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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

Wednesday, October 20, 2004

8:30 a.m.

CDER Advisory Committee Conference Room

5630 Fishers Lane

Rockville, Maryland

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PARTICIPANTS

Arthur H. Kibbe, Ph.D., Chair

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

MEMBERS

Patrick P. DeLuca, Ph.D.

Paul H. Fackler, Ph.D.

Meryl H. Karol, Ph.D.

Melvin V. Koch, Ph.D.

Michael S. Korczynski, Ph.D.

Marvin C. Meyer, Ph.D.

Gerald P. Migliaccio, Ph.D. (Industry

Representative)

Kenneth R. Morris, Ph.D.

Cynthia R.D. Selassie, Ph.D.

Nozer Singpurwalla, Ph.D.

Marc Swadener, Ed.D. (Consumer Representative)

Jurgen Venitz, M.D., Ph.D.

SPECIAL GOVERNMENT EMPLOYEES SPEAKERS

Judy Boehlert, Ph.D.

Gordon Amidon, Ph.D., M.A.

FDA Staff

Gary Buehler, R.Ph.

Lucinda Buhse, Ph.D.

Jon Clark, M.S.

Jerry Collins, Ph.D.

Joseph Contrera, Ph.D.

Ajaz Hussain, Ph.D.

Monsoor Khan, R.Ph., Ph.D.

Steven Kozlowski, M.D.

Vincent Lee, Ph.D.

Qian Li, Ph.D.

Robert Lionberger, Ph.D.

Robert O\'Neill, Ph.D.

Amy Rosenberg, M.D.

John Simmons, Ph.D.

Keith Webber, Ph.D.

Helen Winkle

Lawrence Yu, Ph.D.

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C O N T E N T S

PAGE

Call to Order

Arthur Kibbe, Ph.D. 5

Conflict of Interest Statement:

Hilda Scharen, M.S. 5

Committee Discussion (Continued) 8

Science in Regulation - Visionary Overview

Arthur Kibbe, Ph.D. 43

The \"Desired State\" of Science-and Risk-based

Regulatory Policies

Ajaz Hussain, Ph.D. 74

Organization Gap Analysis

Helen Winkle 75

Scientific Gap Analysis

Ajaz Hussain, Ph.D. 103

Policy Gap Analysis

Jon Clark, M.S. 135

Generic Pharmaceutical Association Perspective

Shahid Ahmed, M.S. 152

Pharmaceutical Research and Manufacturers

of America Perspective

Gerry Migliaccio, Ph.D. 164

Committee Discussion and Recommendations 182

Pharmaceutical Equivalence and Bioequivalence

of Generic Drugs

The Concept and Criteria of BioINequivalence

Concept of BioINequivalence

Lawrence Yu, Ph.D. 205

Criteria of BioINequivalence

Qian Li, Sc.D. 222

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C O N T E N T S (Continued)

PAGE

Committee Discussion and Recommendations 234

Bioequivalence Testing for Locally Acting

Gastrointestinal Drugs

Topic Introduction

Lawrence Yu, Ph.D. 273

Scientific Principles

Gordon Amidon, Ph.D. 275

Regulatory Implications and Case Studies

Robert Lionberger, Ph.D. 308

Committee Discussion and Recommendations 324

Conclusion and Summary Remarks

Ajaz Hussain, Ph.D. 341

Helen Winkle 349

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P R O C E E D I N G S

Call to Order

DR. KIBBE: Ladies and gentlemen, I would

like to call the meeting to order. The first item

of business is the reading of the Conflict of

Interest Statement.

Conflict of Interest Statement

MS. SCHAREN: Good morning. The following

announcement addresses the issue of conflict of

interest with respect to this meeting and is made a

part of the record to preclude even the appearance

of such.

Based on the agenda, it has been

determined that the topics of today\'s meeting are

issues of broad applicability and there are no

products being approved. Unlike issues before a

committee in which a particular product is

discussed, issues of broader applicability involve

many industrial sponsors and academic institutions.

All Special Government Employees have been

screened for their financial interests as they may

apply to the general topics at hand. To determine

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if any conflict of interest existed, the Agency has

reviewed the agenda and all relevant financial

interests reported by the meeting participants.

