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DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE

Volume II

Wednesday, May 4, 2005

8:30 a.m.

CDER Advisory Committee Conference Room

5630 Fishers Lane

Rockville, Maryland

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PARTICIPANTS

Charles Cooney, Ph.D., Chair

Hilda F. Scharen, M.S., Executive Secretary

MEMBERS

Patrick P. DeLuca, Ph.D.

Paul H. Fackler, Ph.D., Industry Representative

Michael S. Korczynski, Ph.D.

Gerald P. Migliaccio (Industry Representative)

Kenneth R. Morris, Ph.D.

Marc Swadener, Ed.D. (Consumer Representative)

Cynthia R.D. Selassie, Ph.D.

Nozer Singpurwalla, Ph.D.

SPECIAL GOVERNMENT EMPLOYEES

Carol Gloff, Ph.D.

Arthur Kibbe, Ph.D.

Thomas P. Layloff, Jr., Ph.D.

Marvin C. Meyer, Ph.D.

FDA

Gary Buehler, R.Ph.

Kathleen A. Clouse, Ph.D.

Jerry Collins, Ph.D.

Ajaz Hussain, Ph.D.

Robert Lionberger, Ph.D.

Robert O\'Neill, Ph.D.

Keith O. Webber, Ph.D.

Helen Winkle

Lawrence Yu, Ph.D.

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C O N T E N T S

PAGE

Call to Order

Charles Cooney, Ph.D. 5

Conflict of Interest Statement

Hilda Scharen, M.S. 5

Parametric Tolerance Interval Test for Dose

Content Uniformity

Current Update on the Working Group

Robert O\'Neill, Ph.D. 8

Quality-by-Design and Pharmaceutical Equivalence

Topic Introduction

Ajaz Hussain, Ph.D. 10

Using Product Development Information to

Extend Biopharmaceutics Classification

System-based Biowaivers

Ajaz Hussain, Ph.D. 30

Using Product Development Information to Address

the Challenge of Highly Variable Drugs

Lawrence Yu, Ph.D. 79

Using Product Development Information to Support

Establishing Therapeutic Equivalence of

Topical Products

Robert Lionberger, Ph.D. 140

Summary of Plan

Ajaz Hussain, Ph.D. 169

Committee Discussion and Recommendations 192

Criteria for Establishing a Working Group for

Review and Assessment of OPS Research Programs

CBER Peer Review Process for

Researchers/Reviewers

Kathleen A. Clouse, Ph.D. 221

CDER Peer Review Research

Jerry Collins, Ph.D. 243

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C O N T E N T S (Continued)

PAGE

Committee Discussion and Recommendations 258

Conclusion and Summary Remarks

Ajaz Hussain, Ph.D. 273

Helen Winkle 280

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P R O C E E D I N G S

Call to Order

DR. COONEY: I would like to call the

meeting to order this morning.

Conflict of Interest Statement

MS. SCHAREN: Good morning. I am going to

be going through the Conflict of Interest

Statement.

The Food and Drug Administration has

prepared general matters waivers for the following

Special Government Employees: Drs. Charles Cooney,

Patrick DeLuca, Carol Gloff, Arthur Kibbe, Michael

Korczynski, Thomas Layloff, Marvin Meyer, Kenneth

Morris, Nozer Singpurwalla, who are attending

today\'s meeting of the Pharmaceutical Science

Advisory Committee, to:

1\. Receive an update on current

activities of the Parametric Tolerance Interval

Level PTIT Work Group;

2\. Discuss and provide comments on the

general topic of considerations for assessment of

pharmaceutical equivalence and product design;

3\. Discuss criteria for establishing a

working group for review and assessment of Office

of Pharmaceutical Science Research Programs.

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The meeting is being held by the Center

for Drug Evaluation and Research. Unlike issues

before a committee in which a particular product is

discussed, issues of broader applicability, such as

the topic of today\'s meeting, involve many

industrial sponsors and academic institutions.

The committee members have been screened

for their financial interests as they may apply to

the general topic at hand. Because general topics

impact so many institutions, it is not practical to

recite all potential conflicts of interest as they

apply to each member.

FDA acknowledges that there may be

potential conflicts of interest, but because of the

general nature of the discussions before the

committee, these potential conflicts are mitigated.

With respect to FDA\'s invited industry

representative, we would like to disclose that Dr.

Paul Fackler and Dr. Gerald Migliaccio are

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participating in this meeting as non-voting

industry representatives acting on behalf of

regulated industry. Dr. Fackler\'s and Dr.

Migliaccio\'s role on this committee is to represent

industry interests in general, and not any other

one particular company. Dr. Fackler is employed by

Teva Pharmaceuticals, Dr. Migliaccio is employed by

Pfizer.

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.

Thank you.

DR. COONEY: Thank you, Hilda.

I am Charles Cooney, the chairman of the

committee, and will preside over the schedule

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today. We have several topics on the schedule.

The first of these is a current update of the

working group Parametric Tolerance Interval Test

for Dose Content Uniformity by Robert O\'Neill, who

I believe has just come in.

Parametric Tolerance Interval Test for

Dose Content Uniformity

Current Update on the Working Group

DR. O\'NEILL: I am here to just update you

on what we promised you from the last meeting on

October 19th. As you know, there is a technical

working group that has been put together with folks

from FDA and folks from the IPAC group.

We have been working diligently since

then. We thought we would have some

recommendations for you today. We do not, but we

have had approximately eight get-togethers, five

telecons and three face-to-face meetings, the last

of which was about a week, week and a half ago.

What those discussions have been about is

the agreement of the statistical formulations of

the problem. There were a number of discussions

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regarding the coverage probability and symmetry of

coverage, off-target operating characteristic curve

agreements, and things of that nature.

There has been some computer programs that

have been shared back and forth, validation of each

other\'s methods, and I believe there is now

agreement on that aspect of it and that the working

group is turning towards the agreement on where the

operating characteristic curve ought to be placed

and how it might handle certain particular

situations, particularly off-target means.

That is essentially where we are. I think

everyone is optimistic that probably the next time

we report to you, that there will be actual

recommendations for you to respond to, but that is

essentially where we are right now.

I would be willing to take any questions

if you have any.

DR. COONEY: Any comments or questions

from the Committee? If not, thank you very much

and we look forward to the next step.

DR. O\'NEILL: Thank you.

DR. COONEY: We will immediately begin

with the second topic this morning, which is

Quality-by-Design and Pharmaceutical Equivalence,

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to be introduced by Ajaz Hussain.

Quality-by-Design and Pharmaceutical Equivalence

Topic Introduction

DR. HUSSAIN: Good morning. I would like

to introduce to you the Topic No. 2,

Quality-by-Design and Pharmaceutical Equivalence.

We believe we have an opportunity here to explore

and what we plan to do with you is to share some of

our initial thoughts and hopefully, engage the

Advisory Committee in discussion to help us make

sure we are on the right track.

In many ways, the discussions continue

from yesterday where, in essence, we are looking at

opportunities that have been created and

re-examining some of our current policies and to

see how we can realize opportunities to move

towards a desired state.

I would like to put this in the context of

moving from a reactive to a proactive decision

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system for pharmaceutical quality, and recognizing

that this is only a journey, not a destination. I

think in the world of continuous learning and

continuous improvement, really, continuous learning

is your destination in some ways.

I think over the last four years, we have

focused on discussing some of the opportunities in

general, but if I look at some of the reactive

examples on this chart, yesterday, in some way, we

talked about testing to document quality, repeating

deviations in our specification investigations, and

in some ways we will start focusing on the other

aspects of prior approval supplement for process

optimization and continuous improvement, multiple

CMC review cycles, but more importantly, I think,

how can we leverage the opportunity of quality by

design for demonstrating therapeutic equivalence of

generic products.

I think we struggle often in this arena,

and we have struggled and unable to sort of find

ways of approving generic products and the degree

of complexity has increased such as topical

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products and inhalation products, and so forth, so

how can we leverage the pharmaceutical development

information to seek out ways to find mechanisms for

approving complex generic products, I think is a

topic.

I think the proactive examples I think is

quality by design and real time release, right

first time, process optimization and continuous

improvement within the facilities quality system.

But I think in some ways, today, we will

focus on single CMC review cycle, less so, but I

think quality-by- design approach for demonstrating

therapeutic equivalence of generic products would

be a focus.

Therapeutic equivalence. The definition

from the Orange Book is as follows. 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.

Pharmaceutical equivalent products are

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drug products are considered to be pharmaceutical

equivalents if they contain the same active

ingredients, are of the same dosage form, route of

administration, and are identical in strength or

concentration.

Pharmaceutically equivalent drug products

are formulated to contain the same amount of active

ingredient in the same dosage form and to meet the

same or compendial or other applicable standards of

strength, quality, purity, and identity, but they

may differ in characteristics such as shape,

scoring configuration, release mechanisms,

packaging, excipients, expiration time, and within

certain limits, labeling.

So, I think we have certain flexibility

built into the issue of pharmaceutical equivalence,

and one of the desired states is to leverage that

and to say that we want to set specification based

on mechanistic understanding, so if you have a

different mechanism, that is perfectly fine, but

then you set your specification on that.

The discussion yesterday was not to force

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the generic to a particular specification, but

recognize that as part of that.

Today, I think I would like to put this in

the context of risk, uncertainty, and variability,

and I think that framework will help us think more

clearly about the issues.

FDA classifies as therapeutically

equivalent those products: That are approved safe

and effective, so you have to have a reference

product which is safe and effective, and has an

approved pharmaceutical equivalents against the

repetition of that, and are bioequivalent, that

they do not present a known or potential

bioequivalence problem, and they meet an acceptable

in vitro standard, or if they do present such a

known or potential problem, they are shown to meet

an appropriate bioequivalence standard.

In absence of pharmaceutical development

information and quality-by-design aspect, we have

to assume that they present a bioproblem, so we

often go to the second bullet in most cases; are

adequately labeled, and are manufactured in

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compliance to Current Good Manufacturing Practice

regulations.

In a sense, the last four years, our

initiative goals have been to focus on

science-based, risk-based approaches, and there are

certain challenges I think in our articulation of

the problem today.

I want to sort of share with you what the

challenges might be.

Risk-based scientific decisions on

pharmaceutical quality is clearly our goal. Risk

is a combination of the probability of occurrence

of harm and the severity of that harm. The reason

for focusing on that is an aspect that I feel that

we often get entangled in and unable to really

articulate the problem carefully.

Uncertainty with respect to severity of

harm and/or probability of its occurrence and their

modulating factors is that challenge that we face,

what are the critical quality attributes, and what

is an acceptable variability.

I have argued, and I think I will ask the

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Committee to think about this, is my argument sort

of correct, in some ways, in the current decision

system which tends to be reactive, one contributing

factor for the reactive decision system is we

confound uncertainty, variability, and risk.

This is, by nature, how we develop our

products to a large degree. The current paradigm

for product and process development tends to do

this, because our entire effort in new drug

development, for example, is focus on safety and

efficacy of a molecule, but we use a product to

achieve that.

The connection between product quality and

the clinical is generally focused on the molecules

rather than the product. So, that is a part of

this discussion.

Often intrinsic safety and efficacy of a

new molecular entity is confounded with its product

and manufacturing process just by the nature of our

product development and process itself.

We have multifactorial aspects of

pharmaceutical products and manufacturing

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processes, and there is increasing complexity, and

if we can find a way to articulate our problem more

carefully, this may help moving forward more

quickly.

Establishing constraints based on prior

knowledge and limited development experiments that

are done in the development cycle.

What I have argued is there is a need to

entangle or, as I call it, de-convolute

uncertainty, variability, and risk, and then to

achieve truly a scientific integration of these for

quality decisions, how we set specification.

Yesterday, for example, what we proposed

was an assessment of variability, example, begins R

and R. That is an attempt to start characterizing

the variability and attempt to start teasing out

what comes from what.

This may appear to be paradoxical, and it

probably is without the concept of quality by

design, and that sort of links to Dr. Woodcock\'s

paper that we talked about.

Let me illustrate that. When we approve a

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new drug application, we bring assessment of all

the disciplines to bear on a decision which says

the risk to benefit ratio of this proposed drug

product is acceptable when used in accordance to

the label. That is the pivotal decision criteria.

Now, that is based on the pivotal clinical

trials along with the toxicology, and along with

all the studies that go along with that, but the

pivotal clinical trials play the major role there.

What do we use for the pivotal clinical

trials? We use a product, and we often do not have

the opportunity or do not have the intent to gauge

whether the product is modulating the safety and

efficacy of the molecule beyond that of exposure

less the bioavailability.

So, from that aspect, the quality of the

product has to be built in before you get into the

clinical trials, otherwise you confound the

clinical trials with quality problems, and

actually, I will illustrate one example in my

second presentation of that.

As that happens, then, the product is

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approved and then manufacturing is transferred to

production and you have seven production lots, but

that goes to the patient population.

So, you see the disconnect between

pharmaceutical quality or product quality. I am

not talking about the safety and efficacy of a

molecule, I am talking about how a product

modulates that.

So, in many ways, if I look at drug

development program, and here is an illustration of

that, this is actually a real case study. The only

difference I have here is I have a line that made

it more linear. That is the only change I did, but

here is a development program.

The initial formulation was a capsule.

Then, they went to a table, wet granulation tablet,

and each star is a bioequivalent study. So, they

qualified that change from capsule to tablet using

a bioequivalent study. Then, they add a film coat,

then, change the site of manufacture of the drug

substance, and so forth.

You see the changes that were occurring in

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this drug development program, some before clinical

trials were initiated, some during the clinical

trials, site changes, and so forth.

But this company actually qualified, what

they call bridging studies using a bioequivalence

trial. Towards the end of the review time, to

qualify and bridge the clinical trial, pivotal

clinical trial material with the to-be-marketed

product, they opted to use multiple-dose studies of

the traditional thing, and that failed at the last

minute. Actually, it didn\'t fail, it just failed

to establish bioequivalence, so they went back and

actually repeated the study with a larger number of

subjects, but it delayed them.

The point here is all these changes are

being qualified on the basis of their traditional

bioequivalence trial. In new NDAs, we generally

see from 3 to 6 clinical bioequivalence studies,

and that was our number.

Here is a number that was shared with us

by Jack Cook sometime, this is the year 2000, about

7 per approved compound. In a sense, if I look

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at\--this is Gary Buehler\'s slide\--I think in many

ways, the difference between the generic drug

approval and the new drug approval is minimal when

it comes to bioequivalence trial.

In many ways, we use bioequivalence to

gauge information which we don\'t have in the NDA,

but in reality, in some cases, it is simply the two

are comparable. So, from that aspect, I think when

I look at oral products, immediate release

products, and here is my demarcation in an attempt

to sort of categorize what is uncertainty, what is

variability, and what is risk.

The goal of our generic drug approval

process is to approve a generic product. An

approved product is expected to have the same

clinical effect and safety profile when

administered to patients under conditions specified

in the labeling.

Based on the previous slide, I have shown

the characteristics of this decision system is,

one, the first one, the product must be

pharmaceutically equivalent, and here the questions

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are has the applicant demonstrated that it\'s the

same active, identical amount, same dosage form,

route of administration, and so forth, identity,

strength, quality, purity.

So, that is an assessment process of how

good the identical methods are and how good they

have qualified, so it\'s a knowledge-based decision,

there is an uncertainty aspect associated with

that.

Then, we have to define acceptable

variability for that product, and we rely on the

compendial or other standards to do that.

The risk in this case, I am talking about

risk from a clinical perspective, is the prior

knowledge that come from NDA.

Need for bioequivalence assessment for

oral products is that next question, and again the

same words from the Orange Book is if you do not

present a known or potential bioequivalence

problem, acceptable in vitro standard is fine. But

you saw the debate with dissolution, we often don\'t

go there, we often go to a bioequivalence study.

If you go to in vitro standard compendial

dissolution test method, if you go to a

bioequivalence standard, then, the acceptable

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variability is our bioequivalence standard, 90

percent confidence interval for test or reference

ratio for rate and extent of absorption is within

80 to 125 percent.

It has to be adequately labeled and

manufactured in conformance to cGMPs, and in that

case, acceptable variability is what we tolerate in

terms of deviation or specifications, and so forth.

So, that is one way of looking at trying

to partition uncertainty, variability, and risk, so

that we can formulate the right questions.

Clearly, I think the quality-by-design

thinking is intended to focus on the intended use,

and design is about doing things consciously. I

showed this slide to you before.

I think what we would like to consider is

in the context of pre- and post-approval changes,

generic drugs, and even extending that to the

concept of follow-on protein pharmaceuticals, the

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primary goal of a scientific decision framework\--I

am not talking with a regulatory process\--the

decision criteria that we bring, need to understand

the complexity and uncertainty, but the decision

process should be consistent.

I think that is the fundamental basis that

we work under. Furthermore, I think our goal is

also to identify and eliminate unnecessary human

and animal testing for this decision framework,

keeping in mind that most bioequivalent studies are

done in normal healthy subject volunteers, new

drugs and so forth.

If we can avoid exposing normal healthy

subject human volunteers, it is desirable, and that

is part of the regulation. I will share that

regulation with you.

So, Topic 2 today, the premise that we had

in mind was that a quality-by-design approach via

pharmaceutical development information can

potentially provide an excellent means to address a

number of challenges previously discussed at ACPS

meetings without complete or satisfactory

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resolution, for example, bioequivalence of highly

variable drugs, bio-in-equivalence criteria,

pharmaceutical and therapeutic equipment of locally

acting drug products, such as topical products.

Today, Lawrence will bring his thoughts to

you, and these are our preliminary thoughts, and I

think we just wanted to put our preliminary

thoughts on the table to engage you and engage the

community to help us think about this, so that as

we spend our time thinking about this, we already

have some feedback and we are also on the right

track.

Rob Lionberger will come back. He

presented a decision tree to you before, but he

will recast that decision tree for topical products

in the context of quality-by-design.

Yesterday, we focused on dissolution

testing, and as the past chair of the BCS Working

Group, I took it upon myself to sort of go back and

re-examine what were my personal thoughts and what

held me back to make the recommendations that you

see in the guidance and see how we can recast that

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discussion into the quality-by-design thinking, so

that I can take this discussion and give that as a

recommendation to the current Technical Committee

on Biopharmaceutical Classification System.

Again, as I said, these are initial

thoughts, and our goal is to engage you in a debate

and discussion to hopefully give us some

perspective are we on the right track. The three

topics today are:

How can pharmaceutical development

information help to extend the applications of

BCS-based waivers of in-vivo studies for immediate

release products?

How can pharmaceutical development

information be utilized to address the challenges

of highly variable drugs?

How do we use this to establish

therapeutic equivalence of topical products?

Those are the three topics that we would

like to present, and the general question is are we

on the right track, but then more detailed

recommendations on how we should proceed with these

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three topics or other topics that we should have

considered instead of this.

So, that is the Topic 2.

DR. COONEY: Thank you, Ajaz.

We might pause for a moment for any

questions particularly around clarification of

these opening comments from the committee. Art?

DR. KIBBE: The question I always struggle

with is how do we define highly variable drugs.

Are we defining them in clinical outcomes, because

then the dosage form might not be involved in it at

all.

DR. HUSSAIN: The definition hinges on the

bioequivalence drug, the variability that we

estimate from the bioequivalence drug.

DR. KIBBE: But that could be a function

of intersubject variability, subject population

selection, and have nothing at all to do or

minimally to do with the actual product that you

are making.

DR. HUSSAIN: That is the discussion

Lawrence will bring to you, so if you hold that

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question for Lawrence.

DR. KIBBE: Thank you.

DR. COONEY: Ken?

DR. MORRIS: The two comments is that the

Topic 2 premise, the other part of that premise is

that the proper development information is being

generated at the companies which, of course, you

have limited control over, and that is being

shared, just as a caveat.

DR. COONEY: Nozer?

DR. SINGPURWALLA: Two comments. Slide

No. 7.

DR. HUSSAIN: I am sorry, I don\'t have

numbers.

DR. SINGPURWALLA: I know. Components of

the Challenge. The second bullet. That second

bullet is wrongly worded, it has to be changed, and

I will tell you why.

The more important reason is you, on your

eight bullet, are talking about confounding of

uncertainty, variability, and risk. They should

not be confounded. Who is confounding them and

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why?

DR. HUSSAIN: The current system has a

tendency to do that. That is what I mean.

DR. SINGPURWALLA: But that simply means

that the system is not educated enough, because

variability is the cause of uncertainty, is one of

the causes of uncertainty, and risk is a measure,

is a way to measure uncertainty and its

consequence.

So, why is there so much confusion about

these very elementary ideas in the industry and

perhaps in the pharmaceutical community?

DR. HUSSAIN: I don\'t know how to answer

that.

DR. SINGPURWALLA: Well, they need to be

trained, educated.

DR. HUSSAIN: But let me propose this in

the sense, uncertainty is not risk.

DR. SINGPURWALLA: I agree with you. I

agree with what you are saying completely. What I

am asking is, what is the cause of this confusion,

and it is so easy to remove this confusion?

DR. HUSSAIN: I understand the concern you

are expressing, and my premise is for years we have

not utilized the pharmaceutical development, and we

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have treated that as an art rather than a science,

and that is the way to get away from that

confusion. So, that is the premise.

DR. COONEY: Any other comments at this

point? We will have ample opportunity for further

discussion.

Using Product Development Information to

Extend Biopharmaceutics Classification

System-Based Biowaivers

DR. HUSSAIN: Let me go on to the

Biopharmaceutics Classification System. In

preparing for this presentation, I actually went

back and reviewed all the publications that have

occurred in this arena in this discipline, in this

topic area for the last five years, and there has

been a tremendous number of progress in this area.

For example, more recently, Professor Les

Benet\'s article was published on how you can

actually start predicting metabolism, and so forth,

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and how you can sort of add that additional

dimension.

There has been a paper published in Pharm

Research on quantitative instead of, you know,

rigid boundaries, and so forth.

But instead of sort of trying to summarize

the progression signs, what I wanted to do was to

go back and re-examine my own thoughts that were

expressed to the Advisory Committee in the year

2000, so I am actually going to repeat an old

presentation, but in light of what we have learned

in the last four years.

My goal here is to share with you some of

the concerns we had when we proposed the BCS-based

waiver guidance in the year 2000, and to what

extent those concerns remain, and to what extent

quality-by-design may be able to alleviate some of

this concern, and the discussion with you, I intend

to use that as recommendation to the current

Technical Committee on BCS. So, that is the game

plan.

This is an old presentation with some

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minor modification. When I had made this

presentation, I was completely focused on risk, and

the title was \"Biopharmaceutics Classification

System: A Risk Management Tool.\"

In light of the learning that I at least

personally had, I want to sort of bring in the

uncertainty and variability components to this.

Since this is a presentation, probably my

last presentation on the BCS topic before I handed

over the reins of responsibility to Lawrence and

Mehul, the new BCS Technical Committee was formed,

when Helen asked me to move to OPS and the PAT

process got started, so my focus went to PAT for a

reason which connects back to this one.

So, this BCS Technical Committee has been

in place under the leadership of Lawrence and

Mehul, and they have been diligently addressing a

number of implementation issues trying to

coordinate all the submissions, and so forth, and

there has been significant activity on this

guidance on the new drug side, very little, if any,

on the generic side.

You also heard from Mehul the database is

now almost ready, is being audited, database and

prospective research for extensions, links to PQRI

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and FIP, but the PQRI program really didn\'t take

off, and our thoughts were we wanted to explore

extension of BCS-based biowaivers to Class III and

Class II drugs.

Further research at the FDA, which we

completed, and we did extend the BCS-based

biowaivers to \"fed\" bioequivalence studies, and

that was part of the thing, and that work was done

with collaboration with Tennessee.

Continuing education initiatives and

practitioners and public, and the group has been

busy. International harmonization was an aspect,

but to the extent the definition of high solubility

and rapid dissolution, we got into ICH Q6A, the

European Guideline also adopted much of the BCS

recommendation to some extent. There are certain

differences, though, it is not fully harmonized.

With that as a background, let me trace

for you the evolution of the recommendations in the

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BCS guidance that we released in the year 2000.

Regulatory Bioequivalence: An Overview,

from my perspective, this is a graphical

representation of our regulation.

If you look at the dosage form that we

deal with, solutions, suspensions, chewable

tablets, conventional tablets, and modified release

products, for solutions, we consider bioequivalence

essentially is self-evident, bioavailability is

self-evident, and biowaivers are granted, condition

being excipients do not alter absorption, and that

is an assessment based on historical data.

For any product that contains drug in a

solid form, we have a concern, and for pre-1962

drugs, we call DESI drugs, in vivo evaluation for

bio-problem, that was the original biopharm

classification system, if you really look at it,

that had many of the elements of therapeutic index,

PK, the solubility, and so forth.

For post-1962 drugs, generally, in vivo,

some exceptions with IVIVC. Then, we introduced a

SUPAC-IR guideline in \'95, and we introduced the

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elements of BCS guidance, BCS system in that to

give a waiver for minor changes and moderate

changes that Mehul talked to you about yesterday.

For modified release, we don\'t have a

classification system, bioequivalence has to be

demonstrated in vivo with the exception of SUPAC

modified release for within a product. If you have

in vitro bioequivalence, you can make changes.

Again, Mehul summarized that.

I want to trace back the discussion to a

bioequivalence hearing, which I did not attend. I

was just graduating in \'86, but I was connected to

this because I made the slides of a number of

people who presented here, so I knew what was

happening.

This was a pivotal discussion and I think

set the stage for what evolved as bioequivalence

standard. There were two comments that I want to

share with you.

One was Dr. Bob Temple. He said, after

the end of this discussion, it seems sensible to

think that swallowing something that turns into a

36

solution rapidly would be difficult to lead to

differences from one product to another.

So, the clinicians were arguing you don\'t

need biostudies for everything. Arnold Beckett had

made that argument years at that time, so he said

you shouldn\'t go with in vivo for everything, but

we did.

Milo Gibaldi, an eminent pharmacokinetic

professor, \"I have learned that there is no support

here for attempting to provide such assurance

solely with in vitro data.\" So, that was a pivotal

aspect, I think, and I went back and sort of tried

to examine the thoughts and the concerns that were

expressed at that session.

The other aspect that I do want to put on

the table is need to reduce our reliance on in vivo

bioequivalence studies. Why? Ethical reasons. 21

CFR 320.25 says, \"No unnecessary human research

should be done.\" Science continues to provide new

methods to identify and eliminate unnecessary in

vivo bioequivalence studies.

Focus on prevention, \"building quality

37

into products - right first time.\" So you see the

PAT initiative and how this will connect to that

was in the thought process and why we aggressively

moved in that direction, \"right first time,\" I used

before Pfizer.

