally if that type of data is available, it\'s not presented to the
agency. So nobody really has it. So the first one is relatively easy to
find, but the second one is a little more difficult.

What I\'m going to present today is some data using the first example of
two formulations that have been shown to be bioequivalent by clinical
testing.

Within the last year or two, Spear Pharmaceuticals has had a .01 percent
and a .025 percent Retin-A gel, tretinoin gel, shown by clinical testing
in acne to be bioequivalent to the innovator products which are known as
Retin-A. So the question that I am posing and have data to answer is,
will the cadaver skin model reach the same conclusion?

Now, if one focuses on the finite dose part of this, the cadaver skin
model basically is one which uses a finite dose approach, a finite dose
referring here to a situation where we\'re going to be dosing the skin
with amounts that are clinically relevant. We use approximately 5
milligrams per square centimeter, just a little bit more than what most
patients would use. Most patients are probably going to be in the range
of 2 to 3 milligrams per square centimeter, but 5 turns out to be a
little bit easier to use in vitro. So that\'s the dose we use.

Basically the model system involves taking a piece of cadaver skin.
We\'re usually obtaining frozen, cryopreserved skin from skin banks.
From a single donor, one obtains multiple sections, and these multiple
sections are mounted over a chamber in which the under side of the skin,
the dermal side, is bathed by warm isotonic saline, and the top of the
chamber is exposed to ambient conditions, just like exist in this room
that most of us will be applying drugs under those similar situations.

So the key to the model system is that it basically mimics two critical
parameters that determine the rate of absorption. One is that there is a
temperature gradient across the skin going from 37 degrees Centigrade on
the inside to room temperature on the outside which results in a skin
surface temperature of about 32 degrees C. That\'s what exists in vivo
and that\'s what we mimic in the chamber. And likewise, there\'s a water
activity gradient across the skin so that it\'s close to 100 percent
humidity inside and then whatever room humidity is on the outside. These
two physical parameters are key to getting results in vitro that agree
with what happens in vivo.

The receptor solution is stirred, and then of course through the
sampling port, we\'re able to remove at various points in time the
receptor solution and take an aliquot for analysis and then replace with
fresh solution so that there\'s always an infinite sink existing in the
dermal bathing solution.

So this is basically the cadaver skin model. As I mentioned from a
single donor, we get multiple sections. They are all screened using
tritiated water to probe for defects in the skin and certain criteria by
which that skin is either acceptable as being intact or rejected as not
being intact.

Generally, enough sections are obtained from any donor so that the
generic product will be applied to four replicate chambers and the
innovator will be applied to four replicate chambers. The data from
those four replicates will be averaged to give a single value for that
donor, and then in the data I\'m going to present, we had a target
number of eight donors in the particular test.

So this is showing the results, the rate of absorption profile over a
48-hour period for the two tretinoin products at the .025 percent
concentration. The y axis is showing the flux or the rate of absorption
in terms of nanograms per square centimeter per hour, and then the x
axis is time. And we\'re plotting the samples at the mid-time of that
sampling period. So, for example, if the first sample were taken at 2
hours, that data point would be plotted at 1 hour. As you can see,
there\'s relatively good agreement between generic and innovator product
with standard error bars being given.

The next slide shows similar results for the .01 percent gel.
Unfortunately, bigger error bars in this particular case. There were a
couple of donors for which there was larger variation than usual, but
this is presenting the data without any of the data being excluded. This
is simply showing everything as it was obtained, but still in my
estimation not bad agreement between these two products.

Using log-transformed data, we see here the results on top for the .01
percent tretinoin first. AUC is basically total absorption from 0 to 48
hours. Fmax stands for the maximum rate of absorption. And ratio is the
ratio of the generic to innovator product, very close to 1. And then the
90 percent confidence intervals, showing that for the .01 percent
product, they easily feel within the 80-125 percent range, and therefore
the .01 percent tretinoin did seem to be bioequivalent by this
particular test.

On the bottom is shown the same results for the .025 percent tretinoin
products. Again, the ratio for the AUC is very good, very close to 1,
and the confidence interval being met there. Maximum rate of absorption,
because of the greater variability in a couple of the skins, did not
quite make 80-125 but was, indeed, very close.

I will point out here that we are throwing out no data. For those of you
who may not be familiar with the vasoconstrictor test, currently as
we\'ve looked at final reports, the data from greater than 50 percent of
subjects are thrown out. I think the value is closer to 70 percent so
that basically only 1 out of 3 subjects who go through a vasoconstrictor
test end up to be acceptable in that particular test. Here this is our
first cut at the cadaver skin model, and so we\'re throwing nothing out.
But there are easily some constraints that could be put to throw out
data in terms of particular donor skins where the variability is very
large. So we\'ll just point that out, that right now we\'re throwing out
nothing.

So based on the data shown here, we think it clearly shows the cadaver
skin model could be used to determine the bioequivalence of certainly
most topical products, most if not all topical products.

The second part of the criteria that have been raised by the agency of
taking two products which clinically are shown not to be bioequivalent
and then showing them not to be bioequivalent in your model ‑‑ it\'s
hard to get data to answer that particular one. But I will, from this
test, just present the data we obtained in another form.

That is, we had two concentrations here. We had a .01 percent and a .025
percent. Now, as far as I know, there\'s no data from an acne clinical
study to show that those are or are not bioequivalent, but we certainly
know clinically, from the standpoint of irritation, that they are not
the same, and it\'s very easy to generate that kind of data.

So what I\'ve done here is actually take both the Spear data, .01 versus
.025, as well as the Retin-A data, .01 versus .025, and showed that by
this test they are clearly not equivalent, as can be seen here. Since we
know that clinically they\'re not equivalent in terms of irritation, I
think this does go at least part way to meeting the second criteria by
which the agency will judge the use of some test as a surrogate for
clinical testing.

So in this presentation I just hoped to show you that this is a model,
probably a one-size-fits-all model as the tape stripping was hoped to
be, that should be considered by the agency. Obviously, the data we have
at this point is not sufficient, but I think it\'s sufficient to show
that it is a model well worth looking at, and particularly with the
recent demise of tape stripping, it should be looked at.

I\'ll also point out that about 10 to 15 years ago the agency briefly
did consider this method and several symposia were jointly sponsored
with AAPS to look at it. Then all of a sudden, it disappeared off the
radar screen. It was buried without the last rites. I\'ve never heard
why, but I think it\'s time for it to be resurrected.

Thank you.

DR. KIBBE: Thank you. Would you stay a second and respond to questions?
Marvin?

DR. MEYER: Tom, would it be helpful in a test like this if the company
wishing to have approval of their product could actually formulate one
that was 20 percent lower in concentration, all things being equal, and
include that as part of, say, a three-way test so then you could have
kind of your control that it is able to detect a 20 percent difference
or whatever percent?

DR. FRANZ: Yes, it would be very easy to do. Yes, very definitely. The
problem is there\'s no incentive for any company to do that right now
because when they get that data, they still have the clinical data that
they\'ve paid for and now they\'ve got this extra clinical data that
gets them nowhere. So they do it out of the goodness of their heart, and
I haven\'t been able to find a company that\'s willing to do that. But
that is an easy answer to the problem.

DR. MEYER: What would you expect you would see if you did Retin-A versus
Retin-A or Spear versus Spear in a study? Would the confidence limits
fall outside of 80 to 125?

DR. FRANZ: I think so if you\'re talking about testing them clinically.

DR. MEYER: No, no. With this system.

DR. FRANZ: Oh. That\'s what I\'m showing in this last ‑‑

DR. MEYER: Those are two different strengths, though.

DR. FRANZ: Yes. I\'m not showing the ‑‑

DR. MEYER: I\'m saying if you just repeat it. Instead of doing product A
and product B at the same strength, you did product A twice. What\'s the
variability? You had standard errors, as I understand it, which hide
some variability.

DR. FRANZ: Yes. I didn\'t bring data to show that. What we\'ve found,
for example, is we\'ve taken three different lots of Retin-A and run
them side by side on this test and they basically overlie each other.
There are still big error bars, as is true for any test that involves
human tissue, a lot of variation. But when you do enough reps and enough
donors, you do get means and you do get confidence intervals which you
can meet.

DR. KIBBE: Jonathan.

DR. WILKIN: Actually I think I\'ll hold off because I\'m going to give a
presentation later, and I can mention decision criteria, what arms to
have in the study.

DR. KIBBE: Okay.

Pat?

DR. DeLUCA: In your slide here, is that a Franz cell that you\'re using?

DR. FRANZ: Yes.

(Laughter.)

DR. DeLUCA: Is that your cell or what?

DR. FRANZ: Yes. It\'s not patented. I get nothing out of it.

DR. DeLUCA: Okay, no. You\'re very modest.

DR. KIBBE: In this last slide, is there a 2.5 to 1 ratio?

DR. FRANZ: It\'s a little less than that, yes. It\'s not 2.5 to 1. I
think it\'s like 2 to 1, something like that.

DR. KIBBE: Okay. So if you normalize for dose, they wouldn\'t be
equivalent?

DR. FRANZ: There\'s not a linear relationship between concentration and
flux, if that\'s what you\'re getting at.

DR. HOLLENBECK: Is it worthwhile investigating synthetic membranes in
your model?

DR. FRANZ: No. We\'ve tried that and we sometimes get flip-flopping of
data. People have always said, well, maybe it doesn\'t match
quantitatively but it will quantitatively. But we\'ve tried that and
sometimes we find that formulation A is greater than B in human skin and
then B is greater than A in some synthetic membrane. So we\'ve not ever
found that useful, but people continue to look at that. That\'s for
sure.

DR. MOYE: I couldn\'t help but be drawn to the comment you made about
the missing data. If I understood right, you said that all the data that
you had were included in this analysis.

DR. FRANZ: Yes.

DR. MOYE: And I guess I was willing to assume that, but you pointed that
out.

Then you also said, if I understood you right, that up to 70 percent of
patients are excluded or data are excluded from ‑‑ are there other
evaluations, competing evaluations of bioequivalence?

DR. FRANZ: Yes. The vasoconstrictor assay is a pharmacodynamic assay for
the class of topical drugs known as corticosteroids. In the agency
guidance, there\'s a criteria that each subject must respond in a
greater way to a higher dose than a lower dose, and if the ratio between
the high dose and the low dose, what they call D2 and D1, is not greater
than 1.25, that patient is excluded. But we\'ve seen a lot reports from
a lot of CROs where the data from 70 percent of patients are excluded
because they don\'t meet that D2/D1 ratio.

So I think we can look at this test in terms of absolutes, but I think
the other way to look at it is in terms of what we\'ve got now. It\'s
not that great. Whether you look at clinical testing or the
vasoconstrictor assay, they leave a lot to be desired. So let\'s not
hold this to some enormously high standard. Let\'s hold it to the same
standard as we\'re holding these other tests to.

DR. KIBBE: Efraim.

DR. SHEK: I have a question. I don\'t know too much about intrinsic
diffusivity because usually you would expect to see a lag time. And here
it looks like it goes very quickly through the skin, and my question
would be if you have other drugs which don\'t diffuse as well, whether
you\'ll see differences in the lag time and then differences in the
AUCs.

DR. FRANZ: Well, yes. This is an unusual drug in that it does seem to
permeate very fast with very little lag time. We\'ve done this drug many
times in vivo too because it\'s a teratogen, so there\'s a lot of
interest in systemic toxicity. So this is an unusual drug. With most
topicals there is a pretty significant lag time which could become
another parameter for comparison.

DR. KIBBE: Ajaz. Oh, I\'m sorry. Jon.