The Food and Drug Administration has

granted general matters waivers to the Special

Government Employees participating in this meeting

who require a waiver under Title 18, United States

Code, Section 208.

A copy of the waiver statements may be

obtained by submitting a written request to the

Agency\'s Freedom of Information Office, Room 12A-30

of the Parklawn Building.

Because general topics impact so many

entities, it is not practical to recite all

potential conflicts of interest as they apply to

each member, consultant, and guest speaker.

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.

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Paul Fackler and Mr. Gerald Migliaccio are

participating in this meeting as non-voting

industry representatives acting on behalf of

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

Migliaccio\'s role on this committee is to represent

industry interests in general, and not any other

particular company.

Dr. Fackler is employed by Teva

Pharmaceuticals U.S.A., and Mr. Migliaccio is

employed by Pfizer, Inc.

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. KIBBE: Thank you.

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Yesterday, we concluded with a suggestion

that we might want to continue our discussion about

the questions that the Agency has raised, and I

think Dr. Meyer has asked Dr. Hussain to come up

with a straw man, and we have it ready, so I think

we should go there first and then go back to the

scheduled agenda.

Ajaz.

Committee Discussion (Continued)

DR. HUSSAIN: Good morning. I think the

discussions towards the end of yesterday started

honing down on some of the key challenges we face

in the designing of a Critical Path Initiative in

OPS.

I think, reflecting back on the discussion

yesterday, clearly, I think we have a wide range of

research capabilities and programs already in

place, and the challenge would be to sort of direct

these in a very focused way to help the Critical

Path Initiative, keeping in mind that all of our

research will not be focused on critical path,

there are other aspects that we have to focus on.

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I will sort of reflect back on the PAT

Initiative and how that sort of evolved. Clearly,

if you recall, the PAT Initiative led to the GMP,

and there is a whole sequence of initiatives that

have occurred. The PAT Initiative was a model and

we can learn some things from that as a model also.

I will sort of summarize my thoughts here

with a hypothesis statement that Jerry proposed

yesterday, that Critical Path Initiative will

improve the efficiency and effectiveness of drug

development process. That is the hypothesis that

sort of really we are engaged in trying to fulfill

or trying to confirm.

The challenge would be then how do we

measure efficiency and effectiveness of drug

development. That is one of the keys, how do you

measure drug development in terms of the failure

rate, or the time it takes, or the cost of drug

development.

All of these are relevant metrics, but for

the purposes of a hypothesis, what and how should

we approach and define that, because unless you can

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measure something, you cannot improve it. So,

measurement and metrics would be a key factor of

that.

The second aspect then would be what are

the root causes of low efficiency and effectiveness

in all the three dimensions. A number of factors

were put up looking at 1999 or 1991 or 2000, and so

forth.

They were indicators of what may be

happening, but you have to keep in mind that is

partial information, information available to FDA

and available in public is just limited because the

companies have far more information about the root

causes, and so forth. So, you have to sort of

factor that into our decisionmaking.

The next question is who is in the best

position to address these root cause factors that

we identify, what is the role of FDA, what should

FDA do and what should some industry, academia, and

other agencies should be doing is the key there.

I think based on information and based on

experience at FDA, clearly, we are in a good

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position to identify many of the problems, not all

of the problems, but many of the problems, and FDA

has the responsibility to communicate these

findings in some way or form.

If you look at John Simmons\' presentation,

he laid out, as a part of the critical path,

strategic meeting points during the drug

development process. That is one aspect,

communication between sponsors of applications and

our review scientists, if that is timely and in a

coordinated manner, that is one effective means of

that.

So, communication through meetings for

specific drug applications, broader communications

with workshops, and then eventually guidance

documents outlining FDA\'s current thinking on a

given topic are the communication mechanisms that

we have.

For that, clearly, I think you have to

think about resources and how do you facilitate

that process. If you want to sort of move towards

more meetings and more interactions between

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reviewers and sponsors, then, you have to build the

time for that, and so forth. That has to be

considered, too.

Workshops and guidances also take a

significant amount of effort, and so forth, so as

we improve our communication channels, where will

we find the resources and time to do that, I think

that is also a management aspect that has to be

discussed.

FDA\'s knowledge base, I think was clearly

an asset in the sense we have a lot of information.