Time and cost of drug development and

review is a key, because if you see that we have

three to six bioequivalent studies in our NDAs. We

actually at some point said we don\'t even review

some of those because they are redundant, so why

expose normal healthy subjects to a new drug which

is under development with all the risks associated

with that.

So, prior to SUPAC-IR/BCS, in vivo

bioequivalence assessments to justify a majority of

manufacturing changes. So, this was a significant

hurdle, and that changed. In the SUPAC-IR guidance

in \'95, we brought in the classification system and

provided a tiered approach for changes based on in

vitro.

For example, highly soluble, highly

permeable drug, the critical processes for gastric

38

emptying, dissolution is not likely, and

dissolution is not likely to be rate limiting, but

we said 0.1 single point, 85 percent, and so forth.

So, you can see that for each class, we

recommended a tiered approach for waiver of

biostudies for minor changes, and so forth. We

excluded the Narrow Therapeutic Index drugs from

waiver consideration, but we never defined what

narrow therapeutic index was, and we still haven\'t.

The guidance in 2000 really extended that

and put that as a waiver for first time approval,

and also provided the methods to classify your

drug, and so forth. The pivotal recommendation in

that was waiver for in vivo bioequivalence studies.

I do want to stop here and say the title

of this guidance was debated to the nth degree

before we agreed on this internally. The word

\"waiver\" was to signify that we want an in vivo

study for everything that is in solid, so the title

was very carefully chosen to reflect that.

Anyway, it\'s waiver for in vivo

bioequivalence studies is recommended for a solid

39

oral test product that exhibit rapid and similar in

vitro dissolution under specified conditions to an

approved reference product when the following

conditions are satisfied: products are

pharmaceutically equivalent, drug substance is

highly soluble and highly permeable and is not

considered to have a narrow therapeutic range and

excipients used are not likely to affect drug

absorption.

The class membership, the boundaries that

you see, which are rigid, high solubility, the

highest dose strength is soluble in less than or

equal to 250 ml of aqueous buffers over the pH

range that we had 1 to 6.5 or so, whatever that

thing is I forgot.

The reason for 250 ml is the glass of

water that we take when we do a bioequivalence

study. High permeability, the extent of absorption

in humans is determined to be greater than 90

percent.

Rapid dissolution is 85 percent dissolves

within 30 minutes in three different conditions,

40

HCL, pH 4.5 and 6.8 buffers using traditional

settings of dissolution apparatus.

Now, clearly, I had approached this as a

risk to bio-in-equivalence because since we started

with the premise that you needed bioequivalence

trials for approval of changes, and so forth, so

the risk factor for me was the proposal the

recommendations should not result in

bio-in-equivalence.

The risk factors that we had in mind were

clearly manufacturing changes, poor process

capability, high between and within batch

variability, but the thing we focused on, reliance

on in vitro dissolution tests and how reliable that

is, single point specification, sampling,

predictability were the issues.

Clearly, the other factors were there,

deficiencies in BE study design, Type II errors,

and so forth.

Now, assessment of risk, what is the risk

of bio-in-equivalence between two pharmaceutically

equivalent products when in vitro dissolution test

41

comparisons are used for regulatory decisions?

That was the question we asked.

What is the likelihood of occurrence and

the severity of the consequences?

Severity was not meeting the

bioequivalence criteria was unacceptable, but what

was the likelihood, so we needed some information

on that.

Regulatory decision, whether or not the

risks are such that the project can be pursued with

or without additional arrangements to mitigate the

risk, and clearly, acceptability of the decision,

is the decision acceptable to society? This took

four years.

We started working on this in \'96, and if

you think I was busy with the PAT presentations

around the globe, that is exactly had to do the

same thing for this one, too, because the mind-set,

the paradigm was so entrenched in the old system.

Professor Gordon Amidon spent some time

with us, he and I. I had the luxury of having the

biopharm document room right outside my office in

42

the Parklawn Building, so we went through a number

of applications, about 160 applications at that

point, to get a sense of what is happening.

Roughly, what we found was on the new drug

side only, because we have failed studies or we

have all the studies submitted on the generic side,

we couldn\'t use that database because you just have

the passing studies in there.

So, we looked at the new drug side and

said when does dissolution signal

bio-in-equivalence or does not signal

bio-in-equivalence. What we found there was

generally, you see big differences in dissolution,

no difference in blood levels.

But, on the other hand, there were signals

that dissolution fails to signal bio-in-equivalence

about 30 percent of the time, and we wanted to ask

why.

So, minimizing risk of bio-in-equivalence,

does in vitro dissolution process emulate in vivo

dissolution process in vitro and in vivo? Dosage

form disintegration, dissolution, and stability

43

were the concern.

The gastrointestinal fluid volume,

composition, and hydrodynamic conditions were the

concern, and clearly, I think one thing which was

pivotal for the oral discriminating part was the

surface tension, and that could have been picked

up.

Residence time in the stomach and small

intestine were an issue, so we did a lot of

analysis actually of gastric emptying and what

factors affect gastric emptying, and so forth.

Impact of excipient differences on GI

physiology and drug bioavailability were the

questions.

The key question was how well this

emulates in vivo, because this is our standard

dissolution test.

This was a cartoon that I prepared and to

take a look at typical physiologic parameters in a

single dose fasting BE study. We had fairly good

estimates of the gastric fluid plus the 8 ounces of

water. We knew what the gastric pH range is

44

generally in the normal subject.

We had the information on the gastric

emptying time, which is highly variable, but

approximately T50 is 15 percent. The permeability

is low, and that was an advantage in the stomach

compared to small intestine, the surface tension is

lower, and clearly, volumes in the small intestine

were uncertain, and pH, and so forth, and the

permeability was high. Hydrodynamics was a big

question in our minds.

Lawrence summarized to you the debates

that we have had for dissolution for the last 30

years, and that dissolution tests are over

discriminating, on one hand, and in the USP, the

statement that products that dissolve about 70

percent in 45 minutes have no medically relevant

bioequivalence problems, what was the basis of

that.

Dissolution tests are not sufficient to

assure bioequivalence, and demonstration of IVIVC

is necessary, but when you do that, product

specific, so those are two sides of the debate.

I showed you this slide of the problems

with the dissolution tests of false positives and

false negatives, but then we also looked at things

45

that we made decisions on.

Here is a product. The generic product

was Product B. We actually withdrew this product

from the market after approval. This is a pre-62

drugs, it was approved on the basis of dissolution,

meeting the USP specification criteria.

This was a pre-62 drug, one of the older

drugs, and we had a challenge from the innovator,

which is Product A, that the generic is not

bioequivalent, and that was the basis at which we

had withdrawn this product, Product B, from the

market.

The Cmax, you can see is clearly high, but

in many ways, Product B was more reliable, less

variable, and it was more modern technology, but

the constraints on us is you have to be equal, if

not better.

Here are examples of where there were real

dissolution impacts on in vivo absorption. Here is

46

a weak acid where the initial formulation for

clinical was capsule. They went to

wet-granulation, and the to-be-marketed was a

direction compression with dicalcium phosphate, and

the dissolution in this case was Q17 30 minutes in

simulated intestinal fluid.

That\'s the criss-cross you see if you do

acid in alkaline conditions, you don\'t distinguish

that, and this had to be reformulated. But this

was I think in my mind a signal that we probably

are designing our products for dissolution rather

than the intended use.

I wanted to walk through this with you,

and that was one of the reasons for the

quality-by-design thinking.

Here is a Drug X. This is actually a

clinical study, 100 mg dose, so it\'s a highly

soluble drug by all definition. It\'s a weak base

exhibits a sharp decline in solubility with

increasing pH above 3.

Now, the clinical trial material in this

case was wet granulation, drug particle size of D50

47

of 80 microns, and this was a concern, because our

particle size specification was very crude. I mean

what does D50 percent give me. We had lactose,

microcrystalline cellulose, and so forth. You see

that formulation there.

But the point to focus there is the

dissolution 0.1 normal HCL was 65 percent in 15

minutes and 100 percent in 20 minutes.

Disintegration time was 10 minutes.

The way I had presented this, the

to-be-marketed was the formulation of direct

compression, but actually the wet granulation in

this case was a U.S. formulation, a formulation

using U.S. clinical trials, and the European

clinical trials were done with the to-be-marketed,

and we had to bridge those together.

The to-be-marketed formulation, you can

see what happened here. Direction compression,

drug particle size of 300 microns, dicalcium

phosphate, and so forth, and the dissolution is

more rapid now, 0.1 normal HCL - 85 percent in 15

minutes, about 95 percent in 20 minutes, so the

48

initial dissolution burst is very rapid,

disintegration time is 1 minute.

Clinical product exhibits poor dissolution

at 7.4. Can you imagine, I mean this is a BCS Class

I drug. The Cmax or the rate or the exposure of

this in terms of p concentration for the

to-be-marketed formulation in this case was half,

so you see half the blood levels in terms of

height. So, it simply was signal that if you don\'t

get the physicochemical properties of drug

understood, you will have these problems.

So, in vitro and in vivo dissolution,

dissolution methods evolved over the last 30 years.

The year 2000, I said there were reproducible test

methods for lot-to-lot quality assurance, so you

can imagine my surprise of the calibration, which I

was not aware of at that time.

The dissolution media volume and

composition selected to maintain \"sink\" conditions.

In vivo dissolution is a complex process, and you

have to consider pH profile, bile concentration,

motility patterns, and so forth.

In vivo, the \"sink\" condition is created

due to intestinal permeability, and this was a

contention, which Lawrence and others, we recently

49

published to show how permeability actually impacts

in vivo dissolution, so we have published on this

now already.

I will talk to you about in vitro-in vivo

correlation. The formulation specificity of IVIVC

has been known since 1997. This is drug

spironolactone from a publication in J. Pharm

Science in \'97.

So, you can see a change in particle size.

You may have a correlation, but a change in

particle size could be outside that. So, a

correlation itself why this formulation specific

has to be really brought into context.

So, reliance on current dissolution

practice can pose an unacceptable level of risk

from bio-in-equivalence perspective. Compared to

high solubility drugs, risk is higher for low

solubility drugs.

Products with slow or extended dissolution

50

profiles pose a higher risk. The dissolution is

rate limiting.

So, in a sense, we wanted to use

dissolution test only to rule out that dissolution

is not rate limiting. So, that was the basis for

our thought process. So, we constructed a rapid

dissolution criteria for that purpose. We did not

want to use dissolution tests for bioavailable

decisions if there was a hint that dissolution is

rate limiting.

Potential for significant differences

between in vivo and in vitro \"sink\" conditions

higher for low permeability drugs, which we had to

prove later on with a simulation study that

Lawrence did.

Now, to establish a boundary for rapid

dissolution, we simply postulated that since

gastric mucosa does not have high permeability to

drugs, you have a 15-minute time, so you can take

advantage of that.

So, if the dissolution is rapid, then,

much of it is complete before it empties into the

51

small intestine where you have high permeability.

So, in a sense, a very rapidly dissolving drug will

behave essentially like a solution, and it does.

So, here is a snapshot of dissolution

versus AUC and Cmax ratios and the bioequivalence

goalpost of a drug metoprolol. The reason I did

not take the name off here, because this is already

an ACPS presentation, it is already on the website.

So, you can see a solution versus all the

other formulations that we have approved, generic

and innovator, plus there are research

formulations, which we deliberately made to be very

slowly dissolving.

You see that essentially, for the most

part, the slope is zero. We then did extensive

simulation work to establish that if in vivo

dissolution is rapid, as a function of different

gastric emptying as a function of mean intestinal

transit time, you are not likely to see a

difference between solution and a tablet, and that

was the basis for our 85 percent and 30 minute in

vitro criteria for rapid dissolution, but we did

52

not apply that to low permeability drugs because of

the risk factors that we felt were coming from

excipients.

The question we asked was is the current

approach for evaluating excipients for decisions

related to biowaiver for oral solutions sufficient.

That is the database I have.

There were hints that the excipient

effects were not fully appreciated. For example,

there was a study by Ian Wyling\'s group where you

could show mannitol, 2.3 grams of mannitol clearly

had a big impact on bioavailability of cimetidine,

a low permeability drug, and on the other hand,

Fassihi had shown that a high permeability drug had

minimal impact of sorbitol, even 10 grams of

sorbitol.

So, that was a hint, and we actually

conducted a study at the University of Tennessee,

and we have now completed that study, even getting

to a mechanistic basis for generalizing the

permeability effect to other excipients, is to test

this out.

Metoprolol was our boundary drug for high

permeability, so we did a study with ranitidine and

metoprolol, and we did a crossover study in

53

replicate design to get an estimate of subject, the

formulation interaction also.

So, it is a very simple formulation. You

have your drug. You have sucrose or sorbitol, and

you have 15 ml of water. That is the simplest

study.

What we found\--I will just show you a

picture\--just a confirmation for a low permeability

drug like ranitidine, a dramatic effect.

Now we have completed the study of the

dose response, the amount of sorbitol that triggers

this is about 1.2 grams. For metoprolol, the Cmax

was affected, but not to the same extent. AUC was

not.

In addition, there were a tremendous

amount of information coming out of other excipient

effects on transporters, and so forth. So, this

was an evolving issue at that time, and it

continues to be evolving issue, and methodologies

54

were being proposed of in vitro evaluation of this.

I won\'t get into that.

But we also did an extensive evaluation of

excipients and what we found was I think in most

cases, excipients that are used in solid dosage

form really do not have a significant impact, but

the way we had to evaluate that was comparing the

differences in formulation that we have approved,

like, for example, verapamil, and so forth.

But the risk factor was excipients. Is

the current approach for evaluating excipients for

decisions related to biowaiver of oral solutions

sufficient? Well, I think we left the question

there.

For BCS-based biowaivers, a higher

standard was adopted by limiting biowaivers to

highly permeable drugs. Excipients used in solid

oral products are less likely to impact drug

absorption compared to liquid oral products,

because it was simply the volume and amount in

there.

For example, we had products on the market

55

that contains 23 grams of sorbitol in one dose, so

you can see cross interaction possibly.

High permeability attribute reduces the

risk of bio-in-equivalence, decreased small

intestinal residence time by osmotic pressure,

because low permeability generally have a tendency

to be absorbed in small segments of the intestine.

Clearly, on the other hand, the boundary

that we chose for high permeability to be 90,

because there are other surfactants, and so forth,

that could increase permeability, so if you set

your boundary at 90, there is no risk of failing.

There were other examples. There were so

many examples that we had not really paid attention

to. Here is a submission\--not a submission\--this

is a graph that a student of mine sent me from a

company, and they have seen such effect.

Here is a drug, a tablet and a solution.

The solution has almost half the bioavailability of

a tablet, so you can see that, with sorbitol or

mannitol for a low permeability drug, it can have

lower bioavailability.

So, that was the basis that we came up

with the recommendations and the boundaries for the

BCS classification system that gave the basis for

56

waiver for new drug applications.

So, Class I drug, you have jejunal

permeability. This was our research that we

classified the number of drugs, and the volume of

water required to dissolve the dose on the x axis.

Class I dissolution in vivo is not likely to be

rate limiting, and well characterized excipients.

So, dissolution itself is likely to be rapid

inherently, and then we can rely on in vitro

dissolution for that purpose.

Class II dissolution is likely to be rate

determining and complex in vivo dissolution, and

solubilization process, so no, not going there.

Class III was where the debate was. Some

hesitation with the use of current dissolution

test, because the site specific absorption was a

concern, and excipients.

Class IV was generally problem drugs with

in vitro dissolution may not be reliable.

So, that was the basis for our

recommendations.

So, wrapping up, in terms of quality

design thinking, what can we do now? If I

summarize my concerns, one major concern was if we

went towards a dissolution-based method, people

57

will design products for dissolution rather than

the intended use was a concern, and that example

sort of illustrates that, the one to-be-marketed

difference, that was a concern.

So, I wanted to feel comfortable having

some formulation assessment as part of this

extension. Clearly, I think excipients and the

transporters, all were evolving issues at that

time. There is a lot more information available

now than we had.

So, in quality-by-design thinking, you

really have focus on what are the critical

variables that affect dissolution, and these are

easily identifiable especially for immediate

release dosage form.

You easily can start thinking about

58

excipients and what their impact might be on

solubilization, and so forth, and Lawrence himself

has done some work in this area, and so forth.

So, with that in mind, what my thoughts

are, in addition to thinking about evaluating the

boundaries themselves, I would like to recommend to

the group that, first of all, BCS should be, and

probably will be, a key, too, in quality-by-design

decision trees that we talked about.

I mean solubility, permeability

characterization has to be a starting point for the

formulation, so clearly, I think we need to build

these concepts in the decision trees we talked to

you about yesterday, but also quality-by-design and

design space with respect to pre- and post-approval

by bridging studies. Waivers for in vivo studies

based on design space concept, sort of is that

connection to extension concept.

The challenge I think is from a generic

industry perspective, there is a lot of hesitation

to seek for approval, the first time approval, a

biowaiver based on that, concerned with

59

permeability assessment, and so forth.

That concern probably will remain.

It is not a scientific concern, it is a

perceptional concern, it\'s a regulatory concern,

and so forth, but that doesn\'t say that you cannot

classify a drug for a generic product after

approval. The rest of the post-approval changes,

they could be based on that, and that could be

quality by design.

I think those are the key connections that

if the Technical Committee sort of starts building

in, their efforts really get connected to the PAT

and the quality-by-design thinking, so you see the

connections sort of evolved.

Clearly, they have already started

developing in FDA\'s knowledge base, a knowledge

base. Drug-excipient interaction, I think is an

increasing issue from chemistry and clinical

pharmacology aspect, and I think you need to start

connecting those dots.

At the same time, drug substance and

formulation variables and clinical performance that

60

Mehul alluded to the variability, but with what is

happening on the clinical side now, with focus on

biomarkers, focus on surrogate markers, and so

forth, I think we need to proactively keep an eye

on that.

I mean this is an evolving issue, but seek

out some connectivity between quality and clinical,

and be available to what is happening at least, and

that is the point I made also to Jurgen yesterday

when he gave his report.

So, with that, let me stop and open it for

discussion.

DR. COONEY: Thank you, Ajaz.

Comments and questions from the Committee?

DR. MEYER: While I am formulating my

question, I will ask another one, so I will give

you some time to think.

How confident are you that our knowledge

base on excipients allows a reviewer to sit back

and say, well, it has X, Y, and Z, and therefore,

there is no problem?

DR. HUSSAIN: Well, I think the

61

traditional excipients for immediate release dosage

forms that we use as formulation aids for process

ability, and so forth, I am fairly confident that

there are very little concern there.

There are other excipients that are

necessary to aid in the dissolution process, such

as surfactants and other aspect. I think a close

grouping of those would be necessary. I think if

we collect this information, it will start making

the case, but if you have properties, such as high

solubility, and so forth, you probably would not

need those anyway.

So, I think you can carve out excipients

that we know are not an issue.

DR. COONEY: If I can just pick up on

Marvin\'s point for a moment, your initial question

was about knowledge base of the excipients per se,

but it is really the relationship of the excipients

to the drug substance, to the API, that seems to be

the area of uncertainty, and that knowledge, it

seems to me, is much less clear.

DR. HUSSAIN: If I amy sort of put that in

62

the context, traditional screening experiments that

are done for drug excipient compatibility, may

provide not only information that will be useful

for stability, failure modes of the product, but

also hints about the interactions among excipients

and drugs, how they might have a bearing on

dissolution.

DR. COONEY: Ken.

DR. MORRIS: The point you just raised is

the source of my question, as well, since

drug-excipient interactions are typically for

chemical stability.

Is it like particularly for something like

BCS Class III, is it more of the concern that the

interaction with the drug is changing absorption,

or that the interaction of the excipient with the

mucosa or the sites of absorption?

DR. HUSSAIN: I think they are both

concerns in the sense, but the concerns we had when

we were working on this were more on the impact on

the GI membrane, transporters, and so forth, the

concerns with excipient-drug interactions that

63

might be physicochemical were less of a concern,

because we did not really focus on that aspect.

DR. MORRIS: That is sort of where I would

assume it, but I just don\'t know enough biopharm.

DR. HUSSAIN: The aspect I think is this.

I think the draft guidance that we have issued on

polymorphism, for example, I think is a

concentration there, in the sense what we have said

is you could have a different polymorph, but if you

can design your product well and if it meets the

criteria, it\'s fine.

So, I think that is the flexibility that

already sort of comes through that, is that ability

to demonstrate that, you can be different, but yet

meet the intended use.

DR. COONEY: Art, then Marvin.

DR. KIBBE: This is more complex than we

can handle in one or two days. The number of

excipients you use exponentially increases the

possibility that one excipient is reacting with

another excipient, that is reacting with the API.

On top of that, the processing of the

64

product changes things. I mean we know all sorts

of problems with mag. stearate and overblending,

but we know certain issues. The question that

always sits in the back of my mind is we have been

discovering these issues on a regular basis over

the last 20 years, have we discovered them all, and

how can I be naive enough to think I have

discovered them all, and I don\'t think I have.

So, that gives me a basic uncomfort level

with just waiving stuff when I really want a part

that works in my patients. So, I am uncomfortable

with that.

I have a question, a substantive question.

If I make a soft gelatin capsule which contains a

solution, is it a solution or is it a capsule?

DR. HUSSAIN: Capsule. That\'s the way it

is.

DR. KIBBE: On your basic I guess third

slide, I could argue it\'s solution.

DR. HUSSAIN: Yes. That\'s the aspect, I

think now we can start thinking about those aspects

if you have not done so in the past.

But let me go back to the concern you

raised in the sense, impact of magnesium stearate,

and on dissolution, it is clearly documented.

65

Impact of magnesium stearate on in vivo absorption

has not been done yet.

All the studies we have done, we had no

impact of magnesium stearate on immediate release,

and so forth, on in vivo absorption. I could not

find a single paper that conclusively tells me that

what we see in vitro, the big difference is

translating in vivo differences.

There are two reasons for that. One, is

that old study that was published in 1967, J. Pharm

Science, by Professor Newton from the University of

London, where he demonstrated for lithium carbonate

that if you include a very, very small amount, 0.01

percent or 0.001 percent of sodium sulfate in your

formulation, you negate the effect of magnesium

stearate that you see in the solution.

So, that was a hint to me that suggested

that the surface tension differences that we see

between in vivo fluids and in vitro fluids probably

66

are the reason, because all the studies we did at

the University of Maryland, we actually probed this

for a low solubility drug\--I am forgetting the name

of the drug\--we didn\'t see in vivo relevance of

that.

So, now that is the reason we have to

start thinking about is risk-based decision to

really understand the behavior of things in vitro,

because one of the concerns that we had earlier was

you see big differences in vitro, how do you know

this will or will not translate.

If quality-by-design, we are thinking, why

is this assessment, then, that provides a basis to

think about it.

DR. KIBBE: But that argument, I think

would logically lead us to the conclusion that we

have to go to a bioavailability study, we have to

go to a clinical trial. We can\'t rely on any of

the standard tests that we do that are surrogates,

because they don\'t work out, because they either

show a problem that isn\'t real, or they ignore a

problem that is real.

DR. HUSSAIN: Right. That second bullet,

that is what I am really thinking about. If you

have to qualify your design space, your

67

bioavailability studies, if you are a new drug

applicant, that becomes your test of hypothesis is

to say that we have looked at these are the big

differences we see that has an impact.

So, one category of BCS-based biowaivers

would be SUPAC related where you have demonstrated

this in vivo, and that becomes the basis for that,

and not just rely on in vitro testing and lack of

that information.

So, waiver is an extension of SUPAC in

terms of design space is a bigger opportunity

probably in the quality-by-design thinking.

DR. COONEY: Marvin.

DR. MEYER: Ajaz, I think I asked this

question yesterday, and I think you said you were

going to address it and maybe you did and I missed

it, the rigid fixing of the\--

DR. HUSSAIN: Boundaries.

DR. MEYER: \--boundaries. I really don\'t

68

have any problem with the rigid definition of high

solubility, high permeability, I mean we have

pretty well nailed that down, but then you have, of

course, if it\'s soluble in greater or less than or

equal to 250, well, if it\'s only soluble in 300, is

that really poor solubility, and if it\'s only 89

percent absorbed, is that really low permeability,

and, if so, does it fall in that 30 percent

probability of failing a product?

How do you deal with\--you have to draw the

line, but on the other hand, you draw the line, it

becomes somewhat arbitrary and capricious.

DR. HUSSAIN: Very good point. This is I

think an important point because the objective of

this guidance was to make the decision. This is

the decision. You meet this, there is no issue.

If you don\'t meet, you always have an option to

explain, but nobody uses that option.

So, this, in my opinion, is an approach

that we had before. In the new paradigm, the

decision trees that we developed opens the door in

a sense. Here, the decision is pre-made, but

69

instead of premaking that decision, how can you

allow your science to drive a decision process that

can justify the recommendations that come, but that

then becomes specific to a company. It is not a

general guidance. It is a decision tree to arrive

at a proper decision.

So, that would be an extension concept for

BCS, not a general decision recommendation, which

is what we have been trying to achieve. It has

changed the boundaries, and so forth. But to

incorporate that as a decision process, it becomes

demonstrate this, and the decision can be yours

sort of a thing.

DR. MEYER: So, it\'s sort of a work in

progress, so to speak.

DR. HUSSAIN: It\'s not. I mean I think

the group has been busy with a number of things,

but this isn\'t a thing that they could start

thinking about, we have not done so.

DR. COONEY: Ajaz, if I can get clarity on

that point. I think the point you just made is

that the decisions on class membership will be

70

integrated into the thinking about the decision

trees.

DR. HUSSAIN: Yes.

DR. COONEY: Is that correct?

DR. HUSSAIN: Definitely. If you are a

Class I drug and you exhibit the rapid dissolution

with the conditions we have outlined, the decision

is okay. Anything else, the guidance does not

recommend a waiver. That\'s how it is.

Based on what Marvin just suggested, and

what I am formulating that as, this is a decision

for every sponsor right now. Their design and

process understanding would vary from one end to

the other end, but one way of extending this

concept is not a general decision that this is

where you get the waiver, but to define a decision

tree and how you demonstrate to the degree of

confidence that we need, that waiver would be you

have demonstrated an understanding that the waiver

will be granted.

That will be Class I, that will be Class

II, that will be Class III, so you have different

71

levels of complexity in those, but the signs and

the level of understanding could drive you to that,

but that probably will become a post-approval as

part of the design space.

DR. COONEY: Tom.