DR. WILKIN: In terms of not looking at the data from 70 subjects in the
topical corticosteroid assay, my understanding of how the Office of
Generic Drugs actually asked this study to be done is they\'re looking
for the 30 percent or 50 percent of human subjects who are actually very
sensitive to the effects of the topical corticosteroids over a wider
range of concentrations so that in essence, they are better detectors.
They\'re better subjects for picking up subtle differences from one
preparation to another. The subjects who are no longer used, which may
be 70, but it may be a lot smaller percent, turn out to not
vasoconstrict quite as readily or else they are relatively
vasoconstricted from the beginning. I think that\'s the major piece.
It\'s the idea of selecting subjects who are sensitive and good
responders for the assay.

DR. KIBBE: Okay. Seeing no one else, thank you very much. I appreciate
it.

Now we\'re going to get with our FDA presentations, and Ajaz has one.

DR. HUSSAIN: Well, again, good afternoon.

As I mentioned this morning, topical products pose significant
challenges for us in terms of approving therapeutically equivalent
generic products. I think one of the reasons is that when we measure
blood levels or if you\'re able to measure blood levels, that is not a
level that is reflecting the site of action. Even in Dr. Franz\'s
presentation, he\'s looking at flux, which is a receptor phase,
concentration in the receptor phase, but the site of action is the skin.
So you have to infer what was the concentration at the site of action.
So I think that\'s one of the challenges that we face in trying to
arrive at methodologies for approving generic drugs or even, I think,
approving innovator drugs in the post-approval change scenario when
there are significant manufacturing changes.

For the last 10 to 12 years, we have been working on this, and I do want
to acknowledge Dr. Vinod Shah and others who have worked extensively on
this and have actually created quite a body of scientific literature and
knowledge on this that had led to a draft guidance on
dermatopharmacokinetics, skin stripping, where we were unable to
establish consensus between the clinical community and the
pharmaceutical community.

As a result, I think we took that guidance, withdrew the draft guidance,
and said, but that doesn\'t mean that that methodology is off the table.
In fact, as we come through this discussion and when we come through a
proposal for moving forward, I think we would like to bring that back as
a focal point for discussion in sort of a different light. So I don\'t
want to get the message out that DPK is not a method on the table. It is
a method on the table, but I think we\'re going to reposition that.

For today the goal of this discussion is to take a step back, go back
and reexamine the challenges, reexamine different perspectives, and
propose a path forward in terms of a research program. After you listen
to the presentations, then what I would like to do is come back and
propose a path forward in terms of a research program which we will
bring for an extensive discussion at a subsequent meeting. Whether that
is the entire advisory committee or the Subcommittee of
Biopharmaceutics, we haven\'t decided. But that\'s the plan.

So this is an awareness topic for all of you to go back and reflect on
the challenges we face. And the three presentations we have on the
challenges are Dale Conner, Dena Hixon, and Jonathan Wilkin. The
sequence of the presentations is somewhat different than what we have on
the screen. So I\'ll ask Dale to start the presentations, followed by
Dena, and then Jonathan Wilkin. Then I\'ll come back with a path
forward.

DR. KIBBE: Does anybody want to ask Ajaz a quick question? He\'s not
escaping, so we\'ll get him later.

Go ahead, Dale.

DR. CONNER: As usual, my task is usually to go over the basics of
bioequivalence while others give the more meaty and perhaps even more
interesting topics. Obviously, I go first because you need to understand
the basics before you understand the more important or high level
concepts.

Actually topical drugs fall into what we largely refer to as locally
acting products. Those of us who are involved in doing bioequivalence
every day have found these an extremely challenging set of issues to do
bioequivalence. If you\'re used to being a pharmacokineticist and doing
systemic drugs, by comparison those seem very straightforward and easy
even though not always.

First, we have to clearly say what we\'re talking about here because for
those who don\'t deal with dermatologic products or deal with the skin
all the time, there is sometimes confusion. What we\'re dealing with in
this discussion is products applied locally to the skin to treat
diseases or conditions of the skin. So, for example, what\'s been
discussed earlier before lunch, creams, ointments, gels, however you
define all those, solutions, suspensions, and other things that are used
for the above, to treat diseases of the skin.

We want to make very clear we are not talking about transdermals, nor
are we talking about certain types of products that might exist as an
ointment but whose endpoint is to administer drug into the systemic
circulation to treat a systemic disease. So those particular products,
transdermals especially, are using simply the skin as a route of entry
into the body rather than the actual site of activity or the site of the
clinical condition. So it\'s very important because that is, strangely
enough, a point of confusion for some.

First, I\'d like to go over a very brief single slide about the
evolution of scientific thinking. Perhaps you could say that
dermatologists have a history of not trusting generic drugs or generic
drug products. Early, way back in the ancient era, decades ago, the
early regulatory approaches to generic topicals were simply to treat
them ‑‑ if they were pharmaceutical equivalents, it was an ointment
versus another ointment, it had the same amount of drug in it ‑‑ pretty
much the assumption was, well, there\'s going to be no problem with
inequivalence or these are not going to be non-therapeutically
equivalent. By today\'s understanding, it was kind of naive view that
the skin is very simple and these products are very simple and I don\'t
really have to worry too much about the clinical effectiveness of these
products as long as they have some fairly superficial similarities. So
back then, waivers of in vivo studies were granted for most, if not all,
of these products.

The result of this, by today\'s understanding this is not a simple
situation and the skin is not a simple organ nor are these products
simple, uncomplicated products. And therefore we ended up with clinical
observations at first by dermatologists that some of these products that
were supposed to be equivalent and switchable were not in any way
therapeutically equivalent in their hands. They were seeing very large
and noticeable clinical differences in the community in the patients
they were trying to treat between these products which were supposed to
be equivalent.

So we come to a point in time where the corticosteroids, which at least
at the time made up a large percentage of the dermatologic products,
most of the observations were in the corticosteroid area.

McKenzie and Stoughton developed a bioassay that was related to the
ability of topical corticosteroids to cause a blanching effect of the
skin. This is a pharmacodynamic effect probably caused by a steroid
effect of vasoconstriction in the superficial vessels of the skin. So if
you apply a strong steroid to the skin, you\'ll see, within perhaps a
few minutes to an hour, the skin becomes light. After the removal of the
drug, it\'s a temporary effect. It might last 24 hours or perhaps a
little bit more, depending on the drug.

But these investigators attempted to quantitate that with, at first, the
potency of different steroid agents, and eventually Dr. Stoughton
actually applied this technology to try and discern if there were any
differences in equivalent products containing the exact same drug. His
work, which was published in one or two different articles, showed that
many of the steroid products on the market that were allegedly
bioequivalent were, indeed, not bioequivalent or therapeutically
equivalent by his assay.

So this and other advancing knowledge in this area led to a change in
the way these products were regulated, in that it changed to, for a
great many of them, certainly the new products being tested through in
vivo bioequivalence testing rather than just simply granting waivers for
all of them.

One of the successful developments that developed from McKenzie and
Stoughton\'s original work was the current Guidance on Topical
Dermatologic Corticosteroids, which uses that same blanching effect and
attempts to have a quantitative measure of this blanching effect and
relate it to potency and certainly bioequivalence of pharmaceutically
equivalent products.

So first off, a definition of bioequivalence. This is definitely with a
generic drug\'s flavor, in that we term them as pharmaceutical
equivalents whose rate and extent of absorption are not statistically
different when administered to patients or subjects at the same molar
dose under similar experimental conditions.

The pharmaceutical equivalence part has some importance to the topic
that we discussed earlier before lunch because those definitions that
you debated and discussed really are one of the defining characteristics
of whether two products are pharmaceutically equivalent. By
pharmaceutical equivalence, we mean it\'s the same dosage form. It
contains the same amount of drug and is used for the same conditions
with presumably the same labeling and indications. So the definition of
the same dosage form, a cream versus an ointment, a gel versus a cream
or a lotion, that has a great deal of importance when you\'re
determining pharmaceutical equivalence. Therefore, if a drug is an
ointment and somebody else develops another formulation that doesn\'t
happen to meet your definition of an ointment, it cannot be matched up
as a generic drug against that first reference-listed drug. So the
definition of dosage form has a great of importance when you\'re
determining pharmaceutical equivalence.

So just a few thoughts on bioequivalence. What we\'re trying to achieve
here through bioequivalence is therapeutic equivalence. We want the
products that are switched for each other to be equivalent when used in
patients, and that\'s equivalent both on the efficacy side and to have
equivalent safety profiles as well. So that\'s really the endpoint that
we\'re all looking for. If one is, for example, either a new formulation
of a currently approved product or a generic drug product that can be
substituted for a reference-listed drug, in the end when those
substitutions or changes are made, through objective measures the
patients and their physicians should not be able to tell the difference
based on therapeutic evaluation between those two products. That\'s the
ideal and what we\'re striving for.

Bioequivalent products, therefore, can be substituted for each other
without any adjustment in dose or additional therapeutic monitoring over
and above what\'s normally done for that type of patient and the most
efficient method of assuring that TE is to assure that the
pharmaceutically equivalent formulations perform in an equivalent
manner.

So one of the important messages that I always try to get across,
because sometimes people get confused, is that bioequivalence testing is
all about the formulation. It\'s a test or comparison of the
formulations as opposed to bioavailability where there are many other
issues that are studied, including drug substance characteristics and
how the absorption characteristics of the drug substance, regardless of
which formulation it\'s in, also play a factor in what you would really
like to know. With bioequivalence and formulation comparisons, it\'s all
about how that formulation performs in making its drug available to the
body.

The regs in 21 C.F.R. 320.24 lay out a number of different ways to
approach the demonstration of bioequivalence. As you see, for this
topic, for these topical products, choice number one ‑‑ and these are
thought to be in order of preference for most products, especially
systemic products ‑‑ may not be suitable for this particular set of
products. Usually we are faced with doing topical dermatologic products
with number two or number three, either a pharmacodynamic comparison or
a clinical comparison, to try and determine equivalence and therapeutic
equivalence.

I show this. This is one of my favorite slides. I show it even when I\'m
not talking about bioequivalence sometimes because I like it so much.
But it really displays to me what this whole process is. I drew it out
for myself so that I can understand and explain what is the object in
bioequivalence.

We have a series of processes. The first slide I\'ll show you is the
oral product, and then I\'ll change this a little bit to show you two
versions or two ways of thinking about the topical products.

So the oral one is something that we, I think, all know something about.
It starts out with a dosage form that\'s manufactured or designed by
formulation scientists to have certain characteristics. Usually in this
particular case, the drug is in solid form, and it makes a transition
during this process into a solution which is then absorbed through the
GI tract. It ends up going through the gut wall, ending up in the blood.
Eventually the blood carries it to the site of activity and you have a
therapeutic effect, whether it\'s a desirable or undesirable one. So
this is a schematic. It\'s not a kinetic description. It\'s simply the
simplistic set of events that happen.

And where do we want to intervene and take measurements to determine
what actually happens with the dosage form? Because that\'s really what
we\'re trying to do. Most of the things that I put in green and blue are
characteristics that are determined by the patient or the study subject.

The thing that we have control of and are trying to test as formulation
scientists are how this dosage form performs when you give it to
patients or to study subjects. Unfortunately, we\'re not able to look
directly at those events and measure them, so we have to measure them at
some downstream event, normally in the blood or in some cases at a
pharmacodynamic or therapeutic effect.

The important points to make from this is normally blood is best for
systemic purposes because it has some very nice properties. It\'s not
extremely variable. It\'s not too many steps in my little scheme away
from the event we\'re really trying to get some insight about. It either
has a linear ‑‑ I drew a little plot down here to show you. The response
is on the y axis that we\'re actually measuring, which are the plasma
concentrations, and the dose is on the x axis. So it usually either has
a very nice linear relationship of response to dose, or at worst, it has
some kind of nonlinear relationship, which actually kind of goes up in
the air on this plot, which in effect makes the test even more sensitive
than it normally would if it were linear. So based on those properties,
it\'s a very nice way to actually determine equivalence and
bioavailability.