DR. LAYLOFF: I think I am not confused,

but I don\'t understand some things like when a drug

goes into the intestinal space, it is bound, not by

water, but probably proteins and various other

things that are present in the medium, and then it

is absorbed through different sites depending on

how it is wrapped in with the rest of the medium,

and that is a drug-specific property, which then

can be affected by an excipient, which might change

the transport site, it may change the structure of

the solution characteristics, is that correct?

DR. HUSSAIN: No, I think the basic

premise is this, yes, you can have binding, you can

have a number of other complexation reactions, and

so forth, that occur. Many of those are ionic and

loose, so you establish equilibrium.

For some drugs, you have complexation that

72

really are almost very tight like with calcium and

tetracycline, and so forth, there are a few such

examples, but in this scenario, what we are talking

about are equivalent behavior of the same drug

molecule in two different formulations.

So, if there are intrinsic properties of

the drug molecule itself that will contribute, but

that molecule is the same, that we are dealing with

two formulations. Now, how do formulations act

with that behavior is a concern.

I will sort of extend that concern to a

paper that we had, a poster that we had, is that of

precipitation. A weak basis will dissolve very

rapidly in acid conditions, but when they get

emptied, there is a potential for precipitation,

and so forth, and that could be a very complex

process, and the size of the particles, not

precipitation, crystallization may differ based on

the excipients you have and the conditions you

have.

There is a potential that excipients could

impact that. So, that is generally Class II drugs,

73

that\'s the boundary for Class I for high solubility

was intended to prevent some of those things from

occurring, too.

DR. LAYLOFF: Do you think the

complexation and coordination around the drug

substance would actually affect the transport site,

change the site of transport, would change the

properties of the system?

DR. HUSSAIN: Yes, it is clearly possible,

but unlikely for an immediate release dosage form

with the type of excipients we use.

DR. MORRIS: You know when I think about,

it sort of makes my head hurt, but when I think

about\--

DR. HUSSAIN: It\'s complex.

DR. MORRIS: \--the amount of time we spent

working on developing design spaces for the

processing end of things, which as Jerry says, may

be a way off, but still in comparison relatively

simple to the larger problem, is there an

opportunity in the context of using development

data to somehow leverage tox studies to be able to

74

get early reads on, not the tox itself, but in

terms of some of the dynamics that are going on

with the dosage forms?

DR. HUSSAIN: I have a decision tree,

which I did not present yesterday, but it was part

of the handout. That decision tree came out of our

AAPS workshop on how to leverage that. The paper

is published, Diane Burgess \[ph\], Eric Duffy from

FDA is on it, so it is there in your handout. I

don\'t have it in this one. Take a look at it.

That leverage is every bit of information

coming from Pharm Tox, and so forth, to start

building that case for that.

DR. MORRIS: For the design of the dosage

form?

DR. HUSSAIN: Yes, for particle size

dissolution and bioavailability concentration.

DR. COONEY: Marvin.

DR. MEYER: Ajaz, when a generic company

sends in their ANDA, it was my understanding that

the generic group does not go back to the NDA to

review the contents of the NDA, so they don\'t look

75

at the excipients and see which excipients are now

different in the ANDA than were in the NDA product?

DR. HUSSAIN: I will let Lawrence answer

that, but we do have a process of inactive

ingredient guide that we consult, and so forth. I

put him on the spot here.

DR. YU: I guess this morning we talk

about excipients, which emphasize how complex the

process is. Yes, with advances in molecular

biology, we discovered I even don\'t know how many

transporters going on. As far as the PGP, at least

32 and 64 is transporters, however, I want to

emphasize that how those transporters impact

absorption we rarely see in clinical settings.

In other words, we very see excipients

impact on absorption of Drug A, B, C, D, but in

vivo setting, we have very, very few, two or three

publications out there compared to tens of

thousands of publications to show that excipients

impact in vitro.

So, I have to say that we still want to

see more evidence to show the impact of excipients

76

on absorption of drugs in general.

Secondly, while we see the impact exceeds

absorption, we very open to see the unique of some

of the products out there. The reality for, say,

70 or 60 percent of immediate release products,

people espouse the intensity, use very limited

number of excipients, I would say 10, within 10.

For example, Avacel almost uses the majority of

products. All those excipients impact, and have

not seen in vitro, as well as in vivo.

Certain, because of those common used

excipients, since we have a sufficient knowledge to

judge whether they are going to impact absorption

or not, will generate and not see the formulations,

however, in very few cases, some cases, we suspect

potential impact of excipients absorption, we will

look into it further before we make any scientific

decisions about approvability of any NDAs.

I hope that answers his question.

DR. HUSSAIN: The other aspect, just to

build on what Lawrence said, traditionally, the

composition, especially for immediate release, it

77

is hardly any different than the quality.

DR. MEYER: My real question was do you go

back and look at the NDA to see if Pfizer used

Avacel, and Teva used who knows what, do you make

that comparison, say, well, wait a minute, they are

putting in two things instead of Pfizer\'s one

thing.

Can that potentially make a difference?

Do you review the NDA product composition?

DR. YU: Well, certainly, we will review

any scientific literature out there and information

available to us to make the best decisions.

DR. MEYER: But do you review the NDA?

DR. HUSSAIN: Marvin, often we don\'t have

to, because it\'s in the label.

DR. MEYER: Well, that\'s true. It didn\'t

used to be.

DR. HUSSAIN: But definitely, the criteria

there is to look at what has been approved and what

has been used in dosage forms and inactive

ingredient guide, and so forth.

DR. YU: I guess the answer is as long as

78

are trying to build in the science base or any ANDA

decisions,

we will use any information which is available,

whether scientific literature or not, to us.

DR. COONEY: Are there any other questions

at the moment? Thank you, Ajaz.

We are running a bit ahead of schedule. I

think this would an appropriate time to take a

break for 15 minutes. We will reconvene at 8 past

10:00 and then begin immediately with Lawrence Yu\'s

presentation.

\[Break.\]

DR. COONEY: I appreciate everyone\'s

diligence to staying on time. It has worked very

well.

Lawrence Yu will proceed with a

presentation on Using Product Development

Information to Address the Challenge of Highly

Variable Drugs.

Lawrence.

Using Product Development Information to Address

the Challenge of Highly Variable Drugs

DR. YU: The assignment to me today, this

morning, is for me to discuss how to use

pharmaceutical development information to address

79

or potentially address the bioequivalence issues of

highly variable drugs.

Before I go on and talk about how to use

or potentially use the pharmaceutical development

information to highly variable drugs by equivalency

issues, I want to give you a very brief overview or

update what has been happening before.

For highly variable drugs, this is not the

first time, it\'s the second time we present it to

you. In the first presentation on April 14th of

2004, we discussed the challenges and the

opportunities for bioequivalence of highly variable

drugs.

At this meeting, the objective was to

explore and define bioequivalence issues of highly

variable drugs, for example, what is called highly

variable drugs and discuss potential solutions to

deal with the bioequivalence of highly variable

drugs.

We invited a number of speakers from

industry, academia to address issues related to

bioequivalence including why the bioequivalence of

highly variable drugs is an issue, highly variable

drugs a source of variability by Gordon Amidon from

the University of Michigan, and the clinical

80

implications of highly variable drugs by Leslie

Benet, and from bioequivalence method include the

skin method by Laszlo, as well as bioequivalence of

highly variable drugs, we had a good discussion at

this meeting.

I want to highlight some of the things

which have been discussed at this meeting,

particularly the slides by Professor Leslie Benet

from the USCSF. His talk with implications of

highly variable drugs, the argument was why highly

variable drugs are safer.

Specifically, he said for wide therapeutic

index highly variable drugs, we should not have to

study the excessive number of patients to confirm,

to demonstrate that two equivalent products meet

the preset statistical criteria or by equivalent

81

standards.

This is because, by definition, highly

variable approved drugs must have a wide

therapeutic index, otherwise, there have been

significant safety issues and lack of efficacy

during Phase III.

Highly variable narrow therapeutic index

drugs are dropped in Phase II since it is

impossible to prove either efficacy or safety.

Now, for the benefit of some new members

for this committee, I have two slides to briefly

review why this issue, why the one-size-fits-all,

what we are using today.

In order to determine bioequivalence, we

normally define as a rate of bioavailability,

defined as a rate and extent of drug absorption.

Bioequivalence is defined as absence of significant

difference in the rate and extent absorption.

In practice, when we give the drugs

orally, for example, to a healthy volunteer, we

will draw the blood. We got the plasma

concentration profile. We are certainly not able

82

to get exactly how much and how fast drug gets

absorbed, therefore, in practice, we use AUC, area

under the curve, to represent extent of absorption.

We use Cmax as a surrogate for the rate of

absorption, certainly in some cases we also look at

Tmax, because indeed, if you look at Tmax and Cmax

here, it represents the rate of absorption.

So, from that, we will define what the

bioequivalence study is passing or not passing.

Basically, the bioequivalence criteria, either

statistical criteria here is 80 to 125 percent.

At this date, that is the

one-size-fits-all regardless drug, drug product,

regardless of therapeutic class, regardless for

anything, that bioequivalence study, you have to

use preset, so-called bioequivalence criteria,

which is 80 to 125 percent.

Now, let\'s look and explain why the highly

variable drug is an issue. Let\'s look at the red

one. If you use a highly variable or intersubject

variability is high. Statistical confidence

interval, if you use the same number of subjects,

83

when variability goes higher, the confidence is

going wider. When confidence gets wider, it

becomes more and more difficult pass the confidence

interval or bioequivalence interval if 80 to 125

percent.

So, that explains when the variability

goes higher, it gets more and more difficult to

pass a study.

On the other side, in order to narrow the

confidence interval, for example, here it is fair

to demonstrate bioequivalence for super red one

here in order to make confidence interval narrower,

you have to use a large number of subjects, because

the higher the variability, the higher the

confidence interval, the higher the number of

subjects in general, the narrower the confidence

interval.

Therefore, for highly variable drugs, you

will have to use higher number of subjects. Just

to give you example here, for example, normally, we

have a 20 percent or 30 percent intersubject

variability. You maybe use 18, 24, even sometimes

84

for good product or good drugs, you only need to

use 12, actually, they can pass the bioequivalence

confidence interval.

But this is not always true, because when

the variability goes higher, now, this variability

could be because of a drug, or it could be because

of a product, so think about if variability goes

100 percent\--some of you think 100 percent, that is

unrealistic, but we do have a drug, we do have

examples\--think about with 100 percent variability,

assume test and the reference, there is 5 percent

difference, you end up it could be 500 or more

subjects, or 300 subjects, so this is certainly a

large number of subjects in order to pass the

bioequivalence study.

So, Leslie argued at the previous meeting,

from the clinical perspective, this is not

necessary. To give you a real example, these are

slides from Leslie Benet. Now, you would argue,

you may ask how do we get intersubject variability.

Certainly, you could get this number from

literature or sometimes company conduct a pilot

85

study, get some kind of estimate how many subjects

need to be used to pass the bioequivalence study.

Of course, in this case, based on

intersubject variability, you need to use 300, now

this is the drug.

So, at the previous meeting, when we

present the issue to you, and also we present some

of the possible potential solutions including

widening the confidence interval. Now, that is

very straightforward. You said by confidence 80 to

125 is too narrow for highly variable drugs, and

your intuitive thinking is just widening the

confidence interval, that is one of the potential

solutions.

Another solution is a scaling approach, in

other words, based on the variability of reference

list product, reference list drugs, and calculate,

use statistical approaches to calculate the

confidence interval, then, to determine whether the

study is passing or not.

Obviously, I have to say this. The active

approach because the confidence interval too wide

86

in order for the study to pass, so let\'s widening

the standards.

You came in and asked to do that, that

certainly the scaling approach, we ought to

carefully look into, the Committee suggested\--a

quote here\--\"the need to understanding where the

variability originated. The members added that

prior knowledge of all biostudies may help set more

appropriate specifications or criteria to make

decisions.

So, you suggest that we have to understand

the origin of the variability. Now, to look at the

mechanistic understanding of variability for drug

substance obviously is the same, reference list

product and the generic product, or any other

product, but the potential difference could be

formulation. Certainly, the generic products could

be narrower or could be wider, the variability.

We believe at this point, in order to

understand the origin of the variability, that

pharmaceutical development report, or

pharmaceutical development information can help us

87

understand the source of variability, can help us

make rigid scientific evaluation.

Now, in order to see the utility of

pharmaceutical development report to evaluation or

reviews of NDAs, let me go back and review some of

the basic fundamentals or the premises for ANDA

approvals.

Ajaz has mentioned about therapeutic

equivalence. Basically, the products are considered

to be therapeutic equivalents only if they are

approved as safe and effective, they are

pharmaceutically equivalent, they are

bioequivalent, adequately labeled, and manufactured

according to cGMP.

Now, here, I want to emphasize the

pharmaceutical equivalence. When we define

pharmaceutical equivalence, we basically have the

same active ingredients, obvious. I know we are

managing about pharmaceutical solid polymorphism,

which was presented to you two years ago, has a

drugs guidance out there and published by FDA in

December of 2004.

You have to be same dosage form, same

route of administration, and identical in strength

and concentration, and may differ the other

88

characteristics, such as shape, excipients,

packaging, and so on, and so forth.

Now, under the same dosage form, I think

what the complexity of dosage form is particularly.

Yes, I would say several decades ago, that dosage

form is reasonably simple and in most cases I would

say the immediate release product or solutions.

Certainly, with advances of pharmaceutic

industry and the pharmaceutic technologies,

so-called dosage form gets more and more complex,

and we now have the soft gel capsules, we have

ricin \[?\] product, we have inhersion \[?\] product,

presents additional challenge to us in terms to

make scientific decisions, in terms of make

scientific evaluations.

We therefore would believe a

pharmaceutical development report,

quality-by-design, designed to be equivalent,

become more and more significant in this regard.

Why does pharmaceutical equivalence

matter? Because of user experience and

expectations. Then, bioequivalence test is

normally conducted in healthy subjects. Certainly,

we have assumption that equivalence in healthy

subjects equals equivalence in patients. Now, we

89

have many, many generic products out there which

are safe, which is a high quality, which are

effective, which is the equivalent to the reference

list product.

So, certainly, we have tremendous

experience with that, and certainly the

pharmaceutical equivalence presents more and more,

become because you want to make sure the data from

the healthy volunteer does the equivalent in

patient, and against novel drug delivery systems

presents a challenge.

That is why we want to use more and more

pharmaceutical development approach to make a

judgment, pharmaceutical development information to

make a scientific judgment.

Highly variable drugs very often have, as

90

I mentioned, a wide therapeutic index, and the

clinical trials of reference list product have

established the acceptable level of variability,

because I said otherwise, these highly variable

drugs, a big window index, they will be dropped in

Phase II.

So, under an ideal situation, you will

think about variabilities very high, so you will

think it should be easier to pass, easier to design

equivalent product simply because they are so wide,

the target is wide, so it is easier for you to

pass.

Obviously, as I said before, if you use

the preset 80 to 125 bioequivalence confidence

interval, it is not the case. While we explore our

tentative approaches to deal with the

bioequivalency issues, certainly, the design issues

come out.

So, now, how do we deal with

pharmaceutical development for highly variable

drugs? Obviously, sponsor need to understand what

are reference products supposed to do with origin

91

of variability, and the purpose of design can be

equivalent, and to evaluate and to verify the

design and hopefully, in the future, use the

bioequivalent study design for highly variable

drugs.

So, we put more emphasis on design in this

regard to establish pharmaceutical equivalence, in

order to establish therapeutic equivalence, which

will be more appropriate.

While we are looking for shared

information for generics with us, there is a reason

for doing that, not only for evaluation for highly

variable drugs, certainly for pharmaceutical

development is required. It\'s one of the CTD

format. It is also outlined in ICH Q8, although

they do not apply to us, but I think some

principles should apply to generic industry also.

Also, more significantly, OGD question

based on review. Now, this is still a work in

progress, but I want to share some questions, I

think it is important to ask to share.

What is the formulation intended to do?

92

What mechanism does it use to accomplish this?

Were any other formulation alternatives

investigated and how did they perform? Is the

formulation design consistent with the dosage form

classification in the label?

So, those questions will help us get

information about a pharmaceutical product, the

report will help us, pharmaceutical product design

and development, make more sound and appropriate

scientific determination or evaluation.

The question often comes up, why do we

need to provide those things to the FDA? That

again is a quality-by-design paradigm, and

pharmaceutical development report is where you

demonstrate the drug is highly variable.

Now, this demonstrate not necessarily to

study, but you certainly use any source available

to show why this drug or drug product is highly

variable, and may use a different criteria other

than 80 to 125 percent confidence interval.

Also, the pharmaceutical development is

where you justify equivalence of design, why do you

93

think the product which you designed is equivalent

to the reference list product.

During the discussion, the members ask

whether it is drug or drug product. Now, for

example, Product A, the variability is the active

ingredient into exceptions, so formulation design

could be rapid release, so demonstrated by

dissolution comparison under physiologically

relevant conditions, if this is BCS Class I drug,

which is highly soluble, highly permeable, even

though they are highly variable, you may still

require biowaiver, otherwise, you will have to

conduct some bioequivalence studies to demonstrate

that they are bioequivalent.

Certainly, the approaches to deal with

highly variable drugs, to deal with the

bioequivalence of highly variable drugs are still

in discussion and still in investigation. I am

hoping in the near future we share with you some

proposal or recommendation we have with respect to

bioequivalence of highly variable drugs.

Another drug could be drug product, the

94

drug product could be highly variable, even drug

substance is I would say low variability, and

certainly design for equivalence begins with the

characterization of the reference list product, and

generic product should target the mean, and the

current system again would have no reward for

narrow or less variability of generic products.

That is why we need to explore the alternative

approaches or more appropriate approaches to deal

with highly variable drug products.

I just want to give you some examples of

what we talk about here. This is real data. This

is single subject replicate design, in other words,

you give the same product to the same patient

twice. Here is the plasma level, obviously, I am

sure that out of 80 to 125 percent confidence

interval, by any standards, it probably does not

need a statistician to figure this out.

You can see here, this is the first period

or this is the second period. It is not in your

handout or printout because this is in color. If

you look carefully, these two curves are

95

significantly different, probably different by I

even don\'t know how many folders.

This is a single-dose study twice,

replicate study design. Sorry, I should do a

better job next time, use red, so you can see it.

DR. KIBBE: I am just looking at the curve

and wondering why we got the hump at the back end

and whether the product is intended to have a

second release.

DR. YU: No, it\'s simply by design, for

whatever reason this peak has come out. Obviously,

a second dose, this peak is no longer there. So,

it\'s not purpose designed, it\'s simply because of

physiology involved.

This is happening because enteric coated,

this is coated to release at the target pH, so when

the physiological pH in the gastrointestinal tract

may fluctuate, and those curves will change.

Think about, for example, if we have a

product designed will release a pH 7, so then in

the terminal ileum, at one point is pH 6.8, you

will not see the release. But a second day,

96

because of food or because of other reasons,

terminal ileum pH becomes 7 or 7.2, you do not see

the release. Otherwise, you will not see it.

So, simply pH effect or significant impact

the absorption.

DR. KIBBE: The product had gotten on the

market because it worked clinically?

DR. YU: Yes. Even though we see the

significant variation in pharmacokinetics, but we

have no reason to believe this variation will

impact safety and efficacy.

So, in order to do more appropriate

pharmacokinetic studies, we also look into what

additional information, for example, develop

information will help support those cases or

bioequivalence cases, because you can see the

bioequivalence obviously is very difficult to

conduct variability probably up to 2 or 100

percent, and the number of subjects very high.

So, we want to see can we use any

additional pharmaceutical development information

to help us to make more proper scientific

97

decisions.

Again, for example, when we are looking,

in many cases, we do get very consistent, the in

vitro dissolution actually out to say the majority

of cases, those help us out to make a more proper

scientific decision or rational scientific decision

when we recommend any method to demonstrate

bioequivalence, but occasionally, we do get very

strange results, and actually, the variability is

extremely high and does not help you.

I just want to show you another case here

when we conduct the dissolution under physiological

relevant pH condition, and you get dissolution all

over the place.

Now, this is a 6 tablet, same lots, same

bottle, put in 6 vessels, you get a distortion

curve.

So, the next question we ask, this is a

large variability because of the operator or

because of other reasons. I think the answer is we

are almost certain those difference is because of

product, not because of other factors.

So, what I can present to you today is we

have challenges to deal with bioequivalence of

highly variable drugs. We use the clinical

98

evaluation and sometimes we are also facing

challenges when we are trying to use in vitro

information to help us make decisions.

DR. SINGPURWALLA: Lawrence, what is the

difference between each curve, different vessels?

DR. YU: Yes, six vessels.

DR. SINGPURWALLA: Six vessels, so it

could be that the vessels are different.

DR. YU: I think I stated that the

variability because other reasons, for example,

vessel difference, media difference, degassing

difference, operator difference, assay difference.

We do not believe all these reasons can explain.

DR. HUSSAIN: Yesterday, this same figure,

Cindy actually showed you the reason for this

difference was the coating thickness, and so forth,

so this is the same slide.

DR. MORRIS: You wouldn\'t get 2 1/2 hours

difference in dissolution time from different

99

vessels. That is not the magnitude you would

expect.

DR. SINGPURWALLA: How am I supposed to

believe that?

DR. YU: You have to believe in me. You

don\'t have any other options.

\[Laughter.\]

DR. SINGPURWALLA: I don\'t believe in

anyone.

DR. KIBBE: This is a constant pH

throughout, right, we haven\'t shifted pH during the

process or anything, right?

DR. YU: Correct.

DR. HUSSAIN: The reason to believe that

is I think it was done by Cindy, and with our

stringent mechanical calibration.

DR. LAYLOFF: He demonstrated it with

variable coating. It\'s variable coating on enteric

coating material, so if there is a crack in the

coating, it disintegrates much more rapidly.

DR. SINGPURWALLA: I think I believe Tom.

DR. YU: Thank you very much.

So, the objective, the case we presented

to you is certainly difficult, I just want to say,

variability issue, whether from clinical evaluation

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or sometimes for in vitro conditions, in vitro

testing, target main performance question. I am

sure you will ask where is the main performance.

I just want to show you that these are the

challenges which we are facing, and certainly we

are open to any suggestions or input from you.

So, in summary, we believe pharmaceutical

development information will help. I quoted here,

that\'s the conclusion made by you April 14th of

2004\. Understanding what the problem is, as well

as the real fundamentals, for example, physical and

chemical parameters, and make coherent and

scientific science-based decision based on

pharmaceutical development information, I think I

present to you the cases to see hopefully how we

use pharmaceutical development information to help

us in most cases, but in some cases, we still have

challenges and we have opportunities for us to move

forward.

Thank you and any comments are welcome.

Thank you very much.

DR. COONEY: Thank you, Lawrence.

We now have time for questions from the

Committee.

DR. SINGPURWALLA: Lawrence, I have two

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kinds of questions. Question No. 1. Is it the

purpose of this presentation of yours to ask the

manufacturers, namely, the industry, to provide

more information to you because there is so much

variability and you are trying to get to the source

of the variability, is that the objective?

DR. YU: Yes, very precise, certainly much

better than I said.

DR. SINGPURWALLA: That is the political

question. The scientific question, and I have heard

this before, what does T/R percent mean in your

Slide No. 8?

DR. MEYER: Test over reference.

DR. SINGPURWALLA: Test over reference.

DR. YU: Yes.

DR. SINGPURWALLA: How was this 80 percent

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and 125 percent figure arrived at?

DR. YU: Slide 9. I am trying to get

Slide 9.

DR. SINGPURWALLA: That\'s it, the picture.

So, 80 percent and 125.

DR. YU: T is the test.

DR. SINGPURWALLA: No, forget that. How

did you get 80 and 125?

DR. YU: That\'s an excellent question, and

we have been asked many times.

DR. SINGPURWALLA: It can\'t be excellent.

DR. YU: It\'s back to it was published

when I was in high school, I would say, 20 years

ago, or even more than 20 years ago, when the

pharmacokinetics, the discipline was developed, and

FDA developed the criteria. Actually, this

evolving process and trying to develop what kind of

standards or criteria can we use to judge a

bioequivalence study is okay or is not okay.

I think at that time, the physicians get

together, as we do today, and the physicians

together made the determination that the 20

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percent, the difference between product would not

be considered clinically significant, because the

20 percent will not be considered significant

difference, therefore, when translated into in vivo

setting, you have 80 percent.

So, you would think from 80 to 120 instead

of 25. Now, in the normal processing of

pharmacokinetic data, they used log normal to be

much better to describe the distribution. So, when

you use log normal, 80 is still 80. When you have

the 1 over 80 or 1 divided by 0.80, equals 1.25.

That is why you see 80 to 125.

Now, at the beginning, I would think 20

percent instead of 19 percent or 21 percent, which

is 20 percent, it was decided. Then, the question

come back to us now can we change 20 percent to 25

to 15, 10, 5 percent, and I guess we have to use,

say, over the 20 or 25 years, we approved product,

they are all safe, they are all equivalent, they

are all high quality, because of those experience

or prior knowledge, determining 80 to 125 percent

works fine.

Now, this does not necessarily mean we

cannot change it, but the criteria we have is very

stringent criteria, we feel confident with that.

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Now, with a statistical interplay\--

DR. HUSSAIN: Lawrence, if I may.

DR. YU: Yes, please.

DR. HUSSAIN: It\'s a \"feel good\" criteria,

we felt good about it.

DR. SINGPURWALLA: I got the answer. I

think I got the answer.

\[Laughter.\]

DR. SINGPURWALLA: The answer is

tradition.

DR. HUSSAIN: No, it\'s rational science.

DR. YU: It is rational science. I think

I proved it.

DR. SINGPURWALLA: Let me make a

suggestion.

DR. YU: Yes, please.

DR. SINGPURWALLA: That tradition with

some dose of rationality was good 20 years ago when

you were in high school. Times have changed.

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These kind of decisions to either prove equivalence

or prove in-equivalence should be based on risk

considerations and should be based on appropriate

utilities.

So, I think it is time to change, and I

think I said that April 14th, 2004. Has there been

any progress made towards changing?

DR. YU: The answer is yes.

DR. SINGPURWALLA: Oh, good. What?

DR. YU: Certainly, you said you want

suggestion of change, and I think under the

leadership of Gary Buehler, that we are exploring

the confidence interval, for example, the window

index drugs, and also we are exploring confidence

interval for highly variable drugs. In other

words, in the future, I am hoping someday, with

your support and agreement, we will have different

criteria other than 80 to 125 to different class of

drug in consideration of the risk interplay.

Obviously, to make any changes, six months

or one year is not enough.

DR. COONEY: Marvin, then Ken, then Paul.

DR. MEYER: Your talk I believe tried to

marry the quality-by-design to the highly variable

drug and show that you could, in part, solve the

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problem by quality-by-design, that\'s the objective.

DR. YU: Yes.

DR. MEYER: Personally, I think if you

have a competent company, then, your highly

variable drug is biological problem which the

company can\'t solve. You have to speak directly to

a higher power to get rid of that variability.

So, I think, yes, there is cases where,

for example, I could cite failure by design if you

want to put an enteric coating on something,

because that is, in my view, not a good dosage form

because it is so dependent on gastric pH and

emptying, and all of that, so you are setting

yourself up for failure.

Now, you can say, well, I dealt with

quality by design by not using enteric coated, I

kind of took the reverse of that. A competent

company looking at Slide 24, the 6-vessel graph,

would never go to a biostudy with a product that

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showed dissolution characteristics like that.

So, indeed, some quality built in that

says whoa, let\'s not spend \$100,000 on a biostudy

when our drug is all over the map in dissolution.

So, I think you can deal with some variability, but

that is fairly straightforward I think for a

company.

So, the issue that really faces us is the

physiological variability and do we extend the

confidence limits, do we have point estimate

restrictions or just do we do 600-subject studies.

DR. HUSSAIN: Marv, may I just sort of put

that in context a bit? In some ways, what we are

seeing here is this. Since we are comparing two

formulations of the same drug, the drug is the

same, the variability, the physiologic, the

variability that is coming is the same for the drug

substance.

If we can compare formulations and say

that all the conditions that are critical to

exposure are well controlled, and so forth, and get

confidence, what will give us the confidence to say

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that the inherent variability is the physiologic

variability, not the quality variability, then, we

can move forward. I think that is the hope that we

hope.

DR. MEYER: Do you think practically, you

can look at the restrictions and the SOPs\--

DR. HUSSAIN: No.

DR. MEYER: \--and just see how a company

is formulating and designing and developing a

product?

DR. HUSSAIN: Not with the traditional

work we do about formulations, putting things

together, and so forth, no, it has to be a

structured design approach that goes through

identifying the sources of variability in your

materials, and so forth, and putting a convincing

case together to say based on the assessment, in

this case it\'s a generic product, and based on

characterization of reference material and your

test product, you can make the case that the

variability that you are seeing in your product is

no more different than of the best argument.

That gives you a leverage to now make a

rational decision with respect to what sort of a

biostudy criteria would be necessary.

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You can build flexibility, and not go

rigid with, say, the Japanese approach, which was

in your background packet, was to say do we really

need confidence interval criteria here. We just

want to confirm the mean values. It\'s a

confirmation rather than a complete full-fledged

study. One option could be that.

DR. YU: I think the message we are trying

to convey is when we explore alternative approach,

which could be a wide confidence interval, or your

scaling approach to show or to demonstrate the

bioequivalence is demonstrated with the additional

information, which is pharmaceutical development

information, will help us to make scientific

coherent decisions.

Right now we don\'t, we don\'t have those

informations. In other words, we are not able to

see how dissolution variability here may change it,

for example, in this case, if we change the pH,

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dissolution is very beautiful, so that is the data

we got. We have now seen this data I showed you on

the screen. Thank you.

DR. COONEY: Ken.

DR. MORRIS: A couple of points. One is I

agree with Marvin in the sense that you wouldn\'t

expect a company to release dissolution, I mean

going to a biostate with dissolution like that, but

I think those studies were done under different

conditions. These were done here, so they wouldn\'t

have seen that under normal dissolution conditions.

My more general question is\--

DR. YU: You are correct, yes, in normal

conditions, especially, for example, USP

dissolution, maybe you are not able to see.

Actually, dissolutions are beautiful.

DR. MORRIS: Right, so that comes back to

sort of our discussions yesterday in a sense. The

question I have is to what level or to what extent

do the ICH initiatives, I mean including the CTD

and Q8, impact on the ANDA, I mean is there an

intent that they follow suit with NDAs?

DR. YU: Obviously, the basic principles

from ICH and CTD, the CTD cure document for drug

substance and drug products, it is not just for NDA

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only, for both NDAs and ANDAs. ICH Q8 is, in

principle, a part into NDAs, certainly the basic

principle also apply to ANDAs.

The way I actively look into this to

document and to see what information will help us

to make scientific decisions. Certainly, as I said

before, we are not looking for information which is

nice to know, we are looking for information which

is essential to know.

DR. MORRIS: I guess to that end, because

this is something, of course, we have been

discussing for several years, but the idea that

rather than having checklists of what the companies

have to do, if they can make scientific decisions

based on the intended dosage forms and the

properties of the API, which should be a lower

hurdle, I mean that should be known more by the

time you get to the generic.

DR. YU: Yes.

DR. MORRIS: Instead of having to do a lot

of the other testing that might normally be done,

if they can focus on the identification of the

critical to quality attributes of the product and

capture that in a development report, it seems like

that is a reasonable way forward.

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DR. YU: That is correct. In fact,

industry is coming forward and they share some of

the pharmaceutical development report with us, we

are actively looking into this to develop some kind

of review templates which will incorporate

pharmaceutical development information into our

review process.

Again, I said we are looking for

information which is essential to know, not nice to

know.

DR. MORRIS: Maybe this is for Paul, is

that a reasonable stance as far as how you look at

generic development?

DR. FACKLER: I am not sure exactly what

you are asking.

DR. MORRIS: I can clarify if you want,

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but basically, if you could, instead of having to

do sort of checkbox testing, if you could do

testing that was largely prescribed by your need to

establish certain scientific issues, rather than

having to do as many, let\'s say, sort of\--what is

the word\--statutory testing, if you will, is that a

reasonable stance for you guys?

DR. FACKLER: I don\'t see a problem with

that. What I didn\'t hear here was that there are

any different statutory requirements for highly

variable drugs.

If a generic company still needs to pass a

bioequivalence study, and we are going to assume

that the pharmaceutical equivalence is simple, I

don\'t understand what the generic company

understanding the origin of the innovator\'s

variability has to do with the approvability of a

lot of material that is shown to be

pharmaceutically equivalent and therapeutically

equivalent through a bioequivalence study.

I guess that is the piece I am missing.

Why is the burden on the generic company to

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understand the variability of the reference listed

drug, and what value does that have if really all

the generic company needs to do still is

demonstrate a bioequivalent product?

DR. MORRIS: You are talking about BE

variability now, not pharmaceutical?

DR. FACKLER: Yes.

DR. YU: Paul, if we use

one-size-fits-all, which is 80 to 125 percent to

some of drugs, you may have difficulty to pass the

confidence interval. So, when we are exploring the

alternative approach including the scaling

approach, you will have to demonstrate this product

is highly variable or not highly variable.

You have to know that because otherwise,

suppose someday in the future, if the scientific is

mature enough, we have a scaling approach, for

example, for highly variable drugs, your submitted

application did not show these are highly variable

drugs, how would we know these are highly variable

drugs.

So, you have to show, in your development

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report, that is a highly variable drug before we

move forward.

DR. FACKLER: Agreed, but wouldn\'t a

replicate design bioequivalence study inherently

capture the variability of the reference listed

drug?

DR. YU: Yes, if you choose to do so, use

replicate design, certainly, you are able to

demonstrate that reference list product is highly

variable or not.

DR. FACKLER: But that is already part of

an ANDA application is my point.

DR. YU: I guess, Paul, we have not

reached a consensus or we have not made a

determination you have to use replicate design.

DR. MORRIS: Is part of that the fact that

you are still struggling with the concepts that are

entailed in that dissolution plot where you can\'t

factor into the pharmaceutical variability, factor

the pharmaceutical variability from the clinical?

DR. YU: I guess the struggle we have here

is, look, Lawrence, in order for you to get this

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direct for pass, whether you use scaling approach

or you use widen the confidence interval, you

simply widen the confidence interval, let them to

pass. You need to explain why. You need to

explain why you think that is a feasible approach,

you think that is scientifically sound.

So, when you say explain why the

pharmaceutical development report can help us

provide additional information to explain why.

DR. FACKLER: I agree that certainly you

need to understand the variability of the reference

listed drug especially if a generic applicant is

claiming that the variability is an issue for this

particular product.

DR. YU: Correct.

DR. FACKLER: I am not sure what value the

steps that were taken has to that determination of

variability. Variability sometimes is listed in

the label for a reference listed drug; other times

applicants do replicate design studies or run

reference versus reference to measure that inherent

variability, but that would all be part of an

117

application already, as I understand it.

DR. YU: Yes, in many cases actually

lately for some of complex dosage forms. Dosage

form, we very often sent many, many deficiency

letters. Actually, company provide information

during the cycles, and as I said, at the GPA Chair

meeting, we have four or five or six cycles,

provide additional information to us, and

eventually, the product get approval. I am not

saying you not provide that information.

What I am trying to say is with the arena

of pharmaceutical development report in the ICHQ

paradigm, can you provide that information in the

application instead of for us to send many

deficiency letters.

When we see the OGD list receive 25

percent or more of the applications every year,

where do you want to put resource into those

reviews. Suppose you provide those additional

information, which I believe will help us in our

reviews, and they reduce the cycles, I see it\'s a

win/win situation for you and for us.

DR. COONEY: Ajaz.

DR. HUSSAIN: I think look at it from this

perspective in the sense the whole aspect is you

118

are trying to make a decision and you are trying to

choose the right measurement system here.

Now, the Code of Federal Regulations

essentially has a hierarchy of methods that you

choose for bioequivalence. Our current criteria is

a PK crossover, PK-based, pharmacokinetic-based

study is the most discriminating one.

So, you are looking at, you are trying to

now judge approvability of a generic drug, and for

that you need to establish its pharmaceutical

equivalence and its bioequivalence. The

bioequivalence measurement system that we have has

inherent variability, and much of that variability

is coming from the measurement system, and may not

be coming from the test samples that you are doing.

So, is this measurement system the ideal

measurement system right now or not? That is

really the question.

The dilemma that we have is the in vitro

119

characterization and in vitro testing with

dissolution often is not reliable enough by itself

to make that call. If it was, you would not be in

this dilemma.

So, if you really then look at it, what

are we saying, is we have information generally

that even if I give this drug intravenously or as a

solution, and so forth, the variability is coming

from the subjects, it is coming from physiology,

which is inherently variable. If I sleep on my

lefthand side or righthand side, it will make a

difference, I mean it literally happens.

So, that is the measurement system, but

then you are putting your product into that system

and trying to see is there a difference of 20

percent or not, and to meet that confidence

interval criteria, you need 600 subjects or 300

subjects, and so forth.

Can we utilize the signs of design to say,

to confirm, not necessarily to have a confidence

interval, a confirmation that the new formulation

actually is not contributing to that variability,

120

is there sufficient science to do that or not.

If it is, then it opens the door for

saying that the bioequivalence assessment then

could be tailored based on that understanding.

DR. COONEY: Before we go on to some other

questions, I would like to see if your question,

Paul, has been addressed.

I think the question was\--well, first,

Lawrence is proposing that there be a

pharmaceutical development report added to the

information that is part of the application, and

you are asking what will be the implications of

providing that additional information and

facilitating the next step, which is approval of a

bioequivalence.

DR. FACKLER: That is part of the

question. The other part was what would be in a

pharmaceutical development report that isn\'t

already part of an ANDA. That is really what I am

trying to understand, and, of course, then, what

value would that provide.

DR. COONEY: Is there clarity to that

121

question? So, that is back to Lawrence, to Paul\'s

question. What would be in that pharmaceutical

development report that is not already part of the

application?

DR. YU: I thought that was a topic of our

next advisory committee meeting.

DR. HUSSAIN: Let me put it this way.

There is nothing there right now. There is nothing

there to even gauge the aspects of. So, what we do

is our decisions are made based on one batch test

results and the biostudy. That is what it is.

DR. MORRIS: Can I just weigh in? I think

part of this is that a lot of what would go in the

development report is stuff that people are already

doing, but doesn\'t just get included in a summary

fashion, much like we have discussed earlier, that

there is development studies you do, but you don\'t

put together.

That is what we were talking about

yesterday, is that, as a reviewer, if you have to

try to piece together a development rationale from

data here and there, you end up with sort of a

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development rationale that the person filing really

wouldn\'t want to be there displayed to the world,

you know, sort of a Frankenstein development

report.

So, if the company does it, then, they can

see the logic that you use. Whether they agree or

not is a different question. So, in my sort of

concept of this, which may be flawed, of course, if

the company, let\'s say, had used Cynthia\'s

dissolution method, because they said this is what

has really mattered, and they got those curves to

overlay, then, that is a big step forward to say

that the variability that may come out of the BE

studies are not due to our change.

So, if you see the variability of the BE

studies and you have demonstrated that it is not

due to the lack of adherence to a design space, for

lack of a better word, then, that has got to be as

good as the innovator. That is my concept. This

may be down the road, as Jerry said.

DR. YU: I want to make comments that when

we say the pharmaceutical development information,

123

I think I emphasize those information that is

essential to know, not just for nice to know.

We are looking into this, what additional

information will help us in making decisions, and I

think we are happy to share with you in the future,

but at this point, we cannot say that for every

single ANDA or for every single product, you need

the pharmaceutical developed, because you have a

prior knowledge, some of the information already

there, so this need clarification when you are

understanding what additional information is

provided. I think we need to discuss and work it

out.

DR. FACKLER: I understand. To Ken\'s

point, you start over here and the bioequivalent

product is over here, and sometimes you take a

direct approach to it and sometimes you don\'t. You

are right, oftentimes it is over here and then you

realize you need to be over here, and then finally,

you get where you need to be.

But I am not sure I understand the value

or what it matters what path you took as long as

124

you end up in the right place. All this

information does exist, of course, and the field

inspectors have access to it, and we are just

reluctant to expand the content of an ANDA in the

fear that it will slow down an already overburdened

review process.

So, where the information is critical to

understanding whether a product is pharmaceutically

or therapeutically equivalent, of course, it ought

to be submitted, but where it is not essential for

that evaluation, I just question whether or not it

ought to be added to the burden of the reviewers.

DR. COONEY: Art, then Marvin.

DR. KIBBE: Let\'s get back to what we are

trying to determine, and that is whether or not a

clinician who prescribes this medication for its

effect has got a reasonable expectation of a

therapeutically similar outcome when he uses the

innovator or when he uses the generic. That is

where we are.

If a product is inherently variable, as

manufactured by the innovator, then, we ought to

125

know that early on, and as Les correctly points

out, if that was the case during development and

prior to approval, it wouldn\'t make it on the

market if it wasn\'t that that breath of variability

was allowable for clinical outcome, because if the

clinical outcomes wouldn\'t\--there were times when

there were failures and times when they were

toxicities apart, never gets on the market. which

means that we have already historically established

large variability is okay, because we have that

product on the market.

Now, if I am a generic company, all I want

to do is say that I am going to be no more than, or

perhaps less variable, and I am going to get to the

same therapeutic outcome.

If I can test a replicate design that

shows that my level of variability is lower than or

equal to the variability of the innovator, and my

means are on target, then, I can with reasonable

assurance argue that my product used in the

marketplace on patients is going to have the same

efficacy and failure rate as the innovator.

The second thing is we already have agreed

that dissolution is a hammer when we need a

surgical scalpel to figure out what is going on,

126

and if you make a shift in a dissolution criteria

and all of a sudden you can differentiate tablets

from the same batch, but that batch used in people

isn\'t differentiatable, then, you are making a

differentiation which is of no value to anyone

except if you want to go back and process improve.

In fact, that is what it should be used

for. The companies ought to be investing time and

energy in process improvement by looking for better

differentiators for their own internal consistency,

and perhaps they could narrow the variability if

they found them.

I think the justification for going to the

study that you said that if they used the USP

numbers, they would all pass, and going to your

numbers, we have this high variability, but that

high variability doesn\'t relate to clinical

outcomes.

Now, I am coming on the market as a

127

generic. If I can establish that I am not more

variable than they are, and my means are the same

as they are in a biostudy, how much more

information does the agency need? I don\'t think it

needs much more.

DR. HUSSAIN: Art, you are missing the

point in the sense to demonstrate that your

variability is acceptable, you actually have to do

more now through a bioequivalence or replicate

design, and so forth.

What we are saying is in the sense, there

are ways or there should be ways to sort of the

justification that goes into a formulation that you

move forward, could then become a basis to say you

don\'t have to go through extraordinary means to say

the variability is unacceptable.

So, if we know a drug substance is highly

variable, you mostly have that information that

says you sort of at least definitely will when you

approve the product, then, the signs of formulation

design could provide you a basis for saying there

is no reason your particle sizes, which are

128

critical for your dissolution, your coating

thickness, which are your release mechanism, are

essentially being controlled, and so forth.

So, why should a generic form then have to

do a large study with replicate or with whatever?

Isn\'t there an option available for something\--

DR. KIBBE: So, what you are really

talking about is a waiver of what we would say

would be a standard replicate design to get around

variability.

DR. HUSSAIN: Exactly, so that is what we

are suggesting.

DR. KIBBE: So, the company then would

come with its own development data and show that a

broad range of dissolution numbers are not highly

variable or something.

DR. HUSSAIN: Yes, the way I would think

about that is in a sense if it\'s a tablet, I will

go to the basic mechanisms of what the dissolution

will be affected, and here is my assessment of my

particle size, here is my control strategy, here is

the prior knowledge of similar dosage forms. There

129

is no apparent reason for this to be variable from

that perspective.

So, that becomes a basis for a decision

criteria saying that why would we expose normal

healthy subject volunteers, a large number of them,

to simply get our numbers within the confidence

interval criteria, which is somewhat arbitrary.

That is the crux of this.

DR. YU: I don\'t know if I can clarify,

the point we are trying to make is that if you can

conduct bioequivalence study now to best pass the

confidence interval, this is good enough. I am not

saying this is not good enough. We are not asking

additional information.

The problem which we are facing is you

will not have difficulty, it is not impossible if

you have recruited 1,000 or 2,000 subjects, it is

almost impossible to do by a current study, and

this is scenario that pharmaceutical variability

information may come into play and to help us out.

That is what we are trying to convey. Thank you.

DR. MEYER: I think part of my problem is

130

that I believe what you are putting forth is a

concept without any data, which obviously you can\'t

have yet, because the concept hasn\'t even been

implemented, it is just a concept.

I think certainly from my perspective, if

you have some ideas that might streamline the whole

system, I would say go for it and then let\'s see

the meat once the skeleton is exhumed, so to speak.

That is the bottom line, but I think there

are some other ideas in there that are perhaps

easier for me to understand, characterize the

reference listed drug and then presumably, if you

have done that, FDA will take that into

consideration to explain why you have confidence

limits that aren\'t up to par perhaps.

For example, a simple example, the RLD has

an overage in it of 10 percent. They claim that

isn\'t released ever, so they just have it in there

because their release mechanism doesn\'t allow for

except 100 percent.

You have some evidence that says well, in

fact, it is released 110 percent sometimes, so the

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poor generic company is already 10 percent in the

hole when it comes to AUC. If that can be

demonstrated in some reasonable scientific fashion,

that ought to maybe taken into account.

A better example maybe is with the osmotic

pump. We have done studies where you can harvest

the ghost out of the feces, and sometimes it has 50

percent drug in it, sometimes it has 10 percent,

sometimes it has no drug in it. It seems to be a

direct function of intestinal transit time.

Well, if you are a generic trying to match

without using an osmotic pump, you don\'t have a

snowball\'s chance in hell of coming across and

matching a product that sometimes is 50, sometimes

is 100, sometimes is 10 percent.

So, I think as long as you hit the means,

and you bring that kind of data to FDA, they ought

to have the latitude of saying yeah, we know that\'s

a problem with the RLD, and we can therefore adjust

our thinking when it comes to the generic.

Obviously, that is going to take a fair

amount of work, but I think that these things need

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to be thought of, as well as more statistically

based ways of dealing with high variability. That

is kind of a short-term fix which ultimately once

the statisticians get done fighting, then, the rest

of us can agree, but the other is certainly a

concept worth pursuing, I think.

DR. SINGPURWALLA: I would like to respond

to that.

DR. HUSSAIN: If I may, there is an aspect

what Marv just said in the sense a practice that

all of us know exists is when you have variability,

then, you pick and choose what your comparator is.

I mean it bothers me in a sense to say that, you

know, you can pick and choose what lot you will

compare to, and so forth.

Why do we have to sort of have those type

of decisions where, you know, I think we can be

better than that, so I think just to build on what

Marv says, to say that I think we can really be

confident in what we are doing, and not to feel a

bit guilty that we are picking and choosing what we

test, and so forth.

DR. MEYER: As you well know I am sure,

there are a number of countries. You do your

dissolution on three lots of the RLD and then you

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pick the one in the middle, not the one that is

closest to what your product happens to be.

DR. YU: I want to make comments about

Marvin\'s comments. Yes, in the case here, what you

present, actually, those information is not in the

original ANDA submission, but those information

eventually is shared with us.

So, go through many cycles, many, many

months, or even several years to get us that

information. What we are seeing is that we think

if those information, which you eventually shared,

only a couple that go through the five or six or

seven cycles, shared in first place will help us to

make decisions, will help us to reduce cycles, will

help us actually use the resource wisely. That is

what we are trying to say. Thank you.

DR. COONEY: Nozer.

DR. SINGPURWALLA: General comments.

First thing, Ajaz, don\'t use the word confidence

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limits for those two boundaries. Call them control

limits. Confidence limits are completely

different.

The second thing is you are fighting, at

least there is a lot of discussion because there is

a lot of variability. What you seem to have done

is taken reactive approach, have said variability

is there, what shall we do about it.

Well, yesterday, you talked about 6 sigma

in one of your slides. Well, I think wherever you

have these high variability issues, whether they be

in industry or whether they be within your own

system, I would encourage you to put into practice

what you were preaching yesterday about 6 sigma.

I would say, you know, has anybody thought

about that, because 6 sigma came about in industry

because there was a lot of variability, and they

said how do we control it. Well, you just don\'t

control it by doing statistical methods. You

control it by proper management and proper

procedures, and I would say that you should try to

bring that into the arena.

DR. COONEY: Paul.

DR. FACKLER: The generic industry is just

as interested in minimizing the number of 6 and 7

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cycle reviews on products. Clearly, we have the

same goal in mind.

I guess what I would suggest is that for

highly variable drugs, for instance, it would be

useful for the agency to tell industry the kind of

information that is generally lacking, but with 500

applications a year, or 800, whatever the numbers

might be these days, coming into the agency, I

don\'t think it is wise to require this information

on all of the applications.

I would suggest maybe we clarify the

additional information that is often being left out

of submissions for highly variable products, and

presumably, generic companies in the interest of

having a minimum number of review cycles will

submit it the first time rather than an iterative

process to give you all the information that you

need to make a fair decision.

DR. COONEY: Gary.

DR. BUEHLER: For the development reports

in general, I thank you for not wanting to

overburden us with additional information. We do

have a lot to look at. If we do get additional

information, we will look at it for sure.

I know that we get some amount of this

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information sprinkled through the ANDAs and I would

think Ajaz was a bit draconian when he said all we

get is the batch record and whatever. I mean there

are explanations. We do demand explanations when

there aren\'t any deviations from what we normally

see, that is in ANDAs and we do look at that.

Lawrence and a group is working on a

question-based review for the Office of Generic

Drugs. It is a very detailed project. He is

working with experienced reviewers in our office,

and he is developing this in a very stepwise

manner, both first by involving both the

supervisors and reviewers in our own office, and

then at a certain point we want to sort of unveil

it to industry.

We want to make sure that when we do bring

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this new review method and these new requirements

or whatever you want to call them with respect to

pharmaceutical development reports, the industry is

very aware of what we want and why we want it, so

that they will feel good about giving us this

information, and like Lawrence said, it will

hopefully reduce the number of cycles we have, it

will not overburden the reviewers, but, in fact,

reduce the burden on the reviewers, because they

won\'t have to see the same applications four, five,

or six times, and they will understand why we need

this information.

It is also a risk-based system, so that

there are some applications that you won\'t have to

provide this type of information, because there are

some applications obviously that are easier than

other applications, and the applications for

complex dosage forms and unique dosage forms

obviously, we are going to ask for more information

than for the vary standard solid orals that are

fairly easy to manufacture.

But we are doing this over a two-year

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period and hopefully, sometime toward the end of

this year, we will be able to begin to tell

industry what we hope to expect in the future

applications and industry will be comfortable with

it.

DR. MORRIS: I just have a quick question

for Gary. I am assuming that development reports,

as you say, depending upon the complexity of the

dosage form, I mean they can be relatively brief if

it\'s a very simplistic or simple dosage form, so I

am not so sure that it\'s the burden if the payback

is fewer review cycles or less clinical studies.

Clinical studies are a lot more expensive than

writing a development report and doing a few more

development studies.

Is that more or less the case, Gary?

DR. BUEHLER: I am not sure it is going to

be able to be submitted in lieu of a study or

whatever.

DR. MORRIS: No, I meant the extensiveness

of a development report.

DR. BUEHLER: Some development reports

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will say we wanted to develop a bioequivalent

formulation, and, you know, here it is, and it

could be a page or two. I mean clearly, it won\'t

be very long for a generic, because the goal of a

generic is pretty evident, but other development

reports will be more extensive, so yeah, you know.

DR. COONEY: It sounds like there is a

need for clarity on what will be requested and

expected, and also for clarity on what the

implications of that will be. It sounds like that

will be forthcoming.

Ajax, what I would like to do is move on

to the next presentation.

DR. HUSSAIN: Just go back to the original

intent. Our initial thoughts that we wanted to get

the discussion started, so we never intended this

to make a proposal, so these are initial thoughts

and we are moving forward with this.

If industry wants to be proactive, they

had better start thinking about it and how they can

use this opportunity instead of asking us what do

we want. I think it is equally burdensome on

140

industry to think about how to develop the products

for the intended use, and make the case, and grab

that opportunity.

If not, the system as it stays, we are

perfectly happy with it.

DR. COONEY: So, there is an opportunity

here for dialogue and there is no doubt from the

last 45 minutes that there will be dialogue.

I would like to ask Robert Lionberger to

proceed with the next presentation.

Using Product Development Information to Support

Establishing Therapeutic Equivalence of

Topical Products

DR. LIONBERGER: Today, I am going to be

discussing how to apply the concepts of

pharmaceutical equivalence to topical dosage forms

and look at how this is related to quality by

design.

Here, I am going to focus on topical

dosage forms that are in the local delivery, so not

products such as transdermal products that are

trying to deliver drugs systemically.