On the other hand, if we move towards further down the stream to perhaps
what we\'re all really interested in, which is the therapeutic effect,
when we do clinical or pharmacodynamic effects, they don\'t quite have
as nice or well-behaved properties. They generally have a sigmoidal
dose-response curve. So if you have a clinical response or a
pharmacodynamic response that you\'re measuring and you want to relate
it to dose or, in the case of bioequivalence, slightly different doses
from different formulations, you\'re faced with this relationship which,
in effect, has three sections. The section on other side, here at the
bottom and here at the top, are plateaus.

So if you\'re testing your two formulations in this dosage range, you
get very little, if any, sensitivity between those doses. So if I were
up here on the plateau, giving much more drug than I really need to get
my maximal effect, I could have perhaps a 100 times different dose and I
wouldn\'t be able to tell the difference. The same thing with the bottom
plateau where I\'m just not giving enough to get an effect. To get a
good bioequivalence comparison you really need to be at this middle
section, the steep part of the dose-response curve. This is my
representation. They don\'t all look like this. I drew it especially
steep for illustration purposes.

So if you were going to do this type of bioequivalence test, it is
really important that you pick your dose to do the test at the proper
part of this curve so you can get sensitivity to tell the difference
between the two doses from your two different dosage forms. So that goes
in a straight line from beginning to end. No problem.

However, that\'s not exactly the set of sequences that we\'re dealing
with with the skin. We have now a locally acting product. Now, I have
two versions of this slide. The first one is what I would call a
simplistic or naive model because people come all the time and say,
well, for skin products why don\'t you simple measure the blood and do
bioequivalence that way?

On my scheme the dosage form partitions drug into the skin. Then it
diffuses to the site of activity. You get a local therapeutic effect,
and then eventually it diffuses through the skin. It\'s picked up by the
superficial blood supply, and it goes into the systemic circulation.
Most people look and think of it this way and say, well, you know, you
could just measure the blood and infer back. Even though in our previous
scheme the blood acts as an intermediary between what we really want to
know and the event we\'re trying to measure, the blood is later. But
perhaps we could still infer back and it would still be okay.

This is, in a way, a naive view that there\'s only one way through the
skin, that any drug that comes into the skin goes to the site of
activity. It goes past the site of activity, is picked up by the blood.
And we have the same types of characteristics of the data and the same
problems I just discussed.

If you talk to dermatologists, though, or people who are experts in the
skin, one of the critiques of that first scheme is, well, perhaps there
not just one way through the skin. The previous slide looked at the skin
as a homogeneous slab with a homogeneous set of layers with only one
pathway through each one. However, if you look at the skin, there are
holes in the stratum corneum, there are other routes through the skin.

So it might be more accurate from the dermatologist\'s view to say,
well, I have my path 1 which passes to the site of activity, creates a
therapeutic effect and goes to the blood, but I might have another path
which bypasses that site of activity and eventually ends up in the blood
without ever being reflected at the site of activity. Or it might
contribute some variable amount to that site of activity in an indirect
way.

Now, this all of a sudden says that if I measure blood, I have some
confounding sources of drug which may not relate back to drug
bioavailability to the site of activity.

So what we\'re left with with this type of scheme is that we really need
to measure a PD or a clinical response to determine what\'s really
happening, how that drug from that product is available to the site of
activity within the skin.

Of course, I mentioned the particular problems of doing pharmacodynamic
or clinical response is that we don\'t have a nice, well-behaved
straight line of response versus dose. We now have some technical issues
to work out to make sure that that\'s a sensitive test.

I have two examples of things that have been tried in this area. The
first I think has been talked about. Dr. Franz talked about it a little,
and I mentioned it before. I guess the success story, or the current
success story, is the adaption of the blanching effect for a biotest to
do topical corticosteroids, to do equivalence of topical
corticosteroids. That procedure has come a long way in the last 30 years
that it has been developed. Now I\'d like to think Dr. Stoughton, who is
no longer with us, would be very happy at how his method has developed
because he certainly had a significant part in it and tested some of the
early developments.

But it involves assessment of the blanching effect. It used to be a
human observer would simply come in and say, that\'s a 1 or that\'s a 2.
And now we have an instrument that actually reads the color change in
the skin. We have some very, very sophisticated pharmacodynamic modeling
methodology that really does do a great job in trying to quantitate this
effect.

As far as the subject washout that we\'ve been talking about, we\'ve
really not seen much more than 30 or 35 percent. Part of the procedure
is a subject enrichment type of approach where you\'re really looking
for responders. If you included all comers, all of us respond to this
blanching effect differently. Some people barely respond at all. Some
blanche at even the slightest amount of corticosteroid. But what you
want are people who have a reasonable response rate over the dosage
range that you\'re actually looking for so that they can tell you, based
on their own response, whether there\'s a difference between the
products or not.

So you tend to want to select out those people who don\'t have any
sensitivity, who either over-respond or perhaps have little, if any,
response. And we all differ. Everyone this room probably has a slightly
different blanching response. So it\'s very important to make sure that
you have the right responders in the study, and often that means that 30
or 40 percent of the people you evaluate don\'t make the cut as far as
being a responder.

One of the problems with dermatologics that, again, most people don\'t
realize is, with an oral drug, if you want to increase the dose you give
to somebody, you just take two tablets or three tablets or four tablets
for most products, and you get four times the dose. With a topical
product, on a given area of skin, you simply don\'t have much control
over the dose. You can stack up thicker and thicker amounts, but that
really isn\'t giving a higher dose per unit time for that area. So your
ability to control the dose and to get yourself into that ideal area of
that curve is very limited.

With this topical corticosteroids method, they did it in a very clever
way in that they controlled that dose by simply putting the product on
the skin for varying lengths of time. So they put it on and they get it
right off again, and that\'s the way they control the exposure to the
skin. It\'s a little bit of an artificial way of controlling things, but
it works very nicely as far as getting this blanching response over time
and over dose.

Part of it is also to establish through testing what the dose-effect
relationship is and that we are indeed studying it on the sensitive part
of the curve. That\'s part of the procedure and part of the subject
evaluation as well. So all of the problems that I mentioned in doing
this type of study and this type of approach ‑‑ there\'s an attempt to
actually do those properly in type of test.

The other one, which has also been mentioned, is termed
dermatopharmacokinetics. So far it\'s been less of a success than of the
other one. We\'ve spent a lot of time and a lot of good research on
this. In that case, the product is placed on the skin and removed at
several time points. The stratum corneum, the upper layer of skin, that
was exposed to the drug is removed by skin stripping with tape, and then
that tape is analyzed to look at how the drug diffuses through the
layers of stratum corneum. So more or less a kinetic approach is used
for the uptake into the stratum corneum which is the outer barrier layer
of the skin.

The problems or the critiques, I guess, of this technique were that, to
go back to my multiple pathways, that this really just studied only one
pathway, the stratum corneum itself. It did not really give much insight
into other ways of getting into the skin or into the site of activity
like hair follicles or sweat glands.

There was limited, if any, relation to drug availability at the site of
activity. So we didn\'t really have a great correlation to the actual
drug appearance at the site of activity.

And last but not least, there were sometimes different results from
different labs. If you were in previous advisory committees, Dr. Franz
was one of the labs that studied this. He\'s a well-known expert in this
area. We had some trouble with different labs coming up with very
different results.

So for those reasons, which obviously if different labs, all done by
well-renowned experts, come up with different results, it really does
shake your confidence quite a bit in any method. So as Ajaz said,
although this method is not completely dead, there are still a lot of
things that would have to be worked out before this would become a
successful method.

So to recap, the special considerations for BE of topical products.

The semi-solid topical products are complex dosage forms in contrast to
what they used to think many, many years ago.

The skin is not a homogenous slab of tissue, and there are several
pathways that the drug can get into the site of activity and into the
body, some of which are stratum corneum, sweat glands, and hair
follicles.

Plasma concentrations, at least in our current way of understanding, are
not suitable for looking at drug availability at the site of activity.
Now, if we really developed this idea and got a lot more data, our ideas
may change in this area, but at our current level of understanding, it
just doesn\'t really look like a good approach.

Surrogate measures, like some of the ones we\'ve discussed, may not
always adequately reflect the availability at the site of activity, and
one of the burdens of validating a surrogate measure is you really have
to show that it does provide information that is clinically relevant as
far as equivalence.

And the clinical PD measures that we currently use, for the most part,
successfully tend to have some problems of their own. There\'s a high
degree of variability, which means that you have to study quite a few
patients. They may, depending on how you do them and the dose issues
that I\'ve referred to, lack sensitivity unless they\'re done correctly.
With all these products, you have a limited ability to control dose.

DR. KIBBE: Does anybody have any questions? Leon.

DR. SHARGEL: Well, Dale, you\'ve heard me before about the use of plasma
concentrations.

DR. CONNER: Yes. Leon is one of the people who always comes in with the
plasma concentration idea.

DR. SHARGEL: But I didn\'t quite finish.

DR. CONNER: Okay.

DR. SHARGEL: We go at this periodically for those who are not aware.

When you\'re doing plasma concentrations, even for so-called
systemically absorbed drugs, it\'s really a surrogate marker for the
site of action in most cases. So if the drug is working in the brain or
in tissues or such, we\'re assuming that the blood somehow is related to
the site of action as well as safety, and it\'s also a measurement of
exposure.

It seems to me that there\'s a paucity of data in most cases in doing
locally acting products. There\'s a discouragement of looking at blood
levels, and the general thing is, well, it may not mean anything.

Is there data available ‑‑ and I\'m beginning to see a little bit here
and there by hearsay, not too much published yet ‑‑ that would say if I
did topical or locally acting products, would I see equivalent blood
levels? And the next question, of course, you could say, well, even if
you see equivalent blood levels, it doesn\'t mean anything because it\'s
not the site of action.

DR. CONNER: Well, I don\'t think scientifically you can ever dismiss
anything, especially when you have no data that supports its dismissal.
What I\'m saying is at our current level of understanding and assuming
that the concepts and the conceptual framework that I\'ve laid out is
correct or accurate, it doesn\'t look good with our current level of
data and understanding.

That does not mean that data wouldn\'t be welcomed to support that. Any
method that we\'ve talked about or any that we have yet to talk about
needs to be explored. Even if they don\'t always look good from our own
current conceptual understanding, that doesn\'t mean that data wouldn\'t
convince us that our conceptual understanding is in correct. So I think
that all of these things that we conceive of, including things that
we\'ve studied in the past and perhaps dismissed, still more data can
change our minds. Good scientific work is always welcome in any of these
areas. I specifically want to say that I\'m not discouraging any work in
any of the areas of any ideas that have been brought up.

DR. KIBBE: Marvin?

DR. MEYER: Dale, are there good examples of where you have a secondary
pathway for absorption and that is able to bypass the site of local
activity? Or is that a hypothetical?

DR. CONNER: Well, I\'m trying to think of ‑‑ usually they\'ve been in in
vitro testing like diffusion cells and things where you can actually
show stain going down into hair follicles. In some of the cases, the
actual site of activity for some products is the hair follicle. So
you\'re actually trying to get drug down in there. Drug that might go
through the stratum corneum and perhaps bypass that is drug that\'s lost
in the therapeutic effect. So a lot of it is theoretical, but I\'m not
currently aware of any that actually says that, although that doesn\'t
mean it does not exist.

DR. KIBBE: Ajaz?

DR. HUSSAIN: Just to sort of add to what Dale suggested, I think when
you have a solution dosage form where it\'s homogeneous, I think those
are not a concern. But as soon as you have a suspension type of a
product, then the particle size ranges, if there are differences, then I
think that brings up a concern in the sense localization of particles in
certain appendages may result in either an adverse effect at that site
or it could be used as a targeting to that site. Dale is right. These
are at least to a large degree in theory, but there is some evidence
that the particle size differences might be linked to certain
differences in therapeutic or safety concerns.