In the Office of Generic Drugs, as you

have heard several times before this morning, our

mission is to provide therapeutically equivalent

141

products to the public. When someone uses a

generic drug, they should expect the same clinical

effect and safety profile as the branded reference

product.

Just to summarize some things that Ajaz

talked about in his introductions, the preface to

the Orange Book explains how we do that. Products

must be pharmaceutically equivalent and

bioequivalent. But I want to dig a little bit

deeper into this and ask why do we actually require

both, why isn\'t bioequivalence by itself enough to

determine that the products are the same.

One aspect of that is that consumers have

some expectation about product behavior. If the

reference product is a capsule, you don\'t want to

replace that with a solution. So, there is some

user experience and expectation.

So, pharmaceutical equivalence

encapsulates concepts related to like the user

142

interface of the product, but then there is another

aspect to it, and I have tried to express it here,

is that pharmaceutical equivalence supports the

determination of therapeutic equivalence based on

bioequivalence study.

We don\'t say that just because two

products pass a bioequivalence study, they are

therapeutically equivalent products. An example

might be an oral solution and a tablet. There can

be many products for which those two dosage forms

would be bioequivalent, but we wouldn\'t say that

they are therapeutically equivalent products.

One aspect of that is that our current

determination of bioequivalence is really very

strongly based on in vivo testing. So, again,

there are limitations to testing. We test these

products in a small population and then we

extrapolate that conclusion to all people who are

going to use the products from all batches in the

future.

So, to sort of back up that extrapolation,

there is some other information. Right now that\'s

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the pharmaceutical equivalence between the products

that supports that.

In the occasions when we do equivalence

studies in patients, there are other differences.

Sometimes the clinical endpoints aren\'t very

sensitive to small differences, bringing in

examples from topical products, you can imagine

there are cases where, say, a cream and an ointment

formulation might have the same therapeutic effect,

but they wouldn\'t be considered pharmaceutically

equivalent products or therapeutically equivalent

products even though the clinical endpoint study

might show equivalent efficacy.

Again, from the sort of pharmacokinetic

studies for one of the challenges that is often

made to some of our bioequivalent studies for

topical products is since the skin is a barrier,

you say, well, healthy subjects have healthy skin

barriers. There is a question. Sometimes people

will claim in patients, the skin might be diseased

or damaged, so that is a common concern. There is

a common challenge to some of our bioequivalence

144

determinations here.

So, inside of the pharmaceutical

equivalence concept, there is some idea of other

things we want to know about the products to sort

of generalize this idea of equivalence.

If you think about this and want to sort

of tie this to quality by design, one way that

might be useful for you to think about this is that

our current definition of pharmaceutical

equivalence might be considered a first step toward

a quality by design.

If you were going to design equivalent

products, the first things you would start with

were some of the concepts that are in our current

definition of pharmaceutical equivalence. You

would want to have the same active ingredient. You

would want to have the same strength, the same

dosage form.

So, if we look at sort of a different way

of looking at our paradigm, maybe instead of a

regulatory framework, a more scientific framework,

what we are doing when we review a generic product,

145

is we are looking to see is the product designed to

be equivalent, and then does it demonstrate

bioequivalence in an in vivo study.

So, you can see sort of this combination

sort of parallels our current sort of regulatory

framework of pharmaceutical equivalence and

bioequivalence leading to a determination of

therapeutic equivalence, where we might say that on

sort of a scientific level, what we might want to

be doing in the future might be to say look at the

quality by design, look at the generic product that

is designed to be equivalent to a reference

product, and then based on this design, choose the

appropriate either in vitro or in vivo

bioequivalence testing for this product to complete

the determination of therapeutic equivalence.

So, I want to bring this sort of

conceptual framework and bring it into this sort of

particular example for topical products. Sort of

to motivate that, I just want to outline some of

the complex issues that we deal with that are

related to pharmaceutical equivalence for topical

146

products.

Again, we have a lot more experience with

immediate release, oral dosage forms in effective

excipients, what excipients you can change, what

excipients you can\'t change. For topical products,

a lot of times the excipients may or may not affect

the barrier properties of the skin and drug

delivery.

We don\'t have as much experience about

that, so a lot of times we are worried about what

differences in formulation are appropriate for

comparing a test in a reference product - is a

change in solvent appropriate, what if the base of

the formulation in ointment or cream has changed

from being hydrophilic to lipophilic, how much

water content should there be in the product. You

might affect evaporation, the feel of the product.

A lot of these sort of differences in

formulation get wrapped up into the question of are

two products the same dosage form. I will talk a

little bit more in detail about that in the rest of

the products.

We also have questions, when we don\'t have

good bioequivalence methods for use for topical

products, what indications should be used for the

147

clinical equivalence studies. Perhaps the product

has multiple indications, which one is the most

appropriate one to use.

These are the kinds of issues that we deal

with in generic topical products. Some of the

implications of these for the ANDA sponsors are

that the approval times for these products can be

longer. If there are these issues that we don\'t

have a good understanding internally, we have to

schedule meetings with the appropriate people, have

to have internal discussions.

When the sort of standards aren\'t clear,

this is an opportunity for the reference listed

drug sponsors to challenge correspondence to OGD or

through the citizen petition process that we have

to address the scientific issues there that aren\'t

sort of clearly defined.

A lot of times, at the end of these

discussions, we will end up going back to the

148

sponsors and asking them for more information to

help us resolve these issues, and then usually that

is done through deficiency letters to them, and it

ends up with sort of multiple review cycles.

So, as we heard in Lawrence\'s talk, there

is the question of more product development

information in the ANDA itself may help OGD deal

with these issues more efficiently.

This is sort of very similar to some of

the things that Lawrence talked about, that there

are harmonization efforts underway that describe a

product development report, but I think it is clear

that these are mainly aimed at new drug

applications, so it is not sort of obvious or clear

how these should apply to ANDA sponsors.

I think the theme of this talk to see this

as an opportunity, these development reports, as an

opportunity to provide information that will help

the agency set rational specifications for products

that are complex, for immediate release oral dosage

forms we have various standard systems set in

place, but for topical products, where we have less

149

experience, the more information that is provided

about, say, why was an excipient changed, and why

do you know that it is not going to have any effect

could be very helpful to us in making efficient

decisions.

Again, the product development reports are

the place in the application to emphasize the

quality by design, that the product is designed to

be equivalent. That will help us set the right

requirements for the bioequivalence testing for

particular products.

This is just a few examples of what some

of these harmonization documents say about a

pharmaceutical development report.

In this case, again, the key part here

might be to establish that the dosage form and the

formulation are appropriate for the purpose

specified in the application, or in the Q8

document, it talks about an opportunity to present

the knowledge gained through the application of

scientific approaches.

Here, it is talking specifically about

150

sort of formulation and development for the topical

products, that there is information that the

company that is developing the generic product

knows about why they made certain choices in the

formulation. It would be very helpful to us in

deciding that that is acceptable, where the agency

itself has less experience with particular dosage

forms.

I have emphasized this concept of quality

by design or, in the case of the generic products,

quality by design means you are designing the

product to be equivalent to the reference product.

So, I want to try to be a little bit more

specific about what that means. There are two

cases. One, the mechanism of release. Clearly,

the mechanism of release between a generic product

and the reference product can be different, but the

intent of those different mechanisms ought to be to

produce the same rate and extent of absorption.

This is the bioequivalence criteria.

Again, we also recognize that depending on

the particular product, that the release rate from

151

the product might not be the rate controlling step

at absorption. So, the determination of how close

release rates might have to match would depend on

the absorption process involved and what is the

rate-limiting step in the absorption process.

Again, between generic products and

reference products, the excipients can be

different. Again, it is a good thing to understand

the differences between the excipients.

The IIG limits are a starting point. They

tell you that this excipient has been used in this

dosage form up to a certain amount, and that really

addresses, specifically in the case of topical

products, safety-related exposures, so you know

that level of exposure.

The thing that complicates the topical

products is when you change the excipients, the

real question that we often deal with is do the

changes in the excipients to the products affect

the permeation of the drug through the skin. I

think that is the sort of challenging question

there for the topical products that we occasionally

152

have to deal with.

Again, as I said, the purpose of quality

by design is to design the equivalent product. I

want to just give sort of three sort of examples of

this process here.

The first is talking about Q1 and Q2

equivalent products for topical products, and then

look at what happens when you make changes to the

formulation, they become Q1 and Q2 different, and

then this leads into the discussion of issues

related to the dosage form classification and how

product development information might help us make

a better decision or more scientific based

decisions on dosage form classifications.

First, I want to start off with the

definition of Q1, Q2, Q3. So, products that are Q1

have the same components, so both the generic and

the reference product would have the same

components.

If products are Q2, they would have the

same components, but they would also have the same

amount of each ingredient.

The Q3 concept is same components, same

concentration, but here I am saying same

arrangement of material or microstructure, and this

153

is particularly important for topical products that

are semisolid dosage forms, so non-equilibrium

dosage forms, where you might have, say, an

emulsion with exactly the same components, exactly

the same concentrations, but say, for example, the

droplet size might depend on how you have

manufactured that product.

So, there is potential differences for

semisolid dosage forms depending on how they are

produced even if overall the composition is exactly

the same.

A contrary example would be a solution.

If a solution is Q1 and Q2, because the solution is

at thermodynamic equilibrium, you would be able to

say we know that this product has exactly the same

arrangement of material in the product.

The importance of the Q3 concept is when

you know that the products have the same

arrangement of material, you know that they are

154

going to be bioequivalent, there is no question

about that. An example of that is again a solution

where you know that the products are in

thermodynamic equilibrium if the compositions are

the same, the structure and arrangement of the

material is the same.

Unfortunately, for most topical semisolid

dosage forms, they are not necessarily equilibrium

arrangements of material, and so a direct

measurement of Q3 level equivalence is challenging.

So, if we have the topical products where

Q1 and Q2 are identical, again, the only potential

differences are differences in this Q3 parameter,

which can come from differences in manufacturing

processes, because they are not going to be

manufactured by exactly the same process.

We know for particular semisolid dosage

forms, such as emulsions, that rheology and in

vitro release rates can be very sensitive

measurements of microstructure and are related to

product performances.

So, the sort of idea that sort of

155

advancing here from a scientific point of view is

when the products are Q1 and Q2, that in vitro

tests should be equivalent to ensure bioequivalence

of the two products, because again here, the issues

are detecting differences due to differences in

manufacturing processes, and the argument would be

that in vitro tests are the best evaluation method

to detect whether any differences in manufacturing

process have significant differences in the product

formulation or performance.

Now, things get more complex when a

generic product and a reference product have

different compositions, and this connects with the

dosage form classification, and these differences

occasionally could be barriers to generic

competition.

A generic company might want to formulate

products that are Q1/Q2 different because the

innovator has formulation patterns, so there might

be either legal reasons or perhaps manufacturing

process reasons why you might want to formulate a

product that is not exactly identical in

156

composition to the reference product.

One of the products, again, one of the

members of the Committee mentioned the sort of

economic effect of uncertainty on product

development if you don\'t know what dosage form the

product is going to be classified as. That adds

cost to the development process because of

uncertainty of what is going to happen to the

product.

In particular, if we think about methods

by which we would classify the dosage form of

topical products, here, I have generated a list of

four possible ways that you could approach this.

One is we would just use whatever the

sponsor says their product is as long as it is

consistent with some of the traditional definitions

that are available in various sources, and we will

look in sort of detail at some of those traditional

definitions.

You might say, well, the generic product

is the same dosage form if it feels the same to me,

so I will just try it out and see if it is the

157

same, if it passes. You know, if the look and feel

of the products are the same. That is getting to

the aspect of pharmaceutical equivalence, a sort of

patient experience rather than sort of scientific

issues related to product performance.

Then, I am going to sort of discuss recent

work that the FDA group led by Cindy has done on

looking at a whole bunch of products and coming up

with a quantitative decision tree to classify

topical products.

Then, sort of the fourth aspect of that is

looking at whether or not issues about dosage form

classification for complex issues would be

something that you would want to include in a

product development report, so justifying the

formulation development as being the same as the

reference product. That sort of might be a more

scientific way to look at these issues.

First, if we look a some of the

traditional definitions. Here, I will just focus

on the difference between a cream and an ointment.

One source is the CDER\'s data standards

158

definitions. These are sort of similar to USP

definitions of these products.

The cream is a semisolid dosage form

containing one or more drug substances dissolved in

a suitable base, and then it says more recently the

term has been restricted to products consisting of

oil-in-water emulsions. That is obvious what a

company should do - does a cream have to be an

oil-in-water emulsion or not.

Then, it talks about products that are

cosmetically and aesthetically acceptable, is part

of the definition of the cream, so that is not very

quantitative. It is hard to say is this product

aesthetically acceptable. That is really opinion

based.

An ointment is a semisolid preparation

intended for external application. It seems to me

that a cream could be a semisolid preparation and

fit under the ointment definition. So, it doesn\'t

seem that those two definitions are really

exclusive.

In another FDA guidance, this is the SUPAC

159

semisolid guidance. It has a glossary with

definitions of dosage forms, but these aren\'t the

same as the previous ones. A cream is a semisolid

emulsion, and an ointment is an unctuous semisolid

and typically based. So, typically based is not

sort of a definition, it doesn\'t have to be based

on petrolatum.

This definition talks about an ointment

being one phase, and not having sufficient water.

Again, the USP definition is sort of similar to the

one in the CDER data standards, but it is not

word-for-word identical, and talks about four

different classes of ointments.

So, again, the problem with the

traditional classifications is they are not really

consistent, and not very quantitative. So, a lot

of the sort of decision process would depend on

what your opinion was of a particular product, and

they might be overlapping, like you might be able

to call\--under a particular definition of a

particular product, you might be able to call it a

cream or an ointment.

So, the result of this Topical Working

Group led by Cindy has been presented to previous

advisory committee meetings, and they recently

160

published a paper outlining this classification

scheme.

What they did was they surveyed existing

products and devised a classification scheme, and I

just included the classification scheme here just

for reference in the presentation.

These are just some slides from their

previous presentations to give you the general idea

of what they did. They measured particular aspects

of products, say, creams and ointments, they

measured viscosity.

They looked at the loss on drying, and

then based on these products that were either on

the market or manufactured for them, they came up

with a classification scheme that sort of put the

products in the right category based on existing

products.

The real advantage of this is it is

quantitative. If you take a product and you go

161

through and you measure the things outlined in

their decision tree, you will always end up in the

same place, and it will always be consistent.

In addition to that, this is a very data

driven approach. They looked at the products and

then drew the lines. It wasn\'t said here is sort

of a mechanistic definition of what a cream or an

ointment should do.

So, the question is, could this be overly

restrictive. If you follow this classification

scheme, you would be restricting products to

essentially what has been done before, and then

there is a question.

They didn\'t survey every product that is

on the market now, so there is a question, if a

reference listed drug falls into a different part

of this classification scheme, then, it\'s labeling.

So, it might be labeled as a cream, but by the

definition, it would be classified as an ointment.

What should a sponsor do in that case?

So, the final sort of approach to dosage

form classification might be to look at a more

162

scientific view of the formulation design. I just

want to point out that sort of the legal aspects,

referring to topical use, sort of point toward this

here from the CFR.

It talks about inactive ingredient changes

for topical products. It says again that

abbreviated applications can use different

ingredients if they identify and characterize the

difference and provide information demonstrating

that the differences do not affect the safety or

efficacy of the proposed drug products.

So, a current way of looking at is a

change in formulation acceptable, you should check

the new excipients against the IIG. As I said

before, this looks at the safety of the individual

excipients.

We also really consider that passing

bioequivalence tests are evidence that the

formulation change is acceptable. That is one

strong piece of evidence against that. But again

the product development report is an opportunity

for sponsors to characterize the differences.

Again, this could be important, you know,

if you are formulating a product and you are on the

boundaries of these, we have this empirical

163

decision tree, what happens if you are on the

boundaries, how do you explain that this product

should be considered the same as the reference

product, you know, from a scientific point of view

rather than empirical classification scheme, of if

someone says, well, no, your product is not really

an ointment because it doesn\'t meet a particular

published definition.

So, again, the product development report

is the opportunity for a sponsor to characterize

the difference that is sort of requested in the

statutes.

Again, also, in the statutes, they list

reasons to reject ANDAs, and they talk about drug

products for topical administration where there is

a change in lipophilic properties of the vehicle.

Again, in this case, a product development

report is an opportunity for sponsors to explain

why the changes, Q1 and Q2 differences are

164

appropriate for this particular product.

If this issue comes up, a lot of times we

will actually have to go from the review process,

you will have to go back and ask sponsors for more

information about these particular issues. So, the

development report is sort of an up-front way to

explain the reasons for doing that.

Just to sort of conclude the discussion

here, the first concept is the importance of Q1,

Q2, Q3 classification to identify appropriate

bioequivalent studies for the level of difference

in the product design. If a few products have

exactly the same active and inactive ingredients,

you might want to request different in vivo

bioequivalence studies than for a product where

there has been a change in inactive ingredient that

may affect the absorption of the drug product.

So, here again, we are looking at the

second concept, we are looking at the evolution of

the concept of pharmaceutical equivalence where we

have these traditional dosage form definitions,

maybe now backed up by empirical decision trees,

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but in the future, looking for a quality-by-design

aspect where the determination of whether a product

should be considered equivalent would depend on the

mechanistic understanding and the formulation

design rather than some traditional definitions,

and that the ideal state would be that this

understanding would reduce the need or allow us to

set the appropriate in vitro testing for a

particular product, and also to expand sort of the

formulation design space beyond past experience.

If you want to formulate a product that

goes beyond, say, an empirical dosage form

classification, this is the sort of way that you

would approach it, by providing the scientific

information to show that the formulation you have

chosen gives equivalent performance in the key

attributes as the reference product.

With that, I will conclude my

presentation.

DR. COONEY: Thank you. I believe the

purpose of your presentation today is to bring us

up to date on the current thinking where you are

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and where you are going as opposed to requesting a

specific action on our part, is that correct?

DR. LIONBERGER: Yes, that\'s right.

DR. COONEY: I would like to invite

questions and comments from the Committee. Yes,

Cynthia.

DR. SELASSIE: This is a very general

question. With all these product development

reports that you get, obviously, there is going to

be a lot of information that is extraneous and

won\'t be useful for that particular application,

but will you all retain this information like in a

database, so that it could have use down the line?

DR. LIONBERGER: I don\'t know if we would

retain it in a database, but I would say that like

as Lawrence said, we are looking at our review

process, and in that, had the opportunity to read

several product development reports.

I find that they are a very useful way to

get an overview of what is going on with a

particular product. You know, an hour of reading

the development report, it seems like a very good

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way to start the review of the application in more

detail, so I think it can be very valuable.

We don\'t have much experience with using

them yet, so in that sense, it could be valuable,

but we don\'t know how we would use that information

or store that information in the future.

DR. HUSSAIN: If you are suggesting that

there is a need to capture and create databases, I

think we do want to move in that direction, and we

tried to do that. Currently, our systems does

capture some of the key aspects. The inactive

ingredient guide is a process that we capture every

inactive ingredient that comes, but developing a

formal knowledge base would really be helpful, and

I think we have been thinking about it.

I tried to do that with immediate release

dosage forms and actually did some modeling with

that data that we have, and so forth, so we will

look into that.

DR. COONEY: Are there any other questions

from the Committee? Marv.

DR. MEYER: Just a quick comment. You

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have my sympathies. I thought it was difficult to

determine how to do the BE studies on topicals, and

now I have been reinforced, you don\'t even know

what slot to put them in the Orange Book if they

are bioequivalent, so you have a big job ahead of

you.

DR. COONEY: If there are no further

comments, Robert, thank you very much.

There have been no requests for

participation in the open public hearing at 1

o\'clock, so we will proceed with the continuation

of the discussion on quality by design precisely at

1 o\'clock when we come back from lunch.

We will begin that by a presentation of a

summary of the plan by Ajaz, and then we will

continue the discussion that we began earlier this

morning.

So, enjoy lunch and we will see you back

at 1 o\'clock.

\[Whereupon, at 11:59 a.m., the proceedings

were recessed, to be resumed at 1:00 p.m.\]

169

A F T E R N O O N P R O C E E D I N G S

\[1:00 p.m.\]

DR. COONEY: I would like to welcome

everyone back from lunch.

We will proceed with the afternoon

schedule. The first topic this afternoon will be

Ajaz Hussain, who will provide a summary

description of the plan to go forward.

Quality-by-Design and Pharmaceutical

Equivalence (Continued)

Summary of Plan

DR. HUSSAIN: I am going to go back to the

slides I used in the morning instead of the ones I

had for this session. That was based on the

discussion that occurred.

Just on reflection, I just want to make a

couple of points. Yesterday, in a sense, as part

of the tactical plan to start our journey towards

the desired state, in a sense what we have done at

this meeting is to take a look back last 10 years

or so to see how our policies have evolved and how

they could evolve with two tools that we have

170

introduced, the PAT guidance and ICH Q8.

Tom Layloff reminded me that in many ways,

some of the topics we have discussed, we have been

discussing for 30 years, and we keep discussing

those topics again and again, and the difference

that we have tried, at the training session that

some of you attended, I am clearly cognizant of the

fact that we are discussing topics that we have

been discussing for 30 years, and the quote I had

was the thing that if you tried to approach the

problem with the same tools and the same approach

again, we are bound to find the same solutions, so

we need something new.

What is new at the issue of this problem

is the science of formulation design, of science of

product design. The key aspect, much of that has

always been considered as an art, and as the

complexity of products is increasing, that art will

not be sufficient to really achieve the performance

we are trying to achieve.

So, it is a reflection back of saying all

right, 30 years of pharmaceutical sciences in

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particular pharmaceutics, industry, pharmacy, and

so forth, what have we learned and what we need to

learn more to do things differently.

In some sense, that is the heart of the

debate. I also sort of mentioned to you, and this

is my original starting point in the thought

process was that you really need at FDA more people

with that background to really make that happen. I

changed my thoughts over the last several years.

What we have at FDA is scientists from

many, many different disciplines who sort of work

together. The reason I changed my mind was I think

looking at some of the practices and formulation

development, and so forth, you really need a

multidisciplinary approach to challenge some of the

inherent assumptions which are in the system.

Therefore, I think what we have is

non-pharmaceutics people evaluating this is an

advantage, not a disadvantage, but then the key is

you have to put this in a scientific terminology

that can become negated across different scientific

disciplines. That is a significant challenge.

So, with that in mind, we want to make

this a scientific process. The review assessment

is a scientific process. Therefore, it has to be

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essentially a scientific format offer hypothesis

tested.

So, with that in mind, if I look back at

the SUPAC guideline, what we have done there is the

guideline was a first step in moving towards this

direction, and in a sense we tried to identify in

that guideline changes that can be classified as

minor, moderate, and major changes.

How did we accomplish that? We

accomplished that through expert solicitation is a

very real thing, not just where we had some

workshops, and where we collected the wisdom of

people in this area to say what are the changes

which are minor, major, and so forth.

Then, we took those recommendations and

actually challenged those recommendations through

experiments and studies that we did at University

of Maryland to design experiments, and so forth.

So, those are pretty much the recommendations in

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the guidance were very conservative. So, that was

the starting point.

Now, quality-by-design thinking forces and

challenges the industry to do this instead of FDA

doing this, and it says simply that if you could

understand your formulations and your manufacturing

process to such an extent that you can start

predicting the behavior of those things, then, you

will start getting process understanding, and that

information can allow you to document and justify

what is critical, what is not critical for your

given formulations instead of having a blanket peer

guidance to say what is critical or what is not.

So, that introduces the concept of needing

to prove that hypothesis of your design space.

With that in mind, what would that

hypothesis be in the sense there are two aspects of

the hypothesis that one could look at?

One is proving that you have understood

your formulation and manufacturing process to an

extent that you can predict the behavior or its

performance in terms of your shelf life, in terms

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of your bioavailability.

So, these experiments that you conduct,

you conduct them, you have to conduct them anyway.

Instead of sort of approaching them as testing for

the sake of testing, if you test those or you

conduct those experiments as a hypothesis, then,

you have a means to document your understanding and

a means to, in a regulatory sense, prove your

hypothesis through a hypothesis testing mode.

So, when you think about it that way, the

tests that you do today are no different except you

are approaching those tests differently as

hypothesis testing.

What that does is that creates a

flexibility for changing based on your

understanding, based on what is critical to your

formulation, and so forth.

There were several challenges to that.

One of the challenges was in terms of trying to

prove your hypothesis, trying to do testing in more

robust way, you do need to have estimates of

variability and bring variability into discussion.

So, yesterday, our discussion then focused

on was a dissolution test procedure, which is a

pivotal test procedure, which is a tool that is

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essential in product development. The implications

and the concerns FDA had in how are we setting

specification, we saw a disconnect there.

The variability in the dissolution test

method may itself not be large, but the disconnect

there was simply the suitability criteria opened a

wider door than what our specifications are, and so

forth.

So, a stringent approach, a stringent

mechanical calibration provides you a better handle

on your target value or your mean values, and doing

assessment of sensitivity of your formulations in

that test system gives you an understanding and

gives you a handle on the variability for your

given formulation.

So, that gives you a better handle on your

variability, and that helps you start setting up

your system to prove a hypothesis, and your

hypothesis could be that my understanding of my

176

formulations is such that I know what will happen

to my shelf life if I change this or what will

happen to the bioavailability if I change this.

So, your stability program, your

bioavailability studies that you do essentially are

a confirmation of that. So, if we repeat that and

use that as a decision criteria, you have become

proactive. So, that sets up the regulatory

flexibility that is needed in the concept of design

space.

Similarly, I think bioequivalence is a

hypothesis test. Instead of approaching it just to

document bioequivalence for the sake of documenting

bioequivalence, you turn that around and say that

is my test of hypothesis, I have understood my

formulation, I have understood my manufacturing

process, and I have also understood the product

that I am duplicating or I am sort of reproducing

to be equivalent, and therefore, my bioequivalence

test now is the test of my hypothesis of how well I

have understood, how well I have designed, and that

opens a door for that test becoming a hypothesis

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test, confirming your knowledge base, and so forth.

So, that combination opens the door for a

scenario that Lawrence talked about, in a sense

dealing with variability, which measurement system

do we use to ask the right question.

Clinical variability clearly is wider, and

the drugs are approved on the basis of clinical

trials. The variability and quality has to be

narrower by virtue of the system, and that is what

Janet talked about in the sense variability and

quality, or bioequivalence, we consider that as a

quality test, not a clinical test, because it is

not a clinical study, it\'s in healthy subject, is a

confirmation that your variability is acceptable.