DR. WILKIN: I can just add that I think it was Hans Schaeffer\'s group
demonstrated for one of the topical synthetic retinoids that particle
size in a certain range would increase delivery into the follicle, not
necessarily the hair follicle, but the sebaceous follicle. So it was a
good target for acne. That\'s where acne develops.

DR. CONNER: I think Hans has also done some animal work where he used
rats and through giving them light burns and allowing them to recover,
the hair follicles are eliminated and the skin comes back with its
normal properties except now there are none of the holes there that were
caused by the hair and did some work on showing the differences in
permeation between having hair follicles and yet the same skin on the
same animal not having those hair follicles and looking at permeation.
So he\'s done some work on that as well simply trying to look for how
much of an effect, having these holes in has on permeation through the
skin, of various drugs with various properties.

DR. KIBBE: Shall we go on? If you think of something else interesting
that you want to ask Dale, he\'ll be around at least for an hour or so.

Continuing our inverse order, we now have Dr. Hixon.

DR. HIXON: Hi. I\'m Dena Hixon. I\'m the Associate Director of Medical
Affairs for the Office of Generic Drugs, and I want to talk about the
clinical endpoint bioequivalence studies that we currently do for these
locally acting drug products. I also want to just briefly discuss the
difference between establishing bioequivalence for these products and
the systemic drugs and then some of the specific challenges that we get
into with dermatology drug products.

As Dale has mentioned, systemic drugs are delivered to the blood stream
specifically for distribution to sites of action in the body.
Bioequivalence of these systemic drug products can be determined with PK
studies. The PK studies are relatively short studies. They show
relatively little variability in their results, and they require
relatively small numbers of subjects. Those are also less expensive
studies than the clinical endpoint studies.

Locally acting drugs are those that are not intended to be absorbed into
the bloodstream and instead are delivered directly to the sites of
action in the body. Of course, with derm products which we\'re talking
about, this involves sites of action in the skin, but we also have
locally acting drug products with sites of action in the mouth, eyes,
ears, nose, vagina, urinary tract, or gastrointestinal tract.

This list of locally acting drugs is certainly not intended to be an
exclusive list, but the types of products that we deal with include
topical acne creams, lotions, or gels; topical or vaginal antifungal
creams or suppositories; oral lozenges for oral candidiasis; ophthalmic
drops for conjunctivitis or other eye conditions; otic drops for
external otitis; oral vancomycin for pseudomembranous colitis; nasal
sprays for rhinitis; and orally inhaled products for asthma.

Now, certainly for these locally acting drugs, as has previously been
stated, the pharmacokinetic studies are not adequate to establish
bioequivalence, and for some products, such as the topical steroids, we
have pharmacodynamic studies, the skin blanching studies that were
discussed. But most of our locally acting drugs require clinical
endpoint studies to demonstrate bioequivalence. And combination products
such as a cream that\'s a combination of a steroid and an antifungal,
for instance, would require both a clinical endpoint study and a
pharmacodynamic study.

Our typical clinical endpoint study is a three-arm comparative trial of
the generic versus the reference-listed drug versus placebo. These
studies involve treatment of an approved indication for the
reference-listed drug in a patient population and according to the
approved labeled dosing. The trial design and endpoints are very similar
to those in the NDA.

I would point out here that the purpose of clinical endpoint studies is
certainly not to establish safety and efficacy de novo, but to show that
the effectiveness of the generic product is equivalent to the
effectiveness of the listed drug.

Both the generic and the reference-listed drug must be statistically
superior to placebo with a p value less than .05 in order to assure that
that study is sensitive enough to show the difference between products
if there, in fact, is a difference. Basically the bioequivalence
requirements are the same as those established for other types of BE
studies, the PK studies specifically.

We have a number of challenges that we face with these clinical endpoint
studies.

First of all, the clinical endpoints are significantly more variable
than pharmacokinetic endpoints but still must meet the same established
bioequivalence limits. This may require several hundred patients in a
bioequivalence study with clinical endpoints.

The study duration may be up to several weeks depending upon the
approved labeling of the reference product, and these studies, of
course, are very expensive to conduct because of the number of patients
involved and the duration of the study.

They also may present more safety concerns than PK studies partly
because they involve a patient population and partly just because of the
duration of exposure.

Some of our challenges are the unknown inter-subject variability within
the reference population. We don\'t know if the difference from one
group of subjects to another in patients just using the reference
population might actually be more different than the bioequivalence
requirements that we have established to show that the generic drug is
bioequivalent to the reference drug.

There also is some difficulty in achieving consistency between studies.
We don\'t have any one required study design that sponsors need to
follow. In fact, we encourage sponsors to come to us with their proposed
protocols for these clinical endpoint studies, but there\'s no
requirement that they all be exactly the same. So, there are some
challenges in looking at study designs to make sure that the population
that is being studied is appropriate and that the endpoints that are
chosen are appropriate. Those are probably the most significant
components of the study design that need to be evaluated and need to be
acceptable.

Of course, some products require multiple studies. Those combination
products that have both a topical steroid and a topical antifungal are
one example. Another example outside of the dermatology field is the
nasal sprays because they require pharmacokinetic studies in addition to
the clinical endpoint studies and some very stringent in vitro studies.

As far as some of our challenges that are specific to dermatology drug
products, we have, of course, the antifungals and other anti-infectives.
We found a significant number of patients in these trials needing to be
excluded from the evaluable population because their baseline cultures
were negative. This, of course, has nothing to do with the performance
of either the reference or the test drug product, but simply because of
the sensitivity of the cultures. In some cases, with antifungals, it\'s
almost half of the study population that has had to be excluded because
of the baseline cultures being negative.

Also, the possibly of false negative cultures has led to some
difficulties in interpreting the outcome of these studies because with
the difficulties in growing fungi and other agents in culture media, it
is quite possible to get a significant number of false negative culture
results. That makes for more difficulties and more expensive studies.

With acne products, we have to deal with multiple endpoints in that acne
involves treatment of not only inflammatory lesions, but also
non-inflammatory lesions. So we end up with lesion counts that are
inflammatory lesion counts, non-inflammatory lesion counts, and total
lesion counts, and there are often some disagreements between FDA and
sponsors in terms of what\'s important: the percent reduction from
baseline, the actual reduction in lesion counts from baseline, or the
actual lesion counts at baseline and at end of study.

In addition, there are some differences of opinion regarding the
duration of studies for these acne products.

We find that sponsors are well aware of the fact that they need a large
number of patients to show bioequivalence, and it appears as though
sometimes the patients who are included are not severely enough affected
to show a considerable effect size, and that really seems to result in
some decrease in the ability to demonstrate bioequivalence with these
products.

Also with topical acyclovir, which is indicated for treatment of
recurrent genital herpes or limited life-threatening mucocutaneous
herpes in an immunocompromised population, we\'ve had a lot of
difficulty in going back and forth with sponsors and our discussions
with the primary new drug review division about what is the appropriate
study population and the appropriate endpoint for studying these
products because herpes can be a very different disease when you\'re
talking about genital herpes versus orofacial herpes and when you\'re
talking about recurrent versus primary disease. It\'s important that we
use a population for which the reference drug is effective in order to
establish bioequivalence between the two formulations.

That basically is the end of my presentation. Does anybody have any
specific questions on clinical endpoint studies?

DR. KIBBE: Does anybody have questions? Marvin?

DR. MEYER: Are there any ethical issues associated with a study
population that\'s known to respond to, let\'s say, the innovator
product, and then you\'re going to ask that patient to either take a
product that may be as good ‑‑ hopefully is but may not be ‑‑ or a
placebo which you know isn\'t going to work? So two-thirds of your
patients are being switched to something that may not work as well.

DR. HIXON: Thanks for bringing that up. I did mean to add that in cases
where a placebo treatment is not considered safe or ethical, that a
placebo is not required. But in a case where a placebo is not being
used, it is very important that we have some justification for why that
study is sensitive enough to show a difference between populations. In
some cases, that\'s very straightforward. If it\'s a case where the
placebo effect is very little, there\'s very little chance of
spontaneous resolution, and the treatment effect is extensive, say, 70,
80, 90 percent, then we can feel more secure that we are, in fact,
looking at a study that can show the difference between treatment
products.

I haven\'t seen a situation where we\'ve had ethical concerns about
doing the trials without placebo, just comparing a test to a reference
product. In cases where it\'s a life-threatening indication or a serious
illness, we certainly have escape clauses where a patient who doesn\'t
respond within a reasonable amount of time is excluded as a treatment
failure and assigned to treatment with a known effective drug product.

I guess that goes back to what some of our endpoint problems are too
because we find that the easiest endpoints to evaluate are those where
we can have a clear-cut success or failure and look at the percentage of
success or failure in the two different populations. But it can get a
little more complicated when we\'re dealing with continuous variables as
endpoints, and of course, sometimes we have to do that.

DR. KIBBE: Lem?

DR. MOYE: If I understood you right, it sounds like there are
fundamental problems with guidelines for the clinical studies here. Not
only has consensus been reached on endpoints ‑‑ and you tell me if I\'m
wrong, but if I understood you right, there\'s been no consensus on
effect size, confidence interval width, sample size, duration of
follow-up. Is that correct?

DR. HIXON: I need to clarify here that we\'re not determining efficacy
of the products so much as we\'re looking at bioequivalence of products.
So these are comparative trials and we\'re looking at the difference in
outcome between the test and the reference. The actual effectiveness of
the product has already been demonstrated in the NDA for the approved
product. So we have the same bioequivalence limits for clinical endpoint
studies that we have for pharmacokinetic studies in that studies with
dichotomous endpoints need to fall within plus or minus 20 percent as
far as the difference between test and reference, and studies with
variable endpoints fall between 80 percent and 125 percent.

Now, as far as our difference in study designs, certainly it\'s probably
not appropriate for us to come up with one design and say that every
generic company that comes in has to follow that design to the T because
what they really need to do is study that product for the approved
indication and show that their drug is as effective as the reference
product.

So, for instance, going back to the acyclovir situation, acyclovir could
be studied either in immunocompromised patients with primary genital
herpes or in the orofacial herpes in immunocompromised patients. As long
as the effectiveness of one of those indications is the same between
test and reference, we can assume that the effectiveness for the other
indication would be the same. And there\'s no reason for us to require
one of those study designs over the other.

DR. MOYE: Well, I\'m glad to hear that because I wasn\'t suggesting
that.

The tenor of your talk to me was that you were having problems with
guidelines. In fact, even though ‑‑ and I would agree with you ‑‑ there
should not be one and only one clinical trial design that\'s
appropriate, there certainly is a family of designs that are appropriate
and other designs that are inappropriate.

Let me ask you specifically. Are you comfortable with the family of
designs that are appropriate?

DR. HIXON: Yes. In fact, for any given product, we look back at what has
been done in the NDA trials and also what has previously been accepted
for ANDAs.

I guess I\'m not making myself clear in discussing that these are
challenges. The challenges are when the very first generic drug comes
in. It takes a tremendous amount of time and effort to go back over all
of the information that has been provided to the agency about the NDA,
what kinds of studies were done in the NDA, what is the labeling for the
approved product, and what is the sponsor proposing to do. We generally
consult with the new drug review divisions and come to a joint decision
about whether the proposed study design is appropriate or not.

On the other hand, many sponsors come in and say what kind of a study do
we have to do. They don\'t even go to the effort of proposing a specific
study. Of course, it takes a tremendous amount of time and effort to
come up with proposals for what they need to do.

DR. MOYE: Well, that to me doesn\'t sound like a problem that is
specific and unique to your group. That to me sounds like a problem
that\'s endemic across the FDA regardless of which class of drugs we\'re
looking at. You have sponsors who come in who have a design that they
think is appropriate and the FDA may disagree and have some discussion
there, and a half hour later, here comes a sponsor who has an open heart
and is willing to do whatever the FDA says they want done.

DR. HIXON: The issue here is that we\'re talking about generic
formulations and the requirement for generic formulations is not to
establish safety and efficacy de novo. The requirement is to establish
bioequivalence, and it puts a tremendous burden on sponsors, as well as
the FDA, to design and conduct bioequivalence trials with clinical
endpoints that may require hundreds of patients and may require weeks of
treatment of those patients in order to get their answer as to whether
their drug is bioequivalent to the comparator. I think our whole purpose
is to talk about what other options are there to try to get around such
complicated study designs and such a complicated way to show
bioequivalence.

DR. MOYE: But still keep rigorous methodology and be able to draw
conclusions that are confirmatory.

DR. HIXON: Right.

DR. MOYE: Thank you.

DR. KIBBE: Ajaz?

DR. HUSSAIN: Just to sort of build on what Dena was discussing and the
sort of challenges I see with respect to the clinical approach to
bioequivalence is essentially one is the goal post she talked about. We
are applying a goal post of 80 to 125 that was essentially derived from
the PK based comparative evaluation. Now, as we look at a clinical
endpoint based comparison, I think one logical question is, is that an
appropriate goal post that we need to consider?

At the same time, should that goal post be one-sided or two-sided?
Because in cases where you have a product which shows just marginally
higher efficacy in the confidence interval criteria, is there really a
difference between the two products?

I think we run into a number of these questions on a daily basis because
now you\'re comparing the equivalence of the two products, and what
should the goal post be would be one way of looking at some the
challenges that we face.

DR. KIBBE: Anybody else? Leon?

DR. SHARGEL: Actually, Ajaz, you raised the point that I was going to
ask. Admittedly a clinical bioequivalence study ‑‑ in a sense you are
looking at a clinical endpoint, though, on these. And because the
variation is a lot greater than PK, and you\'re still sticking currently
to the 90 percent confidence intervals of 80 to 125 percent, should that
be reexamined in lieu of the variance?

And also an ethical issue. You\'re exposing a lot more subjects in order
to try to meet that 80 to 125 as you\'re trying to do that. And is that
appropriate to do that?

DR. HIXON: We certainly are open to the idea that that may not
necessarily be the most appropriate goal posts for bioequivalence, but
we need data on innovator products and just what the degree of
variability is in the innovator product in order to think about changing
those goal posts.

DR. SHARGEL: Do you generally have a dose response on the innovator
products that you can refer back to and give you some idea of that?

DR. HIXON: I\'m not sure that dose response is what we need. I think we
need more of the type of data that takes groups of patients who are
randomized groups, both taking either the same lot or different lots or
different batches of the RLD to see just what the variation is between
those patients and whether we\'re actually requiring a tighter
bioequivalence limit between the test and reference than what you would
see within groups of patients taking only the reference product.

DR. SHARGEL: The reason why I ask in the Emax model you\'re at the dose
which you can\'t see differences in the bioequivalence. This has been
brought up to the agency before. It\'s nice to know whether we would be
able to predict differences in products.

DR. HIXON: An interesting point. I don\'t know that I have a comment to
that.

DR. KIBBE: Anyone else, if we have a comment to that? Wolfgang.

DR. SADEE: If you have a bioequivalence confidence interval and you set
that, well, it depends on the product. On some products it\'s important.
If the method is such that you cannot measure it, because there\'s too
much variability, then I would suggest that delivery through the skin is
inappropriate. So there may be components that just absolutely have to
be dosed exactly, and if you can\'t do it accurately, then it\'s
inappropriate. On the other hand, there are others were it doesn\'t
matter that much and then you can relax the criteria. But it should
really be the drug and the conditions treated that should predicate as
to what you determine there, and it should be flexible.

DR. KIBBE: An FDA comment?

DR. WILKIN: I was responding to the query on whether we have dose
ranging information for innovator topicals, and I can tell you that we
always encourage it. We think it is an important piece of drug
development to find a dose ‑‑ I mean, it\'s both efficacy and safety we
think of in the dose ranging. It turns out that that\'s often one of the
more anemic portions of the NDA when it\'s submitted.

If you look at the ICH document ‑‑ I think it\'s E4 ‑‑ on dose ranging,
there\'s a major portion of that document that\'s devoted to phase IV
dose ranging. So that tells you even on systemic products we\'re not
always getting dose ranging information in the NDA.

So I\'m not sure if OGD came over and went to our document room and
started looking for this whether you would find it very often,
especially on the older products.

I think that was one of the pieces that Dr. Hixon was talking about with
Dr. Moye. One of our difficulties is the endpoints change over time. For
a product to become a generic, that means it\'s off patent. So it may
have been 10 years ago and it may have been the thinking of the FDA and
the industry at that time what were the appropriate endpoints. Those
endpoints may be different for the same indication or the indication may
have been divided into two indications today. Things happen.

And so I think part of this extra work that she\'s describing her group
does is to try to make a fair linkage with what was actually done for
the innovator in the past and still bring it up to the things that
you\'re talking about, making sure that it\'s a good quality trial
design that can be defended in 2003.

DR. KIBBE: Jurgen, we\'ll let you be last. How is that? And then we\'ll
get on to the next speaker.

DR. VENITZ: It sounds good to me.

One question, one comment. The question is in your clinical
bioequivalence studies, are they a parallel group design or crossover
studies?

DR. HIXON: They\'re parallel designs.

DR. VENITZ: So you\'re using basically the 80 to 125 which is based on
crossover PK studies as your target, your goal post, for parallel group
designs. That\'s the reason why you end up with those large numbers.

So my general comment then ‑‑ and I anticipated that you were going to
say it\'s a parallel group design ‑‑ just like Wolfgang said, I don\'t
think there\'s any magic between the 80 and 125 even in the PK sense.
I\'ve been involved in those things for close to 20 years. I still
haven\'t figured out who came up with 80 to 125.

(Laughter.)

DR. VENITZ: Now we\'re applying it in a level above the PK. Now we are
applying it in the clinical endpoint studies. So I don\'t see any
rationale why you shouldn\'t be able to flexibility use criteria that
are more appropriate based on the endpoint that you have and what\'s
considered to be clinical significance.

In addition, we have the argument that the 80 to 125 is definitely
inappropriate because it really assumes that you have a crossover
design. So you\'re looking at the variability within each subject not
between two parallel tracks. So I think you\'ve got a lot of good
reasons to say that 80 to 125 percent is way too strict.

DR. KIBBE: You\'ll still be around and we\'ll be able to get additional
questions, if we need to.

We need to get our last speaker up here. I\'m determined to get done on
time or else I\'ll be late. Go, Jon.

(Laughter.)

DR. WILKIN: I\'ll build on some of the topics that Dr. Conner and Dr.
Hixon presented and describe this from a dermatologist\'s point of view.

As you know ‑‑ and many of you may actually have family members or
people that you know who have chronic skin diseases like atopic
dermatitis and psoriasis, and you know that dermatologic disease can be
chronic, costly, and it\'s very common. So there\'s a huge market out
there. Topical products are the mainstay for most of these dermatoses,
and getting good quality generic topical products would lower the costs
and increase the availability to patients. So I think everyone can agree
that facilitating good quality generics to the market is what everyone
would really like to see.

Dr. Conner and Dr. Hixon have described some of the historical
difficulties. 320.24(b)(4) says that for most topicals, we look at
clinical endpoints.

They mentioned the clinical reports of lesser effectiveness. One of the
additional things that comes out in the derm literature and you hear at
the meetings is that a dermatologist can squirt the innovator in one
hand and the generic in another hand, and they have a very different
feel.

And then there\'s just ill will, bad press. I think there are a few
examples that are probably valid examples, but then you see all these
ads out there. They show a Starbuck\'s coffee and they say, would you
drink generic coffee? Well, then why use generic topicals? And there\'s
not much substance to them, but it\'s out there and I think it does
affect how clinicians think of generic products.

Now, traditionally the focus has been limited to what everyone calls Q1
and Q2. Qualitative sameness. It\'s the same list of ingredients.
Quantitative sameness, those ingredients are there in the same amounts
as found in the innovator. But a noticeable difference in vehicle
properties can also come from Q3, if you will, structural or the phasic
differences. It depends on how one actually manufactures a product that
leads to the structural attributes.

And I\'ll give you sort of a very homespun example. I call it the law of
Duncan Hines and Wilkin.

(Laughter.)

DR. WILKIN: If you ever go to the grocery store, you\'ll see, competing
with Betty Crocker, these boxes of cake mix, chocolate cake mix. My wife
is a cGMP cook. I\'m not. So I had to learn that when it says you
preheat the oven, that means you turn it on and you leave it on but you
don\'t put the cake in until that red light goes out because that means
it\'s actually heated up. So I have solved all of the wrong ways that
you actually do this, although now I think I can do it right.

The point is that over time I have managed, using identical ingredients,
using Q1 and Q2, identical starting properties, to end up with
incredibly different structural creations.

(Laughter.)

DR. WILKIN: But one positive thing I can add is that even when it\'s
really thin and really hard, if you soak it in milk for 30 minutes ‑‑

(Laughter.)

DR. WILKIN: So the point is that there are important vehicle attributes
that also come from the physical structure of these topical dermatologic
products and just simply knowing Q1 and Q2 really does not predict all
of those important properties.

And there\'s another complication. 314.94(a)(9)(v) in the Code of
Federal Regulations tells us that even Q1 and Q2 are not essential for
topical products. It\'s got those nice adverbs that Dr. Meyer pointed
out earlier that FDA uses all the time. It says, generally they\'re the
same. But it allows for the setting where they\'re not as long as the
sponsor can demonstrate there\'s no change in safety.

So the manufacturing process is blinded to the generic manufacturer.
That\'s proprietary information.

Even when Q1 and Q2 are identical, the product can still have different
physical properties, depending on how it\'s been cooked. One example
that Gordon Flynn gave years ago, when speaking to the FDA group, was
using the same recipe, in the evening someone turned the cooling coil
system off so that what was in the vat cooled to room temperature very
slowly, and they got a very different type of product than when they
used the cooling coils to chill it down rapidly. One was fairly viscous
and the other was non-viscous. Just one simple step in manufacturing can
make a substantial difference.

So thinking of all these different degrees of freedom, it\'s helpful to
think about those when we\'re thinking how do we actually facilitate the
approval of generic topical dermatologic products. The question is, what
do we need to know? What is the simplest information structure that has
everything in there that\'s necessary but also sufficient and nothing in
excess that would get us to generic approval? I call that regulatory
elegance, that process of thinking through that.

I use the term \"elegance\" in the sense of the organic chemists who
talk about the synthesis of an organic chemical in the fewest steps with
the highest yield. That same term \"elegance\" is celebrated by the
mathematicians if you have a mathematical proof that starts out with the
fewest assumptions and it takes the fewest steps, and you can end up
proving the thesis.

And I think we should embrace that at FDA, but I think it\'s the larger
regulatory community. It\'s industry and it\'s academics and the
professional societies. We need to look for regulatory elegance. It\'s
the identification of the simplest information structure required for a
regulatory decision. It wouldn\'t be the absence of regulatory creep
that we\'re always accused of, adding new things that we want to know.
And in truth, we\'re all information junkies, everyone. I mean, we\'d
like to know more about things, but we have to focus on what do we
really need to know because information costs money. So it\'s the
opposite of regulatory creep. It\'s trying to find ways to thin out the
parts that are not needed.

So demands focus on what I call the 3 R\'s of regulatory elegance. The
first would be reduction. It\'s the number or extensiveness of required
tests. Refinement would be the optimization of test design for max
information at minimum cost. And replacement, which I think, if we\'re
going to go for honors in approving these generic topicals, is where we
really need to go. We need to replace. We need substitution of a
simpler, cheaper, more informative test.