With the question that we proposed with

highly variable drugs is trying to understand what

is the source of variability. We know that many

drugs are inherently variable because of the

pharmacokinetic characteristics, metabolism, and so

forth, that have nothing to do with the quality of

the product.

So, if you have understood your sources of

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variability in your manufacturing process, and your

manufacturing process and your formulation

strategies is consistent with the principles of

formulation design that you have used previously

and have documented lower variability, that gives

us a handle to say that variability in this product

is not expected to come from the product. It is

going to be inherent from the drug itself.

Then, your biostudy becomes a test of

hypothesis. Now, what is the hypothesis that we

might want to test there? The hypothesis could be

test of means, an analysis of means rather than

analysis of variance, because we have addressed the

issue of variance in terms of being comfortable

that the variance is coming from the drug

substance, and we have enough confidence to say the

variance for product is not expected to be

different.

So, instead of analysis of variance,

analysis of means could be one option to consider

there, instead of trying to do replicate design,

tend to do large subject, and so forth.

These are some of the initial thoughts

that we have, and these are clearly not proposals

at this time, and the intent of this discussion was

179

to simply initiate discussion dialogue, to have the

Pharmaceutical Committee get engaged in the

discussion to see what opportunities we have.

Highly variable drugs, topical products,

we have been debating these issues for decades, and

if we propose the same solutions, we will be

debating those for the next couple of decades.

So, I think it is an opportunity to think

differently. Similarly, I think some of the

biopharm classification system in the context of

design space, I think the biopharm classification

system becomes a pivotal tool for your decision

criteria that drives your decision to certain

aspect based on the drug\'s property and what you

are trying to achieve, and the biostudies that you

do again become a confirmation of your hypothesis.

So, one extension of BCS clearly is in the

post-approval world, more so than the approval of a

brand-new product, is the extension of SUPAC in

180

application of design space. So, that is the point

that we tried to make.

The aspect I think which is very difficult

is industry often relies on us to tell them what to

do, and it is very easy for them to have a check

box. FDA said this, let\'s do it, end of story,

because the goal is to get the products approved.

Well, that\'s one way of doing business,

but in terms of I think FDA\'s role is to clearly

ask the right questions. As I again said at the

training session, I think the decision system that

we have for pharmaceutical quality is owned by the

societies, not owned by the regulators or by the

industry. The decision is that of the society, and

all of us are simply caretakers of that decision

system.

Unless we ask the right question, because

of the scenario of the market failure, where the

patient or the clinician cannot tell the difference

between good quality and bad quality, the system

may have inefficiencies built in, and even may not

be asking the right question. So, I think that is

181

one of the things that we are trying to address.

For the last four years, when we started

the discussion on PAT, and so forth, clearly, the

focus was on manufacturing, and relatively, I mean

that was not an easy task, but relatively, that was

easier to grasp for many because you already have a

revolution of manufacturing that had occurred

outside the pharmaceutical sector for the last 30

years, and we are probably 30 years behind that

revolution.

Now, the most difficult part of the

discussion, the journey starts now, is tackling the

issue of science of design, and the reason I use

the term \"science of design\" is that is a National

Science Foundation terminology, which they have

started a major funding program for focusing on

science of design, because you cannot test quality

in, and the infrastructure for U.S. in terms of

design is so weak, especially in the software area,

that is where the funding starts.

Science of design provides you the

scientific framework to say the empiricism that we

182

have really, when structured, can provide you the

fundamentals that you can start moving towards

hypothesis-based decisions rather than just testing

after the fact.

So, I think that is the journey, and that

is the first step in trying to think about it

publicly. For the last three, four years, or three

years at least, our focus has been discussing only

the first three bullets to a large degree. It is

focusing on supplements, focusing on deviations,

focusing on testing and real-time release, and so

forth.

With ICH Q8, we started discussing the

last two bullets, multiple CMC review cycles. Why

do we get into multiple CMC review cycles? Because

our reviewers are searching, trying to put the

story together to see what are the issues as they

try to approve this.

Often, who gets blamed for the delay is

the reviewers. They are just trying to find the

answers that they see to be comfortable in

approving drug product. If you get into multiple

183

cycles, the reason is they don\'t have all the

answers together.

In Office of New Drug Chemistry, we are

trying to move towards a quality oral summary as a

starting point for this analysis. Similarly, in

OGD, we are moving towards a question-based review

that will help sort of formulate the key question.

But you have to keep in mind one aspect.

That is, FDA does not develop or manufacture drugs.

We are here to assess whether the quality is

sufficient based on the standards that we have.

Expecting FDA to give you the answers of

how to develop and how to innovate and how to sort

of make the case for science of design is expecting

too much. That is the reason why I think we wanted

to sort of get the entire pharmaceutical community

engaged to find and seek answers together rather

than saying this is what we expect.

So, that is the fundamental premise on

which our discussions have been focused on, and

clearly, I think industry has always argued for the

last four years that it will increase the review

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cycle. It will increase the delay over approval.

We don\'t know how we will use it.

One aspect of that argument simply says

either they don\'t know what they are doing, they

are afraid to hide that, or the concern is real.

So, clearly, I think we understand that the

concerns could be real, and that is the reason why

I think we position the peer review process, but

moving towards a quality system for review

assessment, and so forth.

But at the same time, I really think

having the diverse disciplinary background that we

have in the reviewer is an asset, not a liability.

The challenge then is to construct the submission

as a scientific submission hypothesis based.

The key to that is without increasing the

burden, utilizing the existing evaluations that we

do, bioequivalence, stability, and others as part

of hypothesis testing. Suppose the hypothesis

testing is your science that says I understood

this, I expect this to happen, and here is the

proof a priori providing that information.

So, I think you have to think about that

as a basis for discussion, particularly this

morning\'s discussion, where we presented to you

185

three examples, and the three examples essentially

try to address the paradox that we run into, is

trying to ascertain what is an acceptable

variability, and trying to resolve the issue of

whether our test procedures, whether our questions

that we are asking are really reducing that

uncertainty to get to an acceptable variability.

Variability in the clinical, we are not

touching, but that is what really we want to be

lower or smaller than the clinical variability.

So, our test procedures, and so forth, quote,

unquote, I think gives us comfort that they are

more discriminating, but the discriminating aspect

of those test procedures is clearly an experience

rather than science driven.

So, how do you overcome the challenge, I

think is the key issue. So, in terms of

formulation development, I really was fortunate in

terms of getting trained in pharmacokinetics, as

186

well as formulation and physical sciences, so that

was my benefit.

I can go across that and try to see both

sides of it, and from my experience, I can see

easy\--not easy\--approaches to sort of connecting

those dots and aligning the current work that we do

into a scientific structure.

The challenge, the concern, a personal

concern seems that is always with me is I think

people who can connect all these dots are very few,

and unless we build a team approach to this, we

will be missing a lot of things, and much of the

challenge today organizationally are the turf

issues between different parts of the organization.

We saw this very clearly with the biopharm

classification system. For Jack Cook to get the

first submission in, he had to connect the PK

Department, the Formulation Department, and so

forth, and that was not easy, because each

department is set in their own ways of doing

business, their own test procedures, and the

interfaces are difficult to manage, and much of the

187

challenge today we have are dealing with the

interfaces.

So, the challenge is variability, what is

an acceptable variability? At the same time, the

other challenge that we have is that of what is

minimal expectation and what is optional

expectation. That is the definition, and that is

the provision provided in ICH Q8.

In some ways, this table, in my opinion,

seems to give us a direction for trying to tease

out what is the minimal expectation, what is an

optional expectation. Now, if you are a company

with a generic or innovator, you will be making a

tablet for the sake of argument.

How much information does FDA really need

to assess that quality was by design, and so forth?

Actually, depending on how simple the dosage form

is, things could be different.

So, in the case of a conventional dosage

form, what is the primary focus understanding the

materials especially the new material that you are

putting in existing materials, that is the drug

188

substance into existing excipients, how well can

you characterize that and how well can you predict

the behavior in a set of mixtures of excipients

which we have been using for about 150 years or so.

We have been manufacturing hundreds of

different formulations in the manufacturing

process. How can we capture that knowledge base

and bring that? So, if you bring that

predictability and are able to do that, that amount

of information that will be needed would be very

minimal, and nothing probably more than what we

have, but presented differently, that provides a

way forward.

But then you move towards more complex

dosage form, I think where we don\'t have that, then

even there, a science of design concept where you

are testing hypothesis in a structured manner,

leads you to a decision criteria.

So, in this case, for example, I think our

pharmaceutical quality characteristics of

pharmaceutical equivalence, clearly, I think the

minimal requirements are listed in this table, same

189

active, identical amounts, same dosage form, route

of administration.

Same active, I think again how well can

you characterize from simple to complex, there is

an issue, identical amount, hopefully, that is not

a challenge.

Same dosage form raises many issues, and

this is the nomenclature issue that we run into

because we are dealing with nomenclature that

started from Egypt\--no, Egyptian based, no\--our

nomenclature, we have a lot of work to do in the

nomenclature, because the description of our dosage

form, and the performance and expectations, really

have a lot of challenges built into that, and that

is the source of constant legal issues that come

about.

That is the challenge to the pharmacy

community, and just publishing the paper that Cindy

published, the initial reactions from the

reviewers, I was not surprised, but didn\'t see why

it was important, so the pharmaceutical science

community is ignorant of some of those issues.

It is unfortunate because these things

wrap us up in legal battles, and so forth.

So, if you really look at this table, the

190

acceptable variability that we have built into our

system are our materials, our methods, and so

forth. That\'s the common cause variability that is

part of the system, and simply the design aspect is

how well you manage that and how well you make sure

you don\'t introduce special causes.

In terms of measurement system for

bioequivalence, the key question is what is an

appropriate measurement system and how you balance

that with that of your sign that drives you to the

right measurement system is the key and the

goalpost for that.

So, I think with that in mind, I think the

premise that we had in putting this session

together was the quality-by-design approach by

pharmaceutical development can potentially provide

an excellent means to address a number of

challenges previously discussed and have been

previously discussing for years.

The topics of highly variable drugs, I did

not see the discussion that occurred, that focused

or was able to pinpoint a solution to that, and we

didn\'t expect that. That was not the purpose of

it. The purpose of the discussion was to get

started.

191

If you go back to the same old solutions,

we will have the same old results. So, how can we

leverage this? Is analysis of means, which the

Japanese seems to have moved forward towards, a

means to go forward?

Again, it\'s a point of view right now that

needs to be discussed, debated, and so forth, and

how do we make a case. Keep in mind, the way I

look at bioequivalence, the way I look at stability

studies that documents the shelf life, is a

wonderful, final conclusion of a development

report, which is a hypothesis test.

In the regulatory setting, you need that

level of clarity to make a decision, so what the

pharmaceutical development does is provides you a

means to come to that clarity, at that same time

192

provide the right test procedures to create your

hypothesis.

So, that was the premise, and our hope was

to engage you to start the journey together to see

whether we are on the right track in our thought

process, and the proposals or the discussion that

we presented, clearly, is simply an initial thought

of how should we proceed in even thinking about

this.

With that in mind, I will sort of pose the

three questions to you.

Help us structure our thought processes to

discuss this in a structured way, to seek solutions

that have eluded us for the last 10 or 15 years.

DR. COONEY: Thank you, Ajaz.

Questions and comments from the Committee?

Committee Discussion and Recommendations

DR. SINGPURWALLA: Yes, Ajaz. There were

several things you said, and I started making

notes. I think you were trying to say that

hypothesis testing should be a basis for all forms

of approval and all forms of activity, is that

193

correct?

DR. HUSSAIN: I think it gives the

structure\--

DR. SINGPURWALLA: No, answer yes or no.

DR. HUSSAIN: Yes.

DR. SINGPURWALLA: No, I mean\--

DR. HUSSAIN: Yes.

DR. SINGPURWALLA: Good. A simple

question to you. How many statisticians do you

have in your division, in your group?

DR. HUSSAIN: We don\'t have any.

DR. SINGPURWALLA: Well, the first

suggestion is go hire one, because what you are

really looking for is somebody who knows the art of

testing hypothesis, and that is what statisticians

do.

So, I would strongly suggest that if

that\'s the way you want to move, you should at

least have some in-house experience.

DR. HUSSAIN: We have a whole department

of biostatisticians.

DR. SINGPURWALLA: I know, but, you know,

194

you ought to have your own lawyer and your own

doctor, too.

Now, you also said industry looks up to

the FDA as to what to do. Well, as a lay person,

not connected with the pharmaceutical industry in

any form, my sense is that the industry would

rather wish you go away, but given that you are an

approving organization, industry comes to you to

make sure that their chances of getting approval

succeed.

DR. HUSSAIN: True.

DR. SINGPURWALLA: That is just a general

comment, but as far as your three bullets are

concerned, I am very sympathetic to the

presentation made by Lawrence demanding more

information, and I heard the cross fire from my

colleague, Paul Fackler, who was concerned, I

quickly understand. I fully support your thesis.

How can more information hurt you?

The question is how are you going to use

that information judiciously. Otherwise, you know,

you will be loaded with eight volumes instead of

195

the seven.

As far as your second bullet is concerned,

my suggestion is that is the whole premise of

Bayesian inference, how to use data that is not

directly observable on a certain phenomenon, but is

auxiliary, to be able to make your tests of

hypothesis.

So, I can answer the second bullet by

saying that pharmaceutical development information

should be used and should be incorporated in

whatever decisionmaking procedures you use through

this particular inferential mechanism.

That\'s all.

DR. HUSSAIN: Thank you.

DR. COONEY: Ken.

DR. MORRIS: One point that I wanted to

bring up was that in talking to companies, to

generic companies, there will be acknowledgment of

the sort of cycle of questions. When you talk to a

lot of the innovator companies, they all say that

they don\'t go through multiple CMC review cycles.

DR. HUSSAIN: Uh-huh.

DR. MORRIS: So, in that sense, the

question that is often raised is so what do we get

for this. I know you have heard this, too. I

196

guess in partly response to Nozer\'s observation,

which I think is spot on, is that they\--\"they\"

being the industry at large\--wants FDA to

disappear, in a sense, but not in reality.

But what they do rely on, I guess, is FDA

as a consultant as opposed to adopting the attitude

that you would adopt if you were writing a

scientific paper, which is here is my thesis, if

you will, and here is my defense of it. Now, you

can judge whether my defense is sufficient.

I think that is the mentality that has to

shift, is that the industry has to say, now, look,

I am not looking for FDA to tell me how to do this,

I am going to do what I think is appropriate to

make the case and defend the case scientifically,

and then, having done this in a way that makes it

hopefully more obvious to the reviewers, have them

comment on the sufficiency of the application.

I don\'t know if that is a comment or a

197

question, but it\'s an observation in part.

DR. COONEY: Paul.

DR. FACKLER: I guess I should put on the

record that we are not looking for FDA to

disappear.

\[Laughter.\]

DR. FACKLER: That\'s my hypothesis. We

will have to discuss working on that.

Of course, I don\'t think we are looking to

FDA to help us develop drugs. 7,000 drugs

approved, somebody had on a slide over the past

many years. I think a large experience with those

7,000 products to suggest that they are generally

safe and efficacious. I am certain there are

exceptions to that, not a lot I don\'t believe.

There is a handful of products for which

we know how to develop what we consider to be

bioequivalent and pharmaceutically equivalent

products for which there doesn\'t seem to be a

mechanism to get FDA to approve them, and those are

the ones that I think we are really looking to FDA

for guidance on, not how to develop them mind you,

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how to document appropriately that they are

bioequivalent and pharmaceutically equivalent.

We have obviously, records on all the

pharmaceutical development activities. They exist,

so it is not as if we need to do more work to give

those to you, and they are available for the field

inspectors that come to our sites to do the

preapproval inspections, and they often go through

them.

Really, the question in our mind is how

will it help you here at the Center evaluate our

applications, and how will you use those to help us

demonstrate bioequivalence for this small fraction

of products for which the standard analysis and

treatment methods don\'t work.

So, highly variable drugs is one of those

classes. Topical products, we know how to get those

approved, we know how to develop what are

bioequivalent formulations. I think the testing is

a bit onerous, and revisiting it I think is a great

idea.

So, just some thoughts and I guess I will

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leave it at that.

DR. COONEY: Marv.

DR. MEYER: In sense, and in response to

Nozer, I think that, in a sense, the FDA is almost

like the group I have to deal with, the IRB. I

think the FDA is kind of they put the blessing on

something, and now you have a shared marketing

responsibility, a sharing of the guilt, if there is

any to be shared.

The IRB would ask questions. They would

reject protocols or they would accept protocols.

You didn\'t like it when they were rejected, but

sooner or later, you would get it approved.

So, I think the industry probably enjoys

having the partnership of FDA as long as the

products ultimately get approved.

I might rephrase your first bullet. How

can pharmaceutical development information help? I

would be more inclined to say what kind of

information is needed to help extend the

application, be it manufacturing, be it in vitro

permeability or oral water partition coefficient,

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or whatever, some physiological, some\--just don\'t

restrict it to pharmaceutical development, because

I think there are some other things we could put

into play as a measurement and extend that waiver

perhaps.

Bullet No. 2, how can pharmaceutical

development information be utilized? I would say

to make sure we have the best possible dosage form

that one could make within reason before you even

go to the clinic. So, make sure that your\--one

example\--make sure you don\'t have the six-vessel

dissolution example. Make sure that you understand

the solubility and the PKA, and all of those

physicochemical parameters.

So, I think that kind of information, the

idea being let\'s reduce the variability on the

pre-body side, so that when we got on the human,

all we have to do is worry about highly variable

human beings.

No. 3, I am not real sure how to tackle.

DR. COONEY: Pat.

DR. DeLUCA: I really commend your effort

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on the quality-by-design approach. You know, this

is a systematic approach to research and product

development, and it must be hypothesis driven. I

think you are going to get that by establishing the

decision tree, and this is going to be the plan.

I think, you know, I try to encourage my

students when they are going to do some research,

is to map out what they are going to do and what

they expect to get, and what they expect they get,

they may get one thing they are expecting and one

thing that they are not, and what are they going to

do if they get that.

So, to spend a little bit of time, even if

it\'s a couple of days, planning, so that you have

got a pretty good idea what it is you are trying to

do.

I think by your suggesting this to the

industry, this quality by design, so you are

expecting them to kind of carry it out. So, I

think this quality-by-design approach is a two-way

street.

I understand and appreciate what Paul is

202

saying, but I think it\'s a two-way street, and you

have got to be also available to be able to

communicate to them what it is that you expect,

knowing that they are carrying it out.

But I think you can\'t just say, well, you

know, you are doing the development, go ahead,

don\'t ask us what to do, I think they have got to

be able to ask, and you ought to be able to get

some response to this.

I think by carrying out the quality by

design, and the decision tree, that, first of all,

the variability in performance should not be due to

the product. You have pointed that out. I think

by going through this process, you will be able to

assess the acceptable variability.

You know, you have a highly variable

product, maybe the limits can be widened. Probably

with a low variability product, you might be able

to even tighten them. So, those are the things.

The BCS system is a very good tool. I

looked at that and I see it\'s a matter of

solubility here. That\'s all based on solubility.

203

You have II and IV that are low solubility drugs,

and I think in your formulation efforts, the goal

is to try to promote availability and

bioequivalence.

With the I and III, the high solubility,

the goal is not to hinder availability or maybe to

prevent bio-in-equivalence.

So, I think the goal, the formulation

strategy is going to be different where those drugs

are in that classification, and I don\'t think you

can get away, for all but the Class I, with an in

vivo test. I don\'t see how you can waive that for

any of the other classes except I.

DR. COONEY: Art.

DR. KIBBE: This has been a fun couple of

days, it always is. Perspective. To tell the

industry that you do a really good scientific thing

and send it to us, and that will speed up the

process, I think might fall on deaf ears.

The reason is that they have had

experience sending stuff to the agency that wasn\'t

exactly what the agency has been looking for, and

204

it has taken iterations because part of the process

of sending that kind of data is that you have to

educate the people who are reading it to the value

of it.

So, when you get off of a guidance or a

document that fits exactly what the agency has

asked for, when you get off of that, no matter how

good the science is, you have guaranteed yourself

one more round, because there is going to be

questions, and it is not that the agency is being

mean or pejorative, it\'s that the people who are

looking at it are going oh, wow, this looks really

good, and maybe it\'s good and maybe it is really

good, maybe it\'s not so good, boy, I would love to

get them in here and talk about this, let\'s bring

them in and let\'s talk about why they did that, and

let\'s see what some of the background thinking is.

There is no company that can put down all

of that and write a textbook for it, and expect to

do it on one time. So, you are asking the

companies to come in and help you develop what

would eventually be guidances, and they are not

205

really going to leap in there.

I think this committee helps get us there

in some ways, but you are going to end up having to

write guidances for some of this stuff, and

especially when you say give us pharmaceutical

development information, because depending on the

company, you are going to get different kinds of

information.

Different companies have divided their

research and development efforts in different ways,

and they will name it differently, and one company

will give you a bunch of one kind of data and leave

out a little bit of something else, so you really

are going to, after we leave, leave you to your own

devices, you are really going to have to come up

with something that is a little bit more concrete.

DR. HUSSAIN: If I may, it is not exactly

the way. We are planning our decision trees, and we

will be developing the decision trees, and those

will be the questions that we, as consumer

advocates, will be asking.

The rest of the job is through the

206

industry, so we will provide a structure to this.

DR. KIBBE: The next part of where I was

trying to go is that sometimes the questions that

are asked are dependent on what kinds of decisions

you are going to make. A company might have a

series of questions to ask if it wanted to design

in quality.

An academician might look at it and

decide, ooh, wouldn\'t it be nice to know the

mechanism rather than just know how to control it,

and regulation is really aimed at knowing that

whatever you are controlling is going to get me

consistent quality, and those are different kinds

of questions, and all worth asking and worth

knowing about.

I think we have another topic to come up

with, which is the research end of it, and that

kind of feeds into that. It would be really nice

to be able to have a collaborative research effort

with academia and industry and the agency on these

issues that is not going to necessarily be the

answer, but a place to ask really good questions.

Then, of course, the last thing I wanted

to say is it is impossible to read people\'s minds,

so you don\'t really know what they are thinking

207

when they get to that point. You know, it\'s hard.

DR. COONEY: Tom.

DR. LAYLOFF: As we were visiting earlier,

I think that there is enough knowledge base in the

industry and academia for formulation and

manufacturing to produce products which dissolve

and which are uniform without failure.

I think what we see in all of these,

especially No. 1 and 2, is wrestling with an

unknown, and how do you evolve a waiver around

things that are not well defined and unknown.

Certainly, highly variable drugs belong with drugs,

but they don\'t fit in the BCS, because they are not

understood well enough.

The BCS takes a rough cut at physical

properties of the substance, but not at the

transport mechanisms or the metabolic processes

that might control some of the properties of the

drug.

So, I think that the waiver is going to be

hard for broad-brush strokes, but maybe narrow

categories can be trivialized to a few physical

properties. The highly variable drugs are

startling, and I don\'t know where you go, but I

think they are the class that sort of makes you

208

uncertain about the waivers and the BCS. They put

an uncertainty in there also.

The last one, therapeutic equivalence of

topical products, I don\'t know what to do with

that.

DR. HUSSAIN: There is an aspect, Tom, I

think, if I may, the Class IV drug inherently tends

to be more variable, so there is a relationship

between variability and class, I think. Hopefully,

when Raman\'s database is audited and ready, I think

you might see a pattern there, because I think

variability, physiologic variability\--I actually

was going to show a slide that we just finished,

our analysis of a Class IV drug that Raman sent me

over the weekend. You will shocked at the

variability that we see.

But there is a mechanism to sort of start

identifying what is the source of variability with

the GI physiology, with its metabolism, and so

forth, so you can actually start thinking about a

structure to say what characteristics make the drug

more variable.

So, in some ways, I think the BCS

classification, and this is a proposal of Les

Benet, is to extend that. I mean he has simply

209

used that to extend and start predicting the class

of metabolism of those things.

So, I think we could consider sort of

characterizing the sources of variability and see

if we can start.

DR. LAYLOFF: Have you ever tried to put

another column on the box, the BCS box, like

polarizability of the molecule or footprint of the

molecule, geometry?

DR. HUSSAIN: No. What Lawrence actually

has done is actually went back to the structure and

predicted the bioavailability, so there is an

element of that. We recently published a paper on

210

going back and actually predicting the permeability

from the structure, so there is an element of that.

Professor Les Benet has now extended that

to actually a classification system to include

metabolism. So, that is a recent proposal. To

there is lots of progress in that area.

DR. LAYLOFF: So, that will fit into the

possibility of going towards a waiver business.

DR. HUSSAIN: I have not studied some of

the latest ones, so I just have seen the papers,

but not studied them, so I can\'t say, but I think

there are some positive signs there.

DR. COONEY: Ken.

DR. MORRIS: Tom made actually one of my

points better than I would have probably, but to

that point, I think if you look at BCS-3, clearly,

from the data we saw, I was a little surprised that

that was the highest variability class, as we

talked about earlier, but if you include some of

the work that Les has been doing, was that

editorial?

If you include some of the work that Les

211

has been doing, so that you could subdivide Class

III in particular into mechanistic subcategories,

if you will, it certainly seems like there ought to

be something in Class III, that is some element or

some subcategory of Class III that should be ripe

for waiver.

I mean if their premise is valid, the

hypothesis is valid, then, there ought to be a way

to do that.

The other thing with respect to what a lot

of people have talked about, Jerry before, and Paul

and Art to some extent, when I was in industry,

which was admittedly a while ago, we used to

generate what in my particular case we called IDSC,

initial drug substance characterization report.

As we were talking about earlier, these

exist already in most places. The only question I

think, or only caveat I guess that needs to be

added to that would be that once you are to the

point of filing, in the light of what you know post

this initial drug substance characterization

report, you might truncate what you provide only

212

based on what is or isn\'t necessary. It\'s not like

you want to just provide everything.

But in many instances, and I have seen

this in consulting, these documents almost exist in

place already, and it is just really a question of

pulling the right things out or adding what is

relevant in. I think that is relatively common.

DR. HUSSAIN: Again, I do know they exist,

and that was the reason for starting this, because

I knew that was already there, but it was bringing

those into making decisions, because I think Moheb

mentioned we get volumes and volumes and volumes of

things that we have to sort through, which is not

value added.

We get supplements after supplements,

which is not value added. So, the whole idea is to

utilize that and make the decision, and then

without having to get all of those things that we

have to sort through, and so forth. So, that is

one way of looking at it.

DR. COONEY: Michael.

DR. KORCZYNSKI: Just a few generalized

213

comments relative to communicating to the industry.