So how I see this in the paradigm of getting to the new generic topical
dermatologic drugs, in the short term it\'s reduction and refinement.
And Dr. Hixon described the acne studies and how difficult they are. I
submit that you can actually look at a smaller number of subjects, bring
them in at 9 weeks, 10 weeks, 11 weeks, 12 weeks, average their
inflammatory lesion counts, average their non-inflammatory lesion counts
over those different visits, and what you\'ll do is you\'ll take out
intra-subject variability, and by doing so, you can dramatically
increase the power. So I think there are ways that you can maximize
information from a small number of subjects that can be more economical,
and we\'ve offered to participate with OGD and think of ways for the
more common products.

The long term is replacement, and it\'s development of alternative
methods. I intended an \"s\" on the word \"methods\" because I don\'t
think in the end there\'s going to be one method for all of the topical
dermatologic classes. Antifungals. We may find at the end of the day
that there is a role even for DPK, although I know it\'s been through
the committee in the past and gotten a negative response. On the other
hand, there are some other dermatologic conditions that clearly I think
would need something other than DPK. So I think it\'s multiple methods
that we need to think about, and we need to develop ways of guaranteeing
the Q3 sameness, at least to the extent that the innovators have that
consistent from batch to batch, from lot to lot.

Thinking about alternative methods, I\'ll not spend a lot of time on
this because I recognize this group knows about the FDA and USP
performance parameters for new methods. I think they\'re very nicely
discussed in the USP chapter, but I did want to have them in my slides.

Next, in addition to the performance parameters of a new methodology, is
the concept of validation of utility. I think the very first step is
intra-laboratory reproducibility. Can the same investigator on different
days run the same experiment and get the same result?

And then the second stage is can someone else in another lab take the
written instructions for conducting this method and get the same kind of
result.

And then the third step, which is really the highest hurdle, is
demonstration of replaceability. That\'s replacing what we\'re currently
doing.

Now, I would define as the controlled artifact stage that point in the
development of an alternative method where there has been substantiation
of those performance parameters that are outlined in the USP chapter
that reproducibility has been found intra-laboratory and also between
laboratories, and it\'s awaiting that final essential step of can it
really truly replace what we\'re currently using which is the clinical
trial or the corticosteroid multi-point, Stoughton-McKenzie blanching.
That would be another one that could be considered.

So there is a group of folks that will be coming in over the next, I
suppose, three or four years, and they\'ll be presenting their models.
And I call them the Guild of Alternative Method Enthusiasts and
Researchers. Incidentally, that contracts into GAMERs, if you want to
look at the acronym.

(Laughter.)

DR. WILKIN: When they come in, they\'re often sold on the method at the
controlled artifact stage. Although Dr. Franz mentioned he\'s going to
make money regardless of which method is chosen, many of them are going
to make more money if their method is chosen. I think that\'s been
somewhat offputting in the past, maybe a little bit more to the
Dermatologic Advisory Committee than this committee.

But let me just encourage some tolerance here. This is the group that is
actually going to do the brainstorming, the hard work in the lab, take
some risks. If we\'re ever going to have an alternative method, we\'re
going to learn it from this particular group. So the GAMERs ultimately
are our friends.

But when they bring it to that controlled artifact stage, we still need
the evidence of replaceability, and that\'s where this committee and
others need to play a role in what I think of as the peer review
process.

So the final step of validation is peer reviewed demonstration of
replaceability. There are a lot more things that I could have put under
here, but I have limited it to just two.

The first one is does this new alternative method actually make
biological sense. I think one of the things that we had a good
discussion with back for DPK is it was going to be used for skin
diseases where there was no healthy stratum corneum. In fact, many of
the diseases had no remnants of stratum corneum, and yet the method
relied on looking at healthy stratum corneum. So I think those are the
kinds of things that you have to think about the first principles. Do
they actually fit?

And then the second part is can the method reproducibly demonstrate
equivalence between the innovator, the reference-listed drug, and a
clinically demonstrated bioequivalent product so that we have the
clinical data comparing the two.

Superiority or inferiority to a clinically demonstrated superior or
inferior bioinequivalent product in an adequate, well-controlled,
blinded comparative study with at least three arms. And I think it would
be nice to know that it is sensitive enough to pick up differences, but
it\'s also specific. It would be a horrible method if we accepted
something that would actually pick up differences from one lot to the
next for the innovator. I mean, we want to have something that doesn\'t
narrow the goal posts too much but finds it to be just right. So, very
helpful for the future.

I\'ll stop at that point.

DR. KIBBE: Who wants the first crack?

DR. MOYE: I have a question.

DR. KIBBE: Yes, please.

DR. MOYE: The GAMERs\' laboratory is a wet lab or a dry lab? Are they
actually doing experiments on physical entities, composite entities?

The reason I ask that is because there is new emphasis on the use of
computing as a tool to carry out these kinds of research experiments to
the point that there is a new institute at NIH which is involved in
doing essentially simulation at the basic science level. Now, we might
have thought that that was foolhardy 15 years ago, and it still may be.
It\'s yet to be proven, but there have been important advances in
computing technology that suggest that, to some degree, we can move from
a 100 percent reliance on bench biology to a reliance on a hybrid system
that has some real biology components and some mathematical components.

In the era where clinical trials now can cost hundreds of millions of
dollars and there is now a trial being carried out that cost a quarter
of a billion dollars, we are rapidly going to run out of resources to
carry these things out. And in looking at alternatives, computing as a
hybrid is turning into a very admissible approach.

I was wondering what your comments were on that.

DR. WILKIN: Well, I completely agree with you. I think we have to be
very open to computer-based systems, incredibly information-rich ways of
looking at things.

But I can describe, I think, what most laboratories are doing today.

And it just occurred to me I\'m probably going to regret the GAMER
thing. We\'ll have to think of another name for them.

(Laughter.)

DR. WILKIN: But those folks who are the creative minds that get it to
the controlled artifact stage.

Generally what they look at is they look at different concentrations in
the same vehicle. We have to remember that ultimately the alternative
methodology that we\'re thinking about, the ultimate utility is to let
us know that you have two products with the same active at the same
concentration and different vehicles. So it\'s really to tell us that
the vehicles are the same, but most of the work that\'s done at that
very early stage is looking at different concentrations in the same
vehicle, which I think you would want to know anyway. You\'d want to
know that it\'s linear, it has a range that it\'s going to be able to
detect, those sorts of things.

So it\'s, I would say, 99 percent wet in that context, but it\'s not so
much looking at an innovator and a generic. It\'s really looking often
at homemade material that is of different concentrations. I think it\'s
a good first step, though, really.

DR. MOYE: If I could follow up. I would encourage you, if you could
contact your compatriots over at NIH, because they\'re grappling with
this same issue, and they apparently have some very good mathematical
formulations for underlying biologic processes, components of which may
be useful for your group.

DR. WILKIN: Well, maybe they also have some money that can help fund
some of these studies too.

(Laughter.)

DR. WILKIN: I see Ajaz writing all this down.

DR. KIBBE: Anyone else?

(No response.)

DR. KIBBE: Just a couple of chairman comments. I think Vince Lombardi
would be happy to embrace the GAMERs. He believed that those who got
into the fight, whether they won or lost, were better than those who
stood on the sidelines and applauded. I appreciate the innovators and
the entrepreneurs who try to come up with solutions. I recognize us and
the agency need to take a careful look at those proposed solutions to
see which ones really are useful for the public good. But I certainly do
appreciate them coming to the plate.

I want to thank everybody for their presentations. We will have a short
break. During the short break, there is a ‑‑

DR. HUSSAIN: I was going to wrap up.

DR. KIBBE: Good.

DR. HUSSAIN: Well, actually I had dinner with Art last night, and his
advice was, don\'t make any slides. And I\'m following his advice. No
slides. Right?

DR. KIBBE: This is an auspicious occasion where Ajaz has rigorously
followed my advice.

(Laughter.)

DR. HUSSAIN: I think what we wanted to do was to present to you the
challenges we face and then what are the next steps. In terms of the
next steps, what we would like to do is to come back to this committee
or the Biopharmaceutics Subcommittee to present a research plan and a
research plan for moving forward with respect to methods for topical
bioequivalence. The approach that we have in our mind right now is a
tool box approach. One size or one method does not fit all situations.

So to take an example of the dermatopharmacokinetic, the skin stripping,
studies, I think we have an opportunity for improving the protocol and
applying it to a class of products where I think it would be very
appropriate, for example, antifungals where the site of action is itself
the stratum corneum. So I think what we would like to do is bring a
classification system forward where I think we can use a body of
evidence of different methods and different techniques to address a
number of issues. Not all the products would be addressed this way, but
I think it would be a starting point.

In addition, I think we\'d like to open the discussion on the goal
posts. How should we approach the goal posts with respect to topical
products? And I think I totally agree with Dr. Sadee that I think it has
to be based on the underlying risks, underlying mechanisms, and so
forth. So how do we approach, how do we come up with a decision tree to
say how do we decide what is an appropriate goal post for this? Should
it be a one-sided, noninferiority sort of thing? Or what should it be?
So that would be another aspect.

Dr. Wilkin essentially has added Q3. Let me go back and explain that
concept. For example, if we have a gel ‑‑ and now, I\'m defining a gel
as a solution with a 3D structure because of the hydrocolloids. A
generic has to be Q1 and Q2. What does that mean? It has to have the
same ingredients, water, the same hydrocolloids, and Q2, quantitatively
it has to be the same, that is, within plus/minus 5 percent of the
excipient.

Now, with that, if you\'re really looking at it, in my mind from a
pharmaceutics perspective, bioequivalence is self-evident. You really
have to go back and think of that. But that\'s not defendable right now,
and I think we have to defend that position. What is the driving force
there? It\'s the thermodynamic activity. And if you start arguing from
there, I think the Q3 perspective Dr. Wilkin has brought on the table is
the physics of that dosage form, and I think that has been missing. He
created a wonderful opportunity for PAT in this area.

But I think with respect to understanding the rheological behavior and
the physico-chemical attributes of the dosage form, I think we can
provide a high degree of evidence to say that bioequivalence will be
self-evident. And we would like to start proposing a research program to
address, in a step-by-step manner, how do we get there.

We are fortunate. I think we do have funding available for this research
program now, and I think we will not only think about different clinical
studies but at the same time manufacture products ourselves. And I think
we did not have that opportunity before. I think we will have that
opportunity.

So I would like to stop here. I\'ll let you know that when we come back
this is the research plan that we\'ll outline for you and seek your
input in discussions on how do we take the next steps.

DR. KIBBE: We stand adjourned for 15 minutes until 3:30.

(Recess.)

DR. KIBBE: Our break is over.

We\'re down to our last two presenters for the day. I want to
congratulate everyone on their energy and their involvement. I am really
looking forward to these last two presenters getting us started on
another pathway for the agency. My colleague Marv is dragging along
behind, but we won\'t wait for him.

Nancy Sager.

MS. SAGER: Good afternoon. I know it\'s been a long day, so I hope this
will keep your interest until dinnertime or close to it.

I\'m presenting the introduction to comparability protocols, and I will
be followed by Dr. Stephen Moore who will give you some more details on
the protocols. I\'m going to cover what is a comparability protocol, why
has FDA issued a guidance on comparability protocols, what are the
benefits of using a comparability protocol, and what is the purpose in
making the advisory committee aware of this guidance. Then I\'m going to
turn it over to Dr. Moore who will follow with some more details on
comparability protocols.

A comparability protocol is specified in our guidance as a well-defined,
detailed, written plan for assessing the effect of specific postapproval
chemistry, manufacturing, and controls changes on the identity,
strength, quality, purity, and potency of a specific drug product. This
plan is supposed to be designed for future anticipated chemistry
changes. And the protocol would be able to be submitted as part of the
original NDA or ANDA application or it could be submitted as a
postapproval supplement in a prior approval supplement and request
approval at that time.

Why did we develop a guidance? The concept for comparability protocols
was first introduced for biotechnology products in 1997 as part of the
regulation writing process. It was a way of introducing a procedure for
companies to come in and provide plan for these changes in complex
materials. We had gotten a lot of requests from industry to extend this
concept to all drugs, the synthesized chemicals and other things other
than biotech products, and we had gotten requests for additional
guidance, what should be in a comparability protocol. So we in the
Center for Drugs just published a guidance that details what we would
expect in a comparability protocol, the basic elements, and Steve is
going to talk about that in more detail.

Why did we develop it? As I said, we wanted to provide recommendations
to applicants on developing a protocol to assess the effect and give
more specific details.

Again, this is one part of a bigger plan in developing risk-based
approaches to the CMC process at FDA. A well-planned protocol can
provide FDA with sufficient information for FDA to determine whether the
potential for an adverse effect on the product can be adequately
evaluated and whether that risk is lowered so an applicant could report
their change in a lower reporting category, which I\'m going to talk
about in a little bit more detail in a couple of slides.

One of the questions that we often get is why do we have to wait for FDA
approval. We\'ve done the studies. The studies turned out good. Why
can\'t we just implement the change without FDA approval? One of the
reasons we ask for FDA approval on the most complex chemistry changes is
that we need to assure that the right studies were done and that the
study results were interpreted in a way that we would draw the same
conclusion from the same results.

Another aspect of the comparability protocol is it augments the Scale-Up
and Post-Approval Changes, the SUPAC guidance and the Changes to an
Approved NDA and ANDA Guidance. For those who aren\'t familiar with
these two guidances, Changes to an Approved NDA and ANDA Guidance is a
general guidance that specifies reporting categories for certain
postapproval chemistry changes. The SUPAC guidances are dosage
form-specific. We have a SUPAC Immediate Release Solid Oral Dosage Form,
Modified Release Solid Oral Dosage Form, and a Nonsterile Semi-solids
SUPAC Guidance. These actually are very detailed guidances recommending
for specific changes what data should be provided in the reporting
categories. By specifying these up front, it allows for ‑‑ a lower
reporting category to FDA means they can implement the change faster
than if they didn\'t follow this guidance. If a change wasn\'t done
under one of these guidances.

It\'s also consistent with and complementary to FDA initiatives on
pharmaceutical cGMPs for the 21st century, which I think you\'re going
to hear about more tomorrow. I think it\'s on tomorrow\'s agenda. This
will help promote continual process and product improvement and
innovation by facilitating CMC changes.

As I said, I was going to talk a little bit more about the reporting
categories or reporting mechanisms for postapproval chemistry changes.
One of the benefits of using a comparability protocol approach is that
if an up-front protocol is agreed upon, the applicant can propose a
lower reporting category than FDA would recommend if there was not a
protocol that had been reviewed by FDA, if they just came in on their
own without consulting with the agency ahead of time.

The statute specifies four different reporting categories: prior
approval supplement, which means you can\'t implement and sell your
product using this chemistry change, whether it\'s a manufacturing,
chemistry, or control change, until FDA approves the supplement.

Changes being effected in 30 days and changes being effected supplement
still require FDA approval, but these both allow a company to distribute
product at their own risk prior to FDA approval. If it\'s a CBE-30
supplement, it requires the applicant to wait 30 days after they submit
the supplement to FDA before they can distribute the product. The
changes being effected supplement means as soon as it\'s submitted to
the FDA, they can start distributing the product.

An annual report is our lowest reporting category, and these changes
that are annual reportable can be implemented immediately, and they\'re
reported once a year in a cumulative report to us.

So, first of all, a company can get a reduced reporting category with an
approved comparability protocol.

The second important benefit is that an FDA request for additional
information to support a change is less likely when the change is
covered under an approved protocol. We\'ve reviewed the protocol. We\'ve
reviewed the tests and procedures you\'re going to be using. There
should not be a need for additional information requests unless there\'s
some change in the science or technology that maybe warrants additional
questions.

The third benefit is that it could allow an applicant to implement CMC
changes and place product in distribution sooner than without the use of
a comparability protocol. If the reporting category is lowered, then
they may not have to wait for FDA approval before they can start
distributing their drug.

It also allows companies to design their own SUPAC based on their
knowledge of and experience with a product. We have three SUPAC
guidances that we mentioned before. It\'s unlikely that we\'re going to
write many more SUPAC guidances dosage form-specific because there are
so many kinds of dosage forms, and they take a lot of resources to
write. There are only a handful of products maybe in a certain dosage
form class. The immediate release and modified release solid oral dosage
forms probably covers about 50 percent of our applications in the FDA,
but for things like liposomes and these more unusual dosage forms, it\'s
unlikely that we\'ll ever write a SUPAC to cover a very narrow class of
dosage forms. So this allows a company to kind of design their own SUPAC
based on their development information, their knowledge and experience
with the product.

It also allows again the reduced reporting category for a product that
isn\'t covered by a SUPAC guidance or another type of guidance.

So what\'s the advisory committee\'s role? At this time, CDER has little
experience with comparability protocols. We\'ve accepted protocols in
the past typically for packaging changes, changing resins and things
like that. As Steve will explain, these comparability protocols are
almost wide open for use as far as what kind of changes might be covered
under them. There are a few limitations that Steve will describe, but
they\'re really expanding into areas that we have not reviewed protocols
in in the past. So we may at some point ask the advisory committee to
comment on issues raised by the public comments on the guidance or
perhaps even specific proposals for a comparability protocol, asking for
their scientific opinions on the aspects of a protocol.

Just to wrap up my part of the presentation, as I said, the guidance
published on February 25th and it\'s open for public comment until June
25th. I\'ve included the web address for those who are interested in
getting a copy.

Now I\'ll turn it over to Dr. Moore.

DR. MOORE: Thank you. Nancy has given a very nice overview of the
comparability protocols.

I want to speak now on more of the specifics associated with actually
using the comparability protocol and the content of some of the guidance
that\'s out there as a draft on the web.

Some of the specifics I want to cover: When might a comparability
protocol be useful for a CMC change, what are the various
product-specific and process-specific considerations one might have I
think to do a comparability protocol? When might a comparability
protocol be inappropriate? And what are the basic elements of a
comparability protocol, and what are some of the specific issues to be
considered for comparability protocols for various types of CMC changes?

First of all, to address when might a comparability protocol be useful
for a CMC change. As Nancy mentioned, comparability protocols are
applicable to a wide variety of CMC changes. There are some exceptions
as she also mentioned. I\'ll go into that just a little bit later. The
comparability protocols can apply to many of the kinds of changes that
are described in our SUPAC and BACPAC and changes to approved NDA and
ANDA guidances, as Nancy was mentioning.

For example, comparability protocols are not meant to supersede those
guidances, but really to add on to those guidances. One example is that
you could take a SUPAC level 2 change for an immediate release tablet
such as scale-up, and that would be a CBE type of change, or the
category for reporting that change will be CBE. One could use a
comparability protocol and provide the specifics for that particular
drug and that particular process and be able to get a reduction of that
particular change down to an annual report.

Comparability protocols could also cover many types of changes that are
not described in any of our guidances. For example, the BACPAC guidance
specifically excludes changes to products that are derived from natural
sources or products that are derived from biotechnology, and the
guidance we\'re talking about here would, in fact, cover changes you
could make to products that are derived from biological sources, for
example, conjugated estrogens; for example, synthetic peptides. One
might think that this might even be the most usefulness of the
comparability protocol to fill in all those areas where we really don\'t
have any guidance.

Continuing some more with some ideas about when a protocol might be
useful. They\'re useful for single or it could be multiple changes.
Hopefully those changes would be related changes, the same kind of
changes that one might submit in an ordinary CMC supplement, and each of
these changes being discrete and specific. This is not a deviation from
the way we are reviewing supplements in general now.

Changes of a repetitive nature might be particularly useful because one
would have a single document where you have the comparability protocol
described, and then maybe multiple supplements could come from that in
actually implementing changes of a like nature.

But the bottom line is you really have to specify up front what are
going to be the tests and the studies and the analytical procedures, and
most importantly, the acceptance criteria for demonstrating that the CMC
changes will not adversely affect the product, that is, with respect to
its identity, its strength, its quality, purity, and potency, as these
factors may relate to the safety and efficacy.

Turning to some of the product-specific and process-specific
considerations one might go through in determining whether a
comparability protocol would be useful or would be applicable, consider
first the complexity of the product structure. That is associated with
really the ability that we would have with the analytical techniques
that we have to characterize the chemical, physical, microbiological,
and biological properties of the product. For example, routine testing
in the simplest case and inclusion of stability studies. But in other
cases where the change becomes more complex and there may be a
propensity of the change to actually change the structure of the drug
itself, then one would need to go in to do characterization studies too.

Also a consideration to the degree to which the differences in the
product structure and the physical properties can be detected by these
analytical techniques.

And the degree of product heterogeneity, if present. This doesn\'t apply
that much to purified, synthetic chemicals, but it would apply in many
cases to products that are derived or purified from biological sources.

And what is the effect on safety of changes in the impurities? Changing
the process may generate different impurities or the purification
process change may exclude impurities or cause other impurities to flow
through into the final product. So that\'s a consideration one has to
make on safety.

Some more product and process considerations are the robustness of the
product, the ability of the product to remain unaffected by the changes,
and the rigorousness of the manufacturing process. That means the
ability of the process controls to ensure that the product remains
unaffected by changes.

Of course, one is expected to meet the approved drug substance and/or
drug product specifications after a change. This is not much different
than the way we view supplemental changes without a comparability
protocol being involved.

And of course, one has to have in place appropriate and sensitive
analytical procedures. These have to be established and validated or
qualified in the case of characterization type analytical procedures in
order to detect the effect of the change on the product.

I now turn to when a comparability protocol might be inappropriate or
not useful. Comparability protocols have to be specific and discrete, so
protocols that are very broad and for nonspecific plans are not going to
be very useful.

A change whose adverse effect on the product that cannot be definitively
evaluated by the prespecified tests, studies, analytical procedures, and
acceptance criteria also would not be very appropriate.

One has to think about this with respect to the particular product and
the process that you\'re dealing with. Will the analytical procedures be
able to detect changes? The question comes into play if the product is
very complex. Like some of the natural products that we have are
extremely complex. One then questions whether even the high-powered
analytical techniques that we have that are state-of-the-art would be
able to detect the changes.

Any change that warrants a submission of a new IND or a new original
application also. I might also mention changes that a comparability
protocol would try to substitute for information that\'s required to be
in an NDA for our review and approval would not be appropriate.

A change that requires efficacy, safety, that being either clinical or
nonclinical data, or PK/PD data to evaluate the effect of the change.
For example, certain formulation changes, clinical or nonclinical
studies to qualify new impurities. What we\'re talking about in this
last bullet is changes that go beyond just a CMC-only type of change.
They start to become multi-disciplinary changes where medical staff,
pharm-tox staff are involved, for example.

Other examples that may be difficult to justify. Changes in the drug
substance or drug product specifications. There are exceptions here such
as adding a test or changing the specification to accommodate a change
in the analytical method itself without actually causing a decrease in
the product quality.

A change in the qualitative or quantitative formulation of the drug
product, and there are exceptions here. If you have the data and are
able to have a sufficient knowledge and understanding of the product,
you may be able to make changes in the excipients which may be under a
level 3 change in SUPAC, et cetera, and be able to reduce that to a
lower reporting category.

A change in the type of delivery system, of course, is going to be
difficult because it\'s so complex, the interplay between the device and
delivery of the drug.

Also, changes from plant, animal, or multicellular source to a different
source are the kinds of things that are very complex changes likely to
ensue new impurities which then will have to be qualified under
pharm-tox.

Some additional examples that may be difficult to justify under a
comparability protocol. A change in the synthesis from naturally sourced
material to synthesis chemically or vice versa.