As this unfolds and is described to industry, I

think they ought to be reminded that I see the

quality-by-design plan for pharmaceuticals somewhat

analogous to the Center for Radiological Health and

Devices\' developmental design plan, and it is sort

of a similar concept, and they ought to be made

aware that indeed there is an analogous situation

here.

The other thing is I think back when we

talk about industry not knowing what the FDA wants,

well, there was a climate back in the 1980s

relative to sterilization technology of sterile

products, and a number of companies were concerned

when they were making submissions and were

receiving some rejections and questions, gee, what

does the FDA want.

Well, the FDA went on to draft a guideline

for sterilization technology information when

submitted in NDAs, and actually went on several

performances at different cities, about four in

all, and that was discussed openly with industry,

214

and that became very effective and really did a lot

in terms of dispelling some misunderstandings. So,

a similar approach could be undertaken here at some

time.

DR. COONEY: Any additional comments from

the Committee?

The request here for this topic comes,

well, as on the screen, these are our initial

thoughts, are we on the right track. As you can

see, there are three questions that have been

posed, I think somewhat rhetorical questions in

that you are not looking for a vote on these

particular issues.

I have tried to capture what I think is

the consensus of what people have been saying, and

if you will allow me to try and summarize this

point, and the question I want to ask the Committee

is does this\--what I am going to say\--does this

capture what we collectively have said.

I am looking for omissions in this summary

and I am also looking for things that shouldn\'t be

there, so that is the input I am looking from the

215

Committee, and then I will ask if we, in general,

agree that this is a consensus.

The platform here is that there is a need

for a better understanding of the science of

formulation design will lead to improved product

quality with reduced variability. In fact, this is

the foundation for quality by design.

That the implementation of quality by

design will require additional information on the

product development process. This is what has been

generally referred to as the product development

report, and that the FDA wants to use this

information, this product development report, which

is ill-defined at the moment, or loosely defined at

the moment, to do three things, as you have

outlined in your earlier slides:

To extend the BCS-based waiver for

immediate release products, to facilitate approval

of highly variable drugs, and to facilitate the

establishment of pharmaceutical equivalence of

topical products.

So, those are the three general goals, and

216

from this conversation, there is a need that has

been discussed to work with both the industry and

the reviewers, in other words, the system needs to

be receptive to receive and use effectively new

information, and that it is important to add

clarity on what information is required, as well as

how that information will be used, for instance, to

establish a bioequivalence, and that the general

consensus seems to be to recommend that the FDA

continue down this path to address quality by

design and define its use to facilitate issues in

the regulatory approval of drug products.

DR. HUSSAIN: A point of clarification.

DR. COONEY: Please.

DR. HUSSAIN: One aspect also I think,

please consider this, the CTD Q B2 section has the

sections and everything defined. The ICH Q8

defines what information goes where, and so forth.

So, in that sense, it is already

structured, it is already part of the guideline,

and one of the aspects, the timing of this meeting

in relation to ICH also has to be considered here,

217

because starting this Saturday/Sunday, we are

moving towards putting together decision trees for

the dosage forms in Q6A, so you will see the train

leaving the station of how these decision trees

will evolve, and the goal is to get to Step 2 by

2006\. So, that process is beginning next week.

Now, this meeting, one of the other

aspects is also is we focused this on the generic

side for one reason, also was we often have

hesitation as generics really do not have the level

of involvement there, because there are just

observers there.

So, I think is also a plea for the

generics to keep engaged with that process, because

that process is leaving, and Europe already has

their decision trees for all of this, and we are

not fully happy with that. We want to make sure

the decision trees that evolve the next six, seven

months will be the science base.

DR. COONEY: I think that in the

presentation that you have made, Ajaz, the role of

decision trees at multiple points in this process

218

was clarified, so I believe that that is clear.

I would ask the Committee, did this

summary capture what you believe was the essence of

the conversation from this morning and this

afternoon?

DR. SINGPURWALLA: I think in terms of

proper vocabulary, I think the word \"hypothesis\"

was constantly used by Ajaz.

DR. COONEY: I noticed that it was used.

DR. SINGPURWALLA: I also noticed that it

was eliminated from your summary, and so I am just

trying to remind you whether you want to endorse it

or not.

DR. COONEY: I did not leave it out by

design.

DR. SINGPURWALLA: It was because of

variability.

DR. COONEY: It was a bit of variability.

DR. SINGPURWALLA: I would try to give a

strengthening hand to Ajaz and Helen and all in

terms of endorsing what they want to do by

specifically including that in the vocabulary, so

219

that it succinctly conveys the intention of what

they want to do.

I wouldn\'t say anything about the fact

they don\'t have any statisticians in their group.

DR. COONEY: This will get written up in

minutes of the meeting, and I will see to it that

it is appropriately worded and we will check the

vocabulary and the grammar.

DR. SINGPURWALLA: Spelling.

DR. COONEY: Does everyone\--so, the train

is leaving, you should be aboard the train and

rolling down the tracks, and I believe it is fair

to establish the expectation that probably at our

next meeting, we will hear something more

definitive.

DR. HUSSAIN: At least on some aspects of

that.

DR. COONEY: Yes. It would be nice to

have all the problems solved by the next meeting.

I think this brings us to closure of this

topic. We are going to go to another topic which

deals with the research, and I would suggest that

220

we take a five-minute stretch break and reconvene

at approximately 7 minutes past 2:00.

\[Break.\]

DR. COONEY: I realize that a five-minute

stretch break is a very short period of time, but I

wanted to look around and see those who didn\'t get

up and stretch, and that I would go wake them up.

DR. KIBBE: Just so that we keep

everything on point, stretch breaks are an

extremely highly variable process. If you say 5

percent in stretch breaks, that could mean anywhere

from 10 to 40 minutes.

DR. COONEY: I said 5 minutes, and there

has already been a 2-minute variation on that, so

your point is well made, Art. I will take that

into account in the future.

The next topic is a very important one and

it revolves around the Criteria for Establishing a

Working Group for Review and Assessment of OPS

Research.

Criteria for Establishing a Working Group for

Review and Assessment of OPS Research Programs

DR. HUSSAIN: The topic is a request to

form a subcommittee and this advisory committee to

have a peer review process for research. We

221

already have a committee under CBER and we need to

migrate that committee under this to have a process

in place for Office of Biotechnology Research

Program.

But also I think we want to take this

opportunity to put in a place for a peer review for

all of our research programs in one umbrella. With

that in mind, all we seek today from you is an

endorsement to form a subcommittee and define the

scope and charter as the committee gets formed, and

so forth.

But for you, we have just a presentation

of the background of what the current system is,

and then Keith will come back and ask the

questions.

DR. COONEY: The first presentation will

be by Kathleen.

CBER Peer Review Process for Researchers/Reviewers

DR. CLOUSE: I have been asked to put

222

together a simple but concise summary of how we do

peer review for the OBP Research Program.

Hopefully, you can follow along without much

confusion.

I have divided this up into four

discussion topics. The first is an outline of the

Researcher/Reviewer Model. Secondly, how

Researcher/Reviewer Program is monitored. The

process for external scientific review. Then, the

promotion and conversion evaluation or PCE

Committee through which the researcher/reviewers

are converted to permanent positions and promoted

through the GS system.

The Researcher/Reviewer Model is something

that has existed at CBER for a while. We do use it

in OBP. We have individuals who do both research

and review, and we also have individuals that do

full-time review. So, before I describe the

program, I would like to emphasize the fact that

more than 75 to 80 percent of our full-time

reviewers have come up through the

Researcher/Reviewer Program. So, this is also in

223

part a training program for our reviewers.

The responsibility of a

researcher/reviewer, first of all, is to conduct

research that is relevant to the FDA mission, and

this research is generally dealing with specific

products, and that can be for mechanism of action,

for toxicity, or surrogate measures of efficacy.

It can be related to product classes,

specific diseases, or therapeutic modality, and it

can also be associated with the development of

methods and standards by which products can be

prepared.

In addition to the research, the

researcher/reviewer performs regulatory review, and

this is at the level of investigational new drug

applications, as well as biologic license

applications, and they also are involved in

conducting inspections for specific BLAs.

They also contribute to policy development

as they become more senior in the structure.

The funding of OBP research, the majority

of the funding is provided at the OBP level from

224

our operating funds, and it is distributed on a per

capita basis. A portion of the allocation is held

aside, and these additional funds are distributed

by OBP based on research prioritization.

The research prioritization is determined,

not just at the office level, but from guidance at

the agency level and what the agency deems to be a

priority for that given year.

We also have access to competitive funding

through the CDER Review Science and Research or RSR

program.

We have obtained competitive funds through

the Office of Women\'s Health granting program.

We also have access to competitive funding

through the NIH Intramural Grant Program. These

are limited for the most part for research dealing

with AIDS and, more recently, for

counterbioterrorism efforts.

We also have some funds that is obtained

through CRADAs and inter-agency agreements.

The program monitoring is done at multiple

levels. The first tier of monitoring is done by the

225

Lab Chief. Now, the Lab Chief generally has their

own research program and is responsible for several

additional principal investigators.

The Lab Chief does not determine the

research focus, however, they do assess the

research productivity of the principal

investigators and offer some guidance if they don\'t

appear to be productive enough, if they are spread

too thin, and so on.

But more importantly, the Lab Chief is

involved in the actual training of the principal

investigators and any Staff Fellows working under

them on the regulatory review process, and the Lab

Chief evaluates the ability of the individuals to

perform regulatory review.

The next tier for evaluation is the

Division Director, and the Division Director

discusses the scientific productivity and

regulatory abilities at least twice a year, but

this is often done through the Lab Chief, because

they have the first tier of evaluation.

The third level is at the Office Director

226

and Associate Director for Research level. Here,

the scientific productivity is assessed via

publications. What is taken into consideration is

not just the number of publications, but the type

of journals, the impact factor, and also the

relevance to the FDA mission.

Finally, we also have External Scientific

Review or site visits. The purpose of the External

Scientific Review is, first of all, to determine

the relevance of the research program to the FDA

mission; secondly, to evaluate research

productivity; third, to assess the regulatory

contribution, and this is a portion of the External

Review, and also to provide input regarding

resource allocations.

In general, the input is we should get

more resources, but there is usually not much the

agency can do about it.

The External Scientific Review ideally

occurs every four years. Now, the research group

that is reviewed, generally, it is all principal

investigators within a specific research lab, in

227

other words, you have the Lab Chief and whichever

principal investigator works in that particular

lab.

On some occasions, we have grouped site

visits based on expertise, so that the site visit

reviewers don\'t have to be duplicated or they can

overlap in their review process.

The Site Visit Committee, and this is most

important and one reason that we need to bring up

the issue with this advisory committee today, the

Chair of the Site Visit Committee is generally a

member of the parent advisory committee.

Previously, this was the Biological

Response Modifier Advisory Committee, however,

since our transfer from CBER to CDER, they have

renamed the group and refocused the emphasis of the

committee members. That is currently known as the

Cell, Tissue, and Gene Therapy Advisory Committee.

So, what is happening is as individuals

with expertise in our area end their term, they are

being replaced by individuals with more of a focus

on cell and gene therapies.

In addition to the Chair, there are one or

two external scientists with relevant research

experience or expertise for each principal

228

investigator under review. When possible, if there

is a member of the Advisory Committee that has the

relevant expertise, they also will be asked to

serve on the Site Visit Committee.

The format of the external scientific

review, first of all, the committee is assembled,

they are given the review package, and they review

the scientific program in a formal setting.

At the conclusion of the site visit, a

summary is given to the Center and Office

Directors, so that they have a pretty good idea of

how the site visit went.

Several weeks later, a preliminary written

report is sent to the Center for review, and then

that preliminary report is presented by the Chair

of the Site Visit Committee to the Advisory

Committee, and the report is ratified by the

Advisory Committee before it can be used by any of

the scientists.

A copy of the official report is then

provided to the Center and Office Directors, and

individual reports are given to scientists under

review.

The site visit report is used in the

following manner. Within two years of the site

229

visit, a favorable report can be used for tenure or

conversion of the principal investigator to a

permanent position.

Within four years of the site visit, if

the individual is already tenured, it can be used

for promotion to a GS-14 or 15, and these

promotions are permanent. It can also be used as

supporting documentation for internal grant

applications or external grant applications when

applicable.

Now the Promotion and Conversion

Evaluation or PCE Committee actually makes the

decisions on the conversion and promotion of

scientists. So, the purpose of the committee is

the conversion of Staff Fellows to tenured Civil

Service research and regulatory positions. They

230

also are involved in promoting tenured Civil

Service research and regulatory scientists to the

next grade level, as I mentioned before.

The composition of the committee is as

follows. There are two tenured principal

investigators from each of the Research and Review

Offices, so we have our own two representatives

from the Office of Biotechnology Products. That is

myself and also Emily Shakter from the Division of

Therapeutic Proteins.

In addition, there are members from the

Office of Blood Research and Review, the Office of

Cell, Tissue, and Gene Therapy, and the Office of

Vaccines at CBER. Each of those respective offices

has one full-time ad hoc reviewer, so for any one

situation, one of those ad hoc full-time reviewers

also serves on the committee.

There is a representative present from the

Office of Personnel Management to make sure all the

procedures are followed, as needed, and as legal,

and there is one representative from the CBER

Office of the Center Director.

The guidances that are used by the PCE

Committee for Promotion and Conversion, there is a

general CBER guide for the evaluation of research

231

and regulatory scientists from GS-13 to GS-15,

which is available on their website.

There is also a Research Grade Evaluation

Guide, and this is from the General Schedule

Position Classification Guide, which I think is

from the Office of Personnel Management.

Generally, through the use of these

guidances, there is a scoring system, and the

scoring for promotion and conversion is actually

documented by the Office of Personnel Management,

and that is maintained and brought back for

comparison for each subsequent promotion

opportunity.

There is additional information that is

requested by the PCE Committee. This includes a

publication summary, as well as a presentation

summary, and these can be scientific presentations,

as well as regulatory presentations.

You have to include a summary of your

232

regulatory work, as well as examples of your

regulatory reviews. You have to have a copy of

your external scientific review report, and you

also need letters of recommendation from experts

outside FDA that are familiar with the

investigator\'s research.

Now, the use of the site visit and the PCE

Committee systems has advantages and disadvantages,

and this is the slide I will end with.

The current advantages are that scientific

and technical positions are evaluated by scientists

who are actually familiar with the activities

performed, and the scientific community is expected

to have greater confidence in decisions made by

peer scientists.

The current disadvantages to the existing

system, first of all, is the cost to OBP, OPS, and

CDER. Each site visit costs us not just for

bringing the scientists in, but also because the

administrative office overseeing the site visit is

the CBER Division of Scientific Advisors and

Consultants, so we also pay for their time and the

233

coordination of the site visits.

It is also difficult to coordinate site

visits across the two Centers at this point. As I

mentioned before, there is a change in expertise of

the Advisory Committee. Members of the Advisory

Committee have been instrumental in advising us

with regard to the scientific expertise that is

needed to review the biologic therapeutic

applications. We really would be remiss if we

didn\'t have that input from the external

scientists.

There is also a difference in the

regulatory workload among the members of the PCE

Committee, and this has to do with different

structures of the offices. One of the offices has

a structure similar to ours, where the product

reviewer does both research and regulatory.

Two of the other offices actually have a

structure where there is a separate division that

does the majority of the review, and the scientists

are viewed more as consultants, so the workload

varies.

There is also a difference in regulation

of BLAs versus INDs. Very often in the Office of

Vaccines and the Office of Cell, Tissue, and Gene

234

Therapy, the majority of the applications are under

IND, and they don\'t have the experience of dealing

with as many biologic license applications as we

do, so there is some disconnect with evaluating the

actual amount of the work.

There are also differences\--and this is my

latter point\--in the systems for performing review,

and that has to do with whether the

researcher/reviewer has both the full product

review or CMC review responsibilities and

inspections.

DR. COONEY: Thank you.

Some questions? Tom.

DR. LAYLOFF: How many people are involved

in the review side of this group?

DR. CLOUSE: I think it is split about

50-50. Keith can answer that.

DR. WEBBER: Within the office, there is

about 14 full-time reviewers, and there is about 36

235

or so who are research/reviewers, who are supposed

to spend half their time doing review and half-time

research, but I think they spend more time review.

DR. LAYLOFF: The laboratory people, where

are they located?

DR. WEBBER: They are all physically

located down in Building 29A and B of NIH campus.

DR. LAYLOFF: And the full-time reviewers

are located?

DR. WEBBER: They are located in the same

place. They work together and share meetings.

DR. LAYLOFF: So, there is 50 people

there. There is 36 and 14.

DR. WEBBER: Right, plus there are support

staff and technicians who work in the laboratories

for the research program.

DR. LAYLOFF: How many applications or

supplements do they review per year?

DR. WEBBER: Applications, we get

generally around four full field applications per

year, and that varies. Sometimes we have gotten up

to nine. We get about between 150 and 200

236

supplements per year, somewhere in that range, and

then annual reports. INDs, we have approximately a

little over 400 products in IND.

DR. LAYLOFF: Thank you.

DR. SELASSIE: I have a couple of

questions. You said the majority of the funding is

provided at the OBP level. Could you tell me how

these funds are appropriated to each department, is

it a peer review process, do they write proposals,

how those decisions are made?

DR. CLOUSE: No, it is divided, as I

mentioned, on a per capita basis to each of the

programs, a portion of the money, and then there is

a portion that is held back for research

prioritization, which is awarded based on

productivity or the nature of the research and how

it fits in with the current prioritization for FDA.

DR. SELASSIE: I suppose scientific merit

comes in there someplace.

DR. CLOUSE: The scientific merit pretty

much comes in the site visit process and the annual

review of productivity. So, yes it does. We

237

haven\'t had an instance that I can recall where we

have had any lack of productivity. I mean

generally, the thought is the resources would

diminish for someone who is not productive, but we

haven\'t come across that in the years that I have

been there.

DR. SELASSIE: I assume that most of the

Lab Chiefs basically supervise the labs, and they

don\'t do any research, they supervise the PIs under

them?

DR. CLOUSE: No, we do research.

DR. SELASSIE: They do research, too?

DR. CLOUSE: Yes.

DR. SELASSIE: So, how much of your time

is like spent during research and how much on

review activities?

DR. CLOUSE: I was asked that question at

a presentation at NIH last week, and my Staff

Fellow said 200 percent was regulatory. I would

say more than 90 percent of my time right now is

spent on regulatory, and what I do researchwise is

done at home.

DR. SELASSIE: When you do this, the

reviews of your researchers/reviewers, and I guess

go to the various steps, to the advisory committee.

238

At some point, I guess eventually, the reviewer

gets to see the individual report. At some time can

they respond to issues that were raised in those

reports before they go on file as, you know, done?

DR. CLOUSE: Currently, that is a touchy

issue. In general, what has happened in the past,

we get a draft report and if the report is not

consistent with what happened at the summary

meeting, at the level of the Center Director, you

know, the individuals under review or their

immediate supervisors are not allowed to contact

the Advisory Committee members.

It is not considered appropriate. But if

there is an issue, you know, potentially, at the

level of the Center or Office Director, they can

contact the Committee Chairperson, and they would

deal with it at that level.

DR. WEBBER: Generally, an effort has been

made to try to maintain, since we have a

239

multi-tiered review process, to maintain a site

visit as independent as possible, so that there

isn\'t any\--unless, as Kathleen said, if there is a

serious issue, serious problem with the review that

comes from the Site Visit Committee, that they may

have been biased or something like that, we

generally try to avoid getting involved before the

report is made final.

But afterwards, certainly, if there are

issues or concerns or additional information, that

the Site Visit Committee didn\'t have in hand at the

time, that can be added to the review process.

DR. SELASSIE: One other question. In

choosing outside reviewers, does the reviewer, the

person under consideration, do they have a choice

or do they give you a list of outside reviewers,

and can you pick from them?

DR. CLOUSE: Generally, the person from

the Scientific Advisers and Consultants Division

asks for a list of names. This list of names

cannot be anyone that you have collaborated with or

a friend.

That list of names is provided to the

Chair, whoever has been identified as the Chair of

the Site Visit Committee. They are not obligated

240

to choose anyone from those, however, once they do

choose your reviewer, they do let you know or

contact the individual principal investigator and

ask if there is any conflict or problem with who

has been chosen.

So, you have some say in the process, but

you don\'t have the final decision.

DR. SELASSIE: One last thing. You talked

about the cost to OPB of bringing in outside

reviewers. Have you ever thought of doing

videoconferencing? I know the EPA does that.

DR. CLOUSE: For site visits?

DR. SELASSIE: Yes.

DR. CLOUSE: We haven\'t pursued it at this

point, but then again, we are in the process\--

DR. WEBBER: It\'s something we can

consider, but oftentimes it\'s an all day affair,

because you have a meeting in the morning with

presentations from each of the people under review,

241

and then there is discussions within the committee,

and usually, it takes pretty much all day.

We might save some money by bringing

people in by video as opposed to in person, but we

would probably lose a great deal in terms of the

actual interaction.

DR. CLOUSE: It is pretty much like you

have with the interaction of the Advisory

Committee. You would lose a lot if everybody

teleconferenced in consistently. It is just a

little more fluid if you have the people there.

The one thing I did forget to emphasize,

and that is, for the researcher/reviewer, when you

do get an application in, whether it\'s an IND

original submission or biologic license

application, or supplement, that\'s a priority, your

research stops.

So, very often when you look at someone\'s

productivity\--and this is one reason why it\'s

difficult to assess productivity, let\'s say,

annually, your productivity can go like this

depending on what your regulatory workload has been

242

for any given year.

DR. SELASSIE: Thank you.

DR. COONEY: Carol.

DR. GLOFF: Just a couple of quick

questions. So, there are 14 people who are

full-time reviewers, 36 who are half and half,

which we know it\'s not really 50-50. Are there

people who just do research?

DR. CLOUSE: Only technical staff, and if

we have funding for postdoctoral fellows, those

individuals do full-time research.

In the majority of cases, if the

postdoctoral fellow is a citizen or has a green

card, and expresses an interest in doing the

regulatory, the next step for them is to become a

staff fellow. Then, very often, lately, the

majority of our staff fellows have gone on to

become full-time reviewers.

DR. GLOFF: Then, my other question is\--I

know we are going to have a presentation by Dr.

Collins\--I am just curious. Setting aside the

Center for Biologics, and obviously your group now,

243

but are there other review centers or sections in

the other review centers that have a process

similar to what you just described?

DR. CLOUSE: If I recall correctly, NCTR

is the other center that has a structure similar to

ours.

DR. GLOFF: I guess I don\'t think of them

as being a review center, but I may have that

wrong.

DR. WEBBER: I am not sure if CVM has a

research review program, I don\'t know about that,

but that will be something to look into.

DR. HUSSAIN: I think CDRX, CFSAN, they

have research programs. They are not, as Keith

said, reviewers, and they do have aspects of this,

but not in the form that exists under CBER right

now.

DR. COONEY: Let\'s proceed on with Jerry

Collins and the next part of the presentation.

Then, we will have a chance to come back for more

questions.

CDER Peer Review Research

DR. COLLINS: Good afternoon. The

background document that I prepared focuses more on

the review of research programs than on review of

244

individual scientists, but when I realized that we

were going to be covering both topics, you will see

the copies that you have of my slides, I tried to

cover both.

In my time at FDA, in addition to working

in CDER, I have been asked from time to time to

help other centers evaluate their research

scientists or their programs, so, in general, I

would say that the systems for peer review of

individuals in all centers have more similarities

than they have differences.

One of the mentors, Bob Dedick, used to

say that biologists are always looking for

differences, and engineers are always looking for

similarities, so this may just reflect my

engineering background.

Every employee at FDA has a semiannual

management review, so that is the baseline review.

Everything else is built upon that. Within the

245

Center for Drug Evaluation and Research,

non-laboratory scientists, the people do full-time

review and policy work, have promotion letters to

the 14 and 15 through things that we call expert

reviewers or master reviewers.

Those committees are composed of internal

FDA members and they are intended for non-managers

to have a promotion letter. Those promotions,

unlike in our laboratory side, are permanent, and

they are not periodically recertified.

We have a few additional personnel system,

Title 42 and Title 38, that are used for non-lab

personnel and at least until recently they have not

been subject to committee review or

recertification.

Finally, Congress created the Senior

Biomedical Research Service that I will be talking

about that at FDA, is implemented to cover both

non-laboratory and laboratory scientists.

Within CDER, to go back to being a

biologist and to highlight the differences between

the way the OBP Committee has been set up through

246

the CBER system versus the CDER system, we have

always had a requirement of a minimum of 50 percent

to the voting members of our committees to be

scientists from outside our Center, not outside our

research program, not outside our office, but they

have to be outside CDER.

Most often, for convenience and for

compliance with some of the nuances of personnel

review regulations, we have used individual

scientists from NIH and frequently from other

centers, and our staff has also served on the

review committees of other centers.

Their purview is the hiring or promotion

of scientists to GS-14 or GS-15, and effectively,

they are three-year renewable promotions, they are

not permanent. A survey of the record indicates

that very few people are not renewed, but

occasionally, it has been a leverage to use when a

person unexpectedly underperforms. We point out to

them that at their next review, this will be noted.

The Senior Biomedical Research Service is

an agency-wide program. We have an agency-wide

247

Credentials Committee supplemented by external

consultants, and it covers promotions from GS-15 to

essentially above the regular Civil Service pay

scale, and it clearly has a recertification

requirement, so it is either four or five years

depending on the center that the people come from.

That is a recertification with teeth, and

I can\'t discuss individual cases, but plenty of

discussions are made, and it has provisions, for

example, for a one-year renewal instead of a

four-year renewal to keep your feet to the fire if

necessary.

Some laboratory scientists are also

covered by Title 42, and as I said, for the non-lab

folks, up until recently there have been no

committees or recertification associated with that.

Again, I think based on my experience in

consulting for other centers, as well as my

experience within CDER, I think there you could

nitpick some of the differences across the review

of individual scientists. I think generally, there

is a lot more similarities, and it is a lot more

248

effective, understood by all parties, and truly an

ongoing process.

But as I said in my backgrounder, the peer

review of research programs themselves has

considerable polarity, and so as we just heard in

the discussion after the previous speaker, CBER and

NCTR have lab research programs that are much more

like the academic or the NIH model, site visits

conducted by advisory committees.

We have five other laboratory-based

research units at the FDA: Center for Devices and

Radiological Health, Center for Food Safety and

Applied Nutrition, Center for Veterinary Medicine,

the field organization in CDER, and for lack of a

well-defined term, I call that a corporate or a

management model, very similar to what a

pharmaceutical company does for its research

programs.

The primary evaluation of research

programs is internal by the program management.