For synthetic peptides, a change from solid phase to liquid phase.

And lastly, a bullet about changes in manufacturing site if you change
the manufacturing site, a facility, or the area when a prior approval
supplement is normally recommended because a cGMP inspection is
warranted. This is going to be difficult to do under a comparability
protocol because we would not be able to certify or agree that we would
be able to do cGMP inspection that would be required and get that done
before a minimum of 30 days, which is what a CBE-30 has as a cutoff, to
the point which you can then distribute the product.

Going now on to some of the basic elements that are in a comparability
protocol. This is what would be in a protocol that you would submit. It
would include, of course, a description of the planned changes, the
specific tests and studies and the analytical procedures and the
acceptance criteria, which is part of the definition of a comparability
protocol, and then what data would be reported or included with the
comparability protocol. Sometimes there may be some developmental data
which will help in showing that the protocol is in fact feasible and
workable and up front there be data to support that.

And then the proposed reporting category, which is a matter of agreement
between the industry and the FDA what is going to be the final reporting
category for the follow-up supplement that will verify that the change
actually had not an adverse effect on the product.

And an action which would be taken if equivalence is not demonstrated.
This is a contingency. There are going to be some changes in which
things are not going to turn out as planned. So it would be good to have
a contingency in the protocol what\'s going to happen at that point.

And then also a commitment that the protocol will be updated if it
becomes out of date.

Specific issues to be considered when you have different types of
changes. For example, here we\'re talking about for manufacturing
process changes. Some of the considerations one might go into are effect
on the physical characteristics, the effect on impurity profile,
downstream process, and effect on the in-process controls.

For analytical procedural changes, effect on the characteristics used in
the methods validation.

For changes to manufacturing equipment, some examples there, effect on
the manufacturing process of changing that equipment.

And manufacturing facilities, for example, as I just mentioned, the cGMP
inspection status and scope of the changes involved because in many
cases when you\'re changing the facility, you\'re also in many cases
scaling up and changing the process to make it more efficient. So the
scope of some of these kind of changes is very large when you\'re
talking about going to a new manufacturing facility.

Also container closure systems. This is one of the examples where
repetitive changes may be particularly useful, changing the container
closure systems based on a comparability protocol.

And then there\'s process analytical technology, of course. Right now we
haven\'t got guidance out, so we recommend early dialogue with the
agency, and that\'s highly encouraged.

Then there are changes of a comparability protocol that\'s covered under
a DMF. The issue there is the cross-reference to the comparability
protocol.

I\'ll just summarize what Nancy and I have both said. Comparability
protocols allow FDA and industry to agree early on about the specified
CMC changes, the plan for assessing the effect of these changes, and the
reporting category which will be made.

We hope that they will have savings in time of implementation of the
changes and savings in resources for many of the changes.

This is a new regulatory mechanism. Therefore, industry and FDA are
experiencing a learning curve. We have had quite a few comparability
protocols that we\'ve reviewed for biotechnology products, but we have
very little experience for chemical drug products.

This guidance is hoped to stimulate interest in the use of comparability
protocols.

DR. KIBBE: Questions, anyone? Efraim?

DR. SHEK: Just maybe a point of clarification. Reading the proposal,
it\'s being envisioned that the sponsor will submit it at the time of
filing an application or it can be submitted at any time?

DR. MOORE: A comparability protocol can be submitted in a new NDA or it
can be submitted as a supplement postapproval.

DR. SHEK: Okay. So if it\'s being submitted as a supplement, that would
be the time, right, for approval of their comparability? That would be
like any other supplement?

DR. MOORE: The supplement has, yes, four months prior approval due date.

DR. SHEK: And just the efficiency we are going to gain ‑‑ I would assume
both the agency as well as the industry ‑‑ is just moving things faster.
But if I understand what is proposed, it always will be moved only one
level. Oh, it can be moved more than one level?

DR. MOORE: It can be moved more than one level under certain
circumstances, yes.

DR. SHEK: Okay. So whenever there is the agreement on the comparability
protocol, it depends on the protocol whether it moves one level or two
levels. Because the way I read it, I thought it says you can move only
one level.

DR. MOORE: That\'s the usual type of reduction, is one level.

DR. SHEK: Thanks.

DR. KIBBE: We\'ve got two here. Go ahead.

DR. KORCZYNSKI: I think there\'s a major opportunity in industry for a
process comparability protocol. What I\'m referring to is that major
expense, labor-intensive activities center around validation, and
prospective validation is validating your process at the beginning. But
then every 12 to 14 months after that, you go through periodic
validation. In many cases, certain processes have become so well
established that it\'s becoming basically rote. The information is
collected. You still go through that labor-intensive activity.

I haven\'t thought through it all yet, but there seems to be a tie-in of
PAT and comparability protocols in the sense that why couldn\'t one use
concurrent validation, utilizing all the good data that one collects
throughout that 12 or 14 months, and then by some defined protocol, say
I\'ve re-validated the system by this new collection of data or new
analysis of data?

I think that really needs to be thought about and addressed. I think
it\'s a real opportunity because the industry in many cases is going
forward just rotely collecting this data at major expense when they
could utilize some other systems. I think it\'s an opportunity to tie
PAT into that approach.

DR. KIBBE: Gary and then Ajaz.

DR. HOLLENBECK: Well, that\'s perfect. I think, first of all, I speak in
favor of this idea. I think it\'s a wonderful idea to put in the hands
of industry this kind prospective approach to making your own SUPAC, one
of Ajaz\'s favorite things I think. So in a sense I think that is very
encouraging.

I just wondering how the agency is going to handle this. Who reviews
comparability protocols?

DR. MOORE: The comparability protocols are reviewed by the chemistry
reviewers and is signed off by the chemistry team leader, the same as
supplements are being reviewed as of now.

DR. HOLLENBECK: So you wouldn\'t anticipate simultaneously submitting a
comparability protocol with your application would slow it down?

DR. MOORE: It is conceivable that it could if it caused us, of course,
more effort in meeting the user fee goal date for the application, if
there are one or more comparability protocols in the application. But if
they are valid protocols and appropriate protocols, I see no reason why
we couldn\'t ‑‑

DR. HOLLENBECK: I know that developing SUPACs has been a major
challenge, but you could be actually transferring that to a gazillion
SUPACs, you know, one submitted with every product. One would hope that
a process like, if good comparability protocols came out of it, that
they could sort of rise to the top and become generally applied.

DR. HUSSAIN: There are sort of two parts. I think the proposal for
looking at concurrent validation, process validation, and then the
linking I think is an excellent topic for a Manufacturing Subcommittee
discussion, and maybe we\'ll capture that and take that to that
discussion. I think it\'s an excellent point.

The comparability protocol I think doesn\'t come close to what I think
the make your own SUPAC concept essentially is. And I think if I go back
to that concept, essentially that is the University of Maryland-FDA
research model where you have a set of designed experiments which could
be part of the development. See, I think we don\'t use all the know-how
and knowledge that is present in the development reports. I think at
some point we\'ll have to bring this committee to discuss how best to
use all the available knowledge, and then say, here, for this particular
formulation, a .2 percent or .3 percent magnesium stearate change had no
impact, we have this data, but SUPAC says it\'s a level 2 change or a
level 3 change. Why don\'t we sort of use the available data to make
those decisions? I think that\'s the next step in the discussion that we
want to get into.

But I think going back to the question raised on will it slow down the
new drug review process when it gets submitted, I don\'t think that
should happen at all. In fact, I think that would be counter-productive
to the whole situation.

So in many cases, I think these might be after approval. These protocols
will be submitted in the postapproval sort of scenario.

MS. SAGER: Just to follow up on that issue, I don\'t think Steve was
aware of this but I was at a meeting where we talked about comparability
protocols and how to handle them as they were coming in. As Steve
indicated, they would be assigned to the normal reviewer and team
leader, but we are anticipating that we would have some kind of
scientific rounds and discussions on the initial protocols coming in,
trying to get consistency and standards.

There\'s certainly a good opportunity for kind of a lessons-learned
exchange. We could blind protocols or we could issue some kind of
guidance document on what are the problems we\'ve seen in comparability
protocols, trying to exchange information in a way that we can get
everybody on the same level playing field so they\'re not trying to do a
comparability protocol and having the same deficiencies that we\'ve seen
in previous ones.

So we\'re both on a learning curve, and I think we\'re going to have to
take this opportunity to find a way of communicating. If we get good
protocols in, there is always a possibly of, like I say, communicating
some kind of lessons learned in a document.

DR. KIBBE: Dr. Bloom?

DR. BLOOM: Yes. Maybe it\'s out of ignorance. Does the industry select
which kind of supplement they should submit?

DR. MOORE: I\'m sorry.

DR. BLOOM: I mean, can they submit like a PAS or a CBE-30?

DR. MOORE: The comparability protocol itself is a prior approval
supplement in all cases unless it\'s also part of a new drug
application.

DR. HOLLENBECK: I\'ll ask his question. We\'ll see if it\'s the same
question. I think his question is who determines what filing has to be
made by the industry? How would you decide one is supposed to come in as
a CBE or a CBE-30 or an annual report?

DR. MOORE: You\'re talking about the follow-up submission at this point.

DR. HOLLENBECK: Yes.

DR. MOORE: If the comparability protocol itself is prior approval, then
one has to make a proposal what is going to be the category for
reporting that change. We have a lot of guidances out there. We have the
SUPAC, the BACPAC, and the Changes to an Approved NDA and ANDA that talk
about general types of changes and what are appropriate categories for
those changes. That\'s a good starting point for gathering the
information on what is the change by itself without a comparability
protocol. That\'s the starting point. Is it a prior approval change? And
then with a comparability protocol, you might be able to reduce it to a
change that\'s being effected or a CBE-30 change.

DR. BLOOM: Let me ask another one. What if the company submits a CBE-30
and then the agency can change that?

DR. MOORE: Well, the category for reporting will be a part of the
approval of the comparability protocol itself. So that will be agreed
upon at the time that the comparability protocol is approved.

DR. KIBBE: Anybody else?

DR. SHARGEL: I think the idea is very good and allows a lot more
flexibility for the industry.

I\'m curious. Is this a requirement for those manufacturers who are
making more or less standard dosage forms? By that I mean usually solid
oral dosage forms. And there are SUPAC guidances out there. Would there
be a need to put in a comparability protocol if they followed the SUPAC
at this point?

DR. MOORE: Well, comparability protocols are not required. They\'re an
option. So if you can plan far enough ahead what specifically is going
to be change ‑‑ and you have to factor in there\'s going to be a
four-month review of the protocol itself, and then that\'s followed by
gathering the data and then submitting the follow-up submission. If that
time line is shorter on the basis of a comparability protocol, then it
could be useful for that kind of change. But it\'s not required by any
means.

DR. KIBBE: Anyone else?

DR. HUSSAIN: If I understood the question correctly, if I have a SUPAC
change right now, which may be a prior approval supplement, I could use
a comparability protocol to downgrade that reporting requirement.

DR. SHARGEL: That\'s one possibly or just report it as a SUPAC, since
I\'ve already done that. That was a question.

DR. KIBBE: Anyone else? Wrap-ups, thoughts? Kathleen, do you have
something? Business announcements?

MS. REEDY: A couple of things. Those purple folders in front of you are
for both days, so please leave them at the table in front of your seat,
and they will be there for you in the morning, along with the slides for
tomorrow.

The second thing is please leave your name tag with the colored stripe
across the top, and it will be at the table by the x-ray machine in the
morning and you will not have to pick up an orange one, but you will
pick up the one with your name on it. And that will be your badge to
stay here.

DR. KIBBE: Seeing no one else looking to discuss real business, I guess
we are adjourned.

(Whereupon, at 4:07 p.m., the committee was recessed, to reconvene at
8:30 a.m., Thursday, March 13, 2003.)