Within CDER, we have had occasional

episodic external review. They are not formally

249

established, they are not regularly conducted.

Sometimes they are conducted when a problem is

noted by center management in their semiannual

review. Sometimes it\'s just we haven\'t done one

for a while, let\'s do it again.

I think what we are looking for today in

terms of advice from the committee is whether that

is really the most effective model.

In terms of the ad hoc reviews that we

have had, the FDA Science Board, which is another

advisory committee like this one, usually picks one

topic at a time, and might review the program, for

example, in genetics or genomics across all the

centers, rather than just a genomics or genetics

program at CDER.

The predecessor of this committee is

called the Generic Drug Advisory Committee, and it

started the tradition of at least having some site

visit-like character and certainly information

briefings.

So, last October I was here in front of

this committee talking about the OTR research

250

programs. I did that also back in March of 2003.

We have training sessions periodically. I think

those are very valuable in helping to orient you

folks and to prepare you to give advice to us, and

we do get feedback, but that is not the same in any

stretch of the imagination as a formally organized

peer review process.

The ad hoc reviews from external folks of

CDER programs usually are problem solving

exercises. At one time, we had another advisory

committee called the Antiviral Drug Products

Advisory Committee, still have it, and when we

created a laboratory program on antiviral drug

products, we made it part of the charter of that

committee to conduct periodic reviews of that

laboratory.

Unfortunately, that laboratory did not

flourish, and that laboratory no longer exists and

has been abolished. So, our review process does

have teeth, it is not just a friendly pass among

colleagues.

We also had, in the Center for Drug

251

Evaluation, support of a cardiovascular

pharmacology laboratory, and after an ad hoc

external review, that laboratory was decided to be

no longer funded.

So, again, reviews aren\'t as frequent and

regular, and don\'t capture the benefit of that, but

they do provide sort of a final chance to prove

yourself when things are going bad.

Internal reviews. I mentioned a little

bit about this at a training session earlier this

week. There is a tradition of annual presentations

to the Center Director, the Deputy Center Director.

A year might take longer than 12 months to call it

an annual review, but that has been a goal for a

long time.

I think we have had a number of serious

efforts to have a Research Coordinating Committee,

and it is always important when evaluating Center

for Drug Evaluation and Research, is that we are

not primarily about laboratory programs. There is

at least as much, or perhaps more, research that is

conducted outside the laboratory.

Things like reviewing files to find common

class effects of drugs, things like creating

databases to improve the review process, thinking

252

about looking at new standards for either safety or

efficacy.

So, all these programs in a very large and

rambling center like ours is hard to keep track of,

so the Research Coordinating Committee currently,

in its current form, is chaired by the Deputy

Center Director, is an attempt to try to pull

together centerwide databases of research and to

help center management in a pretty tough decision

of resource allocation.

Now, I made a comment at the training

session that the good news is we have high level

visibility with the Deputy Center Director as our

chair. The bad news is because at that level, the

person is so busy, we get a lot of cancellations.

Shortly after that, all our Blackberries

went off and another meeting was scheduled. I

don\'t think there is any connection, but I am

nervous.

Within OPS, for example, one example of

the kinds of non-laboratory research that is

conducted by the Informatics and Computational

Safety Analysis Staff, looking at

structure-activity relationships, and spinning off

various databases in terms of different elements of

253

safety, carcinogenesis, reproductive genetox, and

the like.

Elsewhere, the Biostatistical Biometrics

Office, the Office of Drug Safety, Office of

Information Management, and Office of Clinical

Pharmacology and Biopharmaceutics have

well-established research programs.

Funding has come up in the question and

answer period. The primary sources of funding for

CDER research programs, as with the tradition and

history of OBP when they were in CBER, and now that

they are part of CDER, is primarily determine by

office management.

Managers should be accountable for the way

they spend all their dollars, whether it is for

review, policy development, travel, or research,

254

and that has been the policy in CDER as long as I

have been here.

In addition, there is, as was mentioned in

the OBP presentation, there is an opportunity to

get funds from outside your individual budget

through the Review Science and Research program,

but those funding areas are limited to certain

areas determined by CDER management.

There is an internal peer review by CDER

scientists. Almost always those funds are not

intended for laboratory-based research, but they

are intended to foster primarily activities, such

as database generation within review divisions. In

a sense, they are equivalent of a laboratory.

Within the agency, we have a number

offices, the Office of Health Science Coordination

chaired by the Deputy Commissioner for Science, and

the Office of Women\'s Health, have had a certain

amount of money set aside every year over the last

10 years, and competition agencywide for these

funds is conducted. The priorities, again, the

categories that they are willing to fund are set in

255

advance, so that is the management of the funding

office.

Proposals are peer reviewed both for

quality and for relevance to the priorities that

have been set by the funding office. The peer

review is conducted only by internal FDA staff, but

both lab and non-lab proposals are accepted.

Within our Laboratory Research Program, we

do have CRADAs, cooperative research and

development agreements, which is a source of

outside money. We also have had occasional

interagency agreements with other federal agencies,

primarily NIH.

As you can imagine, those sources of funds

come with strings attached to them. By law, they

can only be spent on the purpose defined in the

CRADA or in the interagency agreement, so there is

a compromise between what might be your primary

mission and the mission of your partner in those

agreements.

I would say, in summary, that I grew up

scientifically, mostly within the NIH system, so I

256

am used to a system of peer review, site visits. I

see a lot of strength in that.

I am also a very strong proponent as a

part-time manager, part-time scientist, of holding

management accountable. I don\'t think it is

necessarily bad to make it a part of the review of

management on how well or how poorly they fund

research and how well or how poorly they evaluate

it.

I am very strongly convinced of the nature

of applied research, relevant research. I probably

have a reputation for pushing that angle too hard.

Whenever I do, I try to remember my own interview

when I was joining FDA, and I had a chance to

interview with Commissioner Frank Young.

He took me in his office and he said,

well, Jerry, I see you come from an applied

background and I am glad to see that because that

is what you should be doing in CDER. So, I thought,

great, I can really depend on the Commissioner to

support this, whenever anybody is off doing blue

sky stuff, I will just tell them what the

257

Commissioner told me.

But he didn\'t finish his sentence there.

He looked out his window and he said, \"You see that

sky. I think your job description ought to include

an element that says you spend 20 percent of your

time looking out the window or at least doing blue

sky research.\"

So, I think applied research, directed

regulatory relevance, is clearly doable, a little

bit of flexibility in terms of pursuing something

that may not quite be there from a regulatory

relevance, but has at least some hope in the

future, not 80 percent, but I will take

Commissioner\'s Young\'s 20 percent.

I was asked by some of the other members

of the Office of Testing and Research to mention

that we do occasionally very short-term projects, a

little bit more of a testing flavor than of

research. They are given by Office of New Drug

Chemistry of Office of Generic Drugs, or another

Office of Pediatrics, one of the other offices

within CDER.

They have a very short turnaround time,

and in a sense they are peer reviewed, because the

offices are either pleased with our work product or

258

they are not, and if they are not, they don\'t come

to see us again.

That really is my view of how the CDER

research operation has worked up until the time

that the merger occurred and OBP joined us.

Committee Discussion and Recommendations

DR. COONEY: Thank you, Jerry.

Are there some questions from the

Committee? Cynthia.

DR. SELASSIE: Just one question. You

mentioned that the funds for research are usually

used for database generation at CDER?

DR. COLLINS: That is in the particular

category of review science and research, so the

primary applicants, in fact, the principal

investigator for all those things has to be a

primary reviewer. Other people can be

co-investigators. So, by its nature, the funds

that are available there tend to be used for

259

creating databases.

At the training session earlier this week,

I talked about the project that we were

co-investigators on, looking at a review of

neuropharmacology NDAs over the last 10 years.

That was an example of a project that was funded by

the Review Science and Research program.

What does it do? In theory, it gives a

little bit of release time to the reviewers. In

practice, they probably just do it on top of their

regular job. It gives us some travel money. The

poster that came out of that meeting, it was

presented at a meeting in Florida. The travel

funds came out of the RSR budget. Publication

expenses come out of that budget.

DR. SELASSIE: But could the Informatics

people help you all with that?

DR. COLLINS: The Informatics people are

sort of built into the process. If you are going

to make a database generally available at FDA, you

have to start by talking to the people who run

either the OIM or the OIT, the Information

260

Management Information Technology. All databases

have to fit the new corporate model, so that is

there.

If in that process, they find out there is

some off-the-shelf software that is available for

it, that\'s great. Our Neuropharm project has used

Microsoft Access, it wasn\'t one of these

mega-databases. The hard part was extracting the

data from paper documents that had come in over the

last 10 to 25 years and putting them in electronic

format.

MS. WINKLE: Let me make it clear, too,

these aren\'t large sums of money. They may be

\$150,000 that are put aside, or may be up to 250

depending on what the budget allows each year, and

the amounts allotted are usually like in small

amounts, 5- or \$10,000 just to keep a project

going. It is not enough to do any real bench

research on.

DR. LAYLOFF: How many people are we

talking about, Jerry?

DR. COLLINS: The Office of Testing and

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Research has about 70 laboratory-based persons.

That includes a handful of support staff. We don\'t

actually have a classification system that permits

us to tease out the technical support staff from

the principal investigators.

So, when we were talking about the numbers

for OBP being 36 review-based scientists, we

actually have, in all, 65 review-based scientists

or something like that, but many of them would be

classified as technical support under a different

classification system. So, we just lump all our

folks together.

DR. LAYLOFF: You don\'t have a review

function corresponding?

DR. COLLINS: There are no line reviews

assigned. There are probably 10 of our staff who

spend more than 25 percent of their time doing

review and policy work. I chair several committees

that are related to the writing of guidance

documents, the FDA-wide Imaging Initiative, which

is primarily a non-lab operation.

Up until this year when these other duties

262

took me away, I did a tertiary review of every

single new molecular entity that was submitted to

the Center for Drug Evaluation and Research, an

average of about 30 a year.

Other scientists, like John Strong, work

in the Drug Metabolism, Drug Interaction area,

picked up the slack as I have moved into other

areas. On the Chemistry side, we have folks who

are consultants to that process, but we don\'t have

signature authority on the review of any product

from within\--

DR. LAYLOFF: There is no growth concept

like people going from research and moving into

doing some review, and then becoming reviewers full

time?

DR. COLLINS: Well, Tom, we call that a

\"stealing away\" phenomenon, not growth. Let\'s be

clear that Ajaz Hussain was the Director of our

Division of Product Quality, and Moheb Nasr was the

Director of our Division of Pharmaceutical

Analysis, and on and on, like that, so it is a

measure of quality and desirability, but you have

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to debate the idea that it\'s growth.

\[Laughter.\]

DR. COLLINS: Just kidding.

DR. COONEY: I think it is probably

appropriate as the next step, Keith, if you would

pose the question that you would like to Committee

to address.

DR. WEBBER: I think what we are looking

for here is not really a lot of discussion about

setting a peer review program or a site visit

program or the pluses or minuses of the various

aspects of it, but really just to come to the

Committee to look for an agreement to support the

creation of a subcommittee that will help us to

develop the criteria and the processes within OPS

to evaluate the research programs, the diverse

research programs that we have within the office

now.

Certainly, you can ask questions in that

regard, I think hopefully, we can come to an

agreement that you would be interested in that,

because we are interested in that.

DR. COONEY: I would like to open up this

question for discussion. Our charge this afternoon

is not to solve this problem, but rather to ask if

264

we concur in making a recommendation towards the

establishment of this committee.

Tom?

DR. LAYLOFF: So, you would basically

create a subcommittee, which would come back and

report to ACPS on the activities?

DR. WEBBER: That would probably be one

avenue or one aspect of developing a subcommittee,

and most subcommittees do come back to report to

the Committee, so I would imagine that would be how

it would work.

DR. LAYLOFF: So, the ACPS then would be

providing guidance to the subcommittee on how to

proceed with this?

MS. WINKLE: Let me point out, too, if you

determine to create a subcommittee, you would have

to have two members of the Advisory Committee that

would serve on this subcommittee, so not only would

you expect for the subcommittee to come back and

265

report to the Committee, the Committee would also

have input into the subcommittee through those two

members.

DR. COONEY: Marv.

DR. MEYER: Well, I don\'t have any

fundamental objection to that approach. I just

wonder why it is necessary. You have several

models out there in different groups in FDA

already.

It would seem like you could use some of

their expertise, as well as some of your own

people, to develop your own criteria for promotion

and for funding and research, and not have folks

like us sitting around the table and muck it all up

for you.

DR. WEBBER: I don\'t know that we are

necessarily looking for that much in terms of

mucking with the process.

\[Laughter.\]

DR. WEBBER: But I think that right now we

have a system within OBP\'s site review system,

which I think clearly needs to be replaced, and we

266

have a system which is now with OTR in the same

office, and I think if we can look at both aspects

of both research programs, and try to come up with

something that works for both, it doesn\'t

necessarily have to be the same, but has to be

something that will be consistent within the Office

of Pharmaceutical Science, and provide us with some

external guidance on the research programs that we

have, something that we have always gotten from\--or

at least with OBP, we have gotten that from the

CBER system, but we need to move forward.

DR. COONEY: I would like to thank Marvin

for introducing technical terminology into the

minutes.

Art.

DR. KIBBE: I think it\'s a wonderful idea

that you have a review of research activities

within the agency, and if you need our help, then,

we should stand ready to do that. So, you lay it

out and we will populate the committee for you.

DR. DeLUCA: I agree. I think you have

certainly given this some thought, and you think it

267

is important. I certainly think you do need some

external input into this, into the research that is

being performed and the caliber of it.

You do, I guess, derive some funding from

NIH, too, right, for this?

DR. WEBBER: Funding from NIH to establish

a peer review? No.

DR. DeLUCA: No, no, for the research.

DR. WEBBER: For the research, no, we get

money from NIH for the research. We get money from

operating funds, we get money, as you saw, from

other sources.

DR. DeLUCA: Maybe we ought to tap that

source.

DR. CLOUSE: There is money from NIH, but

only through Intramural NIH grants, so the money we

can apply for is limited. I mean we have a number

of investigators who have been funded through the

Intramural AIDS programs, and received AIDS grants.

We have received money for equipment

through that program, and this year NIAID has also

started an Intramural Grant program for

268

counterbioterrorism research, and we have people

who have applied for that.

So, we have been successful. That is

competitive with the other NIH institutes, and we

have received funding.

DR. COONEY: I think the fact that there

are different models to look at, both models that

exist within the system now as a consequence of the

merger, as well as alternative models and practices

from other organizations, it would very interesting

and useful to look at.

Perhaps\--not perhaps\--I am sure there are

best practices from alternative models, and I would

hope that this working group would be able to reach

outside and look at a number of alternatives and

come up with recommendations towards a system that

is most appropriate for the diverse activities that

are present here.

DR. WEBBER: I agree with that completely.

I don\'t think we need to reinvent the wheel

entirely, but to look at what other systems are in

place, and take the best practices from those.

DR. COONEY: I personally see this as an

important activity for a working group.

If there are no further questions from the

269

Committee, what I would like to do is to pose this

as a recommendation. I think it is appropriate for

us to vote on it, which I will go around the table

and ask for votes in just a moment.

The alternative votings are yes, no, or

abstention. What we are voting, this would be a

recommendation by this committee to the FDA to form

a working group of the ACPS to address the criteria

and processes for evaluating the OPS research

programs.

We are now empowering the creating of a

committee, but we are recommending that they go

forward with the formation of a subcommittee.

Marv?

DR. MEYER: A point of clarification. You

mean a subcommittee under ACPS with two members

from this group, not members of this group.

DR. COONEY: Yes, that is what I meant.

Thank you.

Since we began with Art yesterday on the

previous vote, we will begin with Tom today, and I

would like to go around and have a yes, no, or

abstention.

Tom.

DR. LAYLOFF: Yes.

270

DR. COONEY: Cynthia?

DR. SELASSIE: Yes.

DR. SWADENER: Yes.

DR. COONEY: Mike.

DR. KORCZYNSKI: Yes.

DR. COONEY: I think I heard yes from

both.

Morris?

DR. MORRIS: Yes.

DR. COONEY: Pat?

DR. DeLUCA: Yes.

DR. COONEY: Carol?

DR. GLOFF: Yes.

DR. SINGPURWALLA: Yes.

DR. KIBBE: Yes.

DR. MEYER: Yes.

DR. COONEY: And yes for myself. We have

a unanimous 11 yes\'s, zero no\'s, zero abstentions,

and 11 yes\'s total to 11 votes.

Thank you very much, Keith. This brings

this topic to a close.

I would just like make two further

comments before I believe we close for this

session. One, I appreciate very much the very

thoughtful contributions that each of the

271

presenters have made in a very nice style. I like

the data-driven presentations, and the fact that

they were very concise.

I would like to thank the Committee

members for their very, very thoughtful comments on

all of the topics that allowed us to move I think

reasonably efficiently through what was a very full

and very important agenda.

This is an important committee to OPS as

it helps them as they go forward and craft an

aggressive agenda being proactive and changing some

of the paradigms with which they work.

I would certainly like to ask the

272

question, if anyone on the committee has thoughts

on things that we should be talking about, should

be addressing that we haven\'t talked about before,

this is an open-ended question. We can deal with

thoughts that you might have now, but it is meant

to be a permanent question on the table, that as we

have things that we think should be addressed by

this committee, I would hope that people would be

very forthright in bringing them up, so that we can

come back to them in an ongoing manner.

Does anyone have any thoughts at the

present time?

Nozer.

DR. SINGPURWALLA: Not on the question you

asked, namely, but I would like to make some

comments about the format of the meeting. I would

like to suggest that the number of presentations be

cut down and the length of each presentation be cut

down, and there be more time for discussion

instead.

This puts not only less burden on the

committee, but it also puts less burden on the

273

staff and yourselves. I know you work very, very

hard, and I know this is a stressful thing for you

to do, and it is not as stressful for us, but I

think cutting these down would be of some value to

us.

DR. COONEY: Any other comments or

thoughts from the Committee?

If there are no objections, I will call

the meeting to a close and thank you all very

much\--oh, I am sorry. Ajaz, Helen, please.

Conclusion and Summary Remarks

DR. HUSSAIN: Let me quickly summarize.

Just wanted to sort of encapsulate some highlights

that were, in my opinion, I think the key

directives and recommendations we heard from the

Advisory Committee.

First, I think I would like to acknowledge

and thank our colleagues from Health Canada who

have attended this session and have shared with us

their perspective as the meeting went along, and

also shared their experience on the same issues. I

think we share quite a bit in common and we are

274

collaborating on many fronts.

The meeting started with a discussion on I

believe an important topic where the tactical plan

that we proposed in some ways is a paradigm shift,

and that is the reason we proposed a tactical plan

instead of proposing putting forward a proposal to

you, because this will allow the community to go

back and debate and vigorously engage in this

topic, so that when we come back with a proposal,

we hope the entire community will connect to that.

The accomplishments there were, in a

sense, nothing new from a quality sense from

outside the pharma sector, but I think we

introduced some of the tools and methodologies that

have been utilized and approaches that have been

utilized successfully in other industries to

attempt to move towards a more probabilistic

approach to setting specifications that allow us to

be risk based and science based, and bring a high

level of ability to manage variability in

measurement systems in the case of dissolution, but

more so I think start to focus on the product of

275

interest and see how we can take that information

and move towards a controlled philosophy that

allows us to gauge the capability of a process and

also the state of control.

I believe that will be extremely important

for our CMC reviewers and GMP inspection staff to

really connect, because establishment of state of

control and ability to have confidence in that is

the part of continuous improvement, and that is one

way of reducing the need for supplements, and so

forth.

So, that becomes a basis for moving

forward, but at the same time, dissolution is just

one of the physical performance attributes of

interest. This becomes a model for all other

specifications especially with respect to physical

attributes.

The challenges are even greater on the

other fronts including particle size, and so forth.

So, I think the strong endorsement of the Committee

really sends a strong signal and provides the

support that we needed to really push ahead with

276

this, and the timing of this could not have been

better, because we start engaging with our European

and Japanese colleagues on putting decision trees

starting next week, and we needed this leverage to

make the case of where we want to go and hopefully,

bring them along with us, because all of us are in

the same boat right now.

So, I think I really thank the Committee

for the discussion, as well as the strong support

they have given us on this front, and I hope the

pharmaceutical community will really engage and

debate this extensively, so that when we have a

proposal to this committee next time, we actually

can build consensus and move forward. Otherwise,

this could be a long debate.

The topics for Day 2, today, clearly, I

think show the challenge that we have with respect

to move towards a tactical plan for the type of

questions, the complexity of the questions that you

saw, but in many ways, what we have done is

addressed or attempted to frame a question on

challenges that we have faced for the last 10, 15

277

years.

I am hopeful that bringing a

knowledge-based approach to tackling that problem

might find a solution. It is not going to be easy,

and clearly, I think we tried to push the agenda in

terms of seeking to tackle a problem like topical

therapeutic equivalence, which will be one of the

most significant challenges.

The challenge will not only be technical,

but also educational, because we will have to

communicate that to the clinicians, the

dermatologists, and the pharmaceutical community in

general.

So, the challenges are not just technical,

but also educational and consensus building across

disciplines to the stakeholders.

With regard to I think highly variable

drugs and the Japanese in many ways have already

made that call. They are moving. They have

already applied what we were seeking to apply.

A re-examination of their decision

criteria and putting more rigor to our approach

278

might find a way, not only to seek harmonization

internationally, but also the challenge has always

been that generics are not part of the

International Conference of Harmonization, but

those do things do impact the general decision

trees that we come up with ICH.

So, again, the reason for bringing topics

more focused on generic drug approval was also to

get the generic industry as part and parcel of the

ICH process as much as we could in this discussion.

The key aspect I think I was hoping and

did get the general consensus on is to focus on a

scientific hypothesis driven process, and that is

important because in a regulatory decision

criteria, you need the comfort, as well as the

rigor of a hypothesis testing concept to make

clear-cut decisions.

In many ways, the bioequivalence, although

the goalposts we can argue are arbitrary, and so

forth, but it does give you a sense of decision

which is less arbitrary than it could have been,

and we have been through that transition.

So, in many ways, if you recast the

current requirements that we have on the regulatory

side, like stability testing, bioequivalence, and

279

all of those requirements in the form of a

hypothesis, and your prior knowledge leading to

that hypothesis testing, that provides a way

forward.

I think we will try to construct our

decision trees with that in mind, so as not to add

more burden, but also be relevant in the questions

we ask, and not direct the development program.

So, I think that hopefully, will provide a

common ground to lay out the decision trees.

Our research programs, I think are

critical and thank you for endorsing our request to

have a subcommittee. I am hoping that the working

group or the subcommittee that we form will find

the best practices to lay and create a foundation

for our peer review.

At some point, I think we are initiating

peer review on our review side, and Moheb has

already moved forward in instituting that, that

280

each review of CMC will\--not all\--but I think

selected reviews will be peer reviewed by their

peers, and at some point I think he will come back

and share with you his thoughts.

Peer review for review is not new. In

fact, Jerry Collins, when I joined the agency years

ago, we had established a peer review for the

biopharm, and that biopharm day now has really

become a nice model, so I thank Jerry for

initiating some of that thought process, and I

think they are just trying to find the best

practices.

With that, I will stop and thank the

Committee for the valuable information and feedback

that you have provided.

MS. WINKLE: It looks like every time we

meet, I am recognizing the same two members of the

Advisory Committee, but I do have beautiful plaques

today for Art and Marv for their services as

members of this Advisory Committee.

Obviously, we have enjoyed having them so

much that we haven\'t let them go away, that we

281

continue to bring them back, because I think they

contribute a whole lot to the conversations and the

discussions we have had.

Anyway, I have some really pretty plaques

for you this time, so I appreciate it. The last

were just certificates, but these are plaques for

advisors and consultants.

I just have a few things I want to say. I

have enjoyed listening to the conversations and

discussions over the last two days. Both of these

topics are topics that I have wanted to discuss for

a long period of time.

For several years now, Ajaz and I have

both been discussing some of the issues over

dissolution, many of the issues over pharmaceutical

equivalence in general, so I was really happy when

we decided to bring these to the Advisory Committee

this time, and to begin to open up our thinking in

these areas.

As Ajaz said earlier when he was talking,

we have actually been learning how to do things for

the last 30 years, and now it is time to apply some

282

of things we have learned, to changing some of the

way we do things.

I think today\'s and yesterday\'s

conversations were our good step forward in doing

that. I started off by talking about the journey

that we were on here and changing the paradigm. I

think that we took some really significant steps.

They may have seemed small to some people, but they

are very significant to us, I think, in OPS as we

move forward along that pathway.

So, I want to thank you all for your

input. One of the things, too, I wanted to mention

that up-front, in my opening, I mentioned the fact

that I thought that, in my mind, one of the

initiatives that we have now been working on, the

GMPs for the 21st Century, the Critical Path

Initiative, and the PAT are all leading to a shared

responsibility for product quality.

I think through the shared responsibility,

we need to do more partnering. We need to partner

with industry, but we also need to partner with

academia, and I think with working through this

283

committee, it is a really good opportunity to

partner and get input from many people who know

things that are going to be beneficial to us as we

do move along our pathway.

So, with that, I want to thank Ajaz. Ajaz

spent a lot of time putting this together along

with everyone else that gave presentations. I know

Nozer felt many of them were long, but I think

there were a lot of good points made in these

presentations this time, and I think they were very

worthwhile in helping us get a better understanding

of some of the issues that we had to tackle.

Also, I want to thank Bob King, who herds

us all through this. It is just like herding cats,

believe me, and he really deserves a lot of thanks

for that.

I appreciate, too, your input on the

subcommittee. I think this is very going to be very

valuable to OPS to take a look at the two research

programs and see how we can better coordinate and

set priorities, et cetera, so I appreciate that.

With that, I will close and turn it back

284

over to Charlie.

DR. COONEY: Thank you. My apologies.

Art?

DR. KIBBE: Listening to the summary made

me think of one thing that I had written down and

forgot to say. I think it would be well if the

agency could assure the industry that when they

provide drug product development information, that

the reviewer who reviews it will have a working

knowledge of drug product development and some

hands-on experience with the equipment and the

materials that are being used to do drug product

development, so that the review is worthwhile on

both ends of the thing.

Second, thanks for the plaque. It has

really been fun irritating Ajaz all these years,

and I continue to look forward to having an

opportunity to continue to do that.

DR. COONEY: Thank you all very much and I

think I can now close the meeting without creating

yet another faux pas. Thank you.

\[Whereupon, at 3:30 p.m., the meeting was

285

concluded.\]

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