If we are able to create a knowledge base that can

be useful, not only for identifying problems that

we see, but also for improving of a predictive

ability in all three dimensions, safety, efficacy,

and industrializations, what are the practices that

lead to success, what are the practices that may

not be as efficient, and so forth.

So, this knowledge base would be useful

for that purpose, but again I will remind in the

sense we have to be cautious, there are limitations

of that knowledge, because we don\'t always have all

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the information, so you have to factor that in.

But based on our knowledge base and based

on communication, and so forth, I think the

laboratory and the research functions clearly have

to focus on improving methodologies. There are

many aspects of laboratory work that only FDA is in

a good position to do, and others either don\'t have

the interest or don\'t have the focus to sort of

address some of the challenges.

For example, in the case of regulatory

decisionmaking, risk-based decisionmaking, the

decision process itself often needs support of

science, and so forth, so that is where the

research really could focus on.

Also for development and validation of new

methodologies, standards development, methodology,

validation, say, from biomarker to any new

technology, unless FDA has a role in achieving

that, it may not be fully appreciated within the

Agency, and some of the Agency concerns would not

be addressed if it is done totally outside, so

there has to be some means of linking our

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laboratory work to standards development,

validation of new methods, and so forth.

Our postmarketing experience again is

unique because that is where I think we have a lot

of information, how do we capture that as lessons

learned and how do we use that. You saw some

examples of how we were learning from that and

going retrospectively and said how could we have

improved the process. Those experiments would be

very valuable.

One aspect is in terms of innovation, in

terms of new technologies, what is an important

aspect of standard setting? Standard setting and

guidances are slightly different in my opinion.

For example, in the PAT Initiative, we opted to

move towards ASTM International as the body for

standard setting.

What that does is allows industry,

academia, every stakeholder to be part of that, and

actually identify what standards are needed, and

actually develop those as quickly as possible.

That relieves the burden on FDA, and FDA

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simply adapt or adopt those standards after

evaluation, so that might be an option that seems

to be moving forward in the PAT Initiative for new

technologies, new methods, and so forth. So, that

could be considered at the same time.

But at the same time, I think as we look

at FDA\'s role, what is the role of industry and

what is the role of other agencies and academia

really have to sort of come together.

The role of industry I think is knowledge

sharing. Clearly, it has far more information, and

reluctance to share knowledge will inhibit the

progress, and how do you do that is a key

challenge.

At the same time, I think in order to

bring all of us together, focused on a given goal,

we really I think have to define clearly the

metrics, the desired state, and so forth, and come

on the same page, so that we can coordinate all of

these activities.

In some ways, FDA could play that role of

coordination, as Viad declared yesterday, not only

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from the prospective of we are not competing in

this arena, eventually, we have to be involved, so

coordination function for FDA would be an important

function for all these activities.

If we have a clear understanding of what

are the issues and what are we trying to achieve,

then, the coordination and synergy would sort of

evolve naturally.

So, those are the sort of thought process

that I could capture.

DR. KIBBE: Anybody? Marvin? You asked

for the straw, you got the straw man.

DR. MEYER: The virus, are you talking

about that later?

DR. HUSSAIN: No, that is a very specific

example.

DR. MEYER: I thought I had more time to

think then, since I was waiting for the virus.

DR. KIBBE: Does somebody else want to\--

DR. MEYER: No, no, I have something to

say.

DR. KOCH: Marvin, just before you\--I

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think I need a point of clarification because some

of what came out yesterday was the desire to have

either shorter development time, more compounds

coming out that could be effective, new

pharmaceuticals, and it seems to be a push towards

industry to try to become more effective, et

cetera, but I saw a couple times yesterday where

things developed within the Agency to improve the

ability to go after materials through some of the

databases and things were certainly ways to help

that process.

The other thing, though, is that when you

looked at that chart that showed an increase in

cost of materials and a few other things, toxicity,

you know, is something that shows up there, and I

think something a little bit insidious over time

has been with improved technologies and increased

concerns over pharmaceuticals, there are new tests

that come in that prolong the evaluation, that

anything the Agency can do to pull things together

to make those things, immunogenicity or other

things that have, you know, you go back two

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generations ago and if you come up with a new

material, would you put it through all of the same

tests, so anything that can be done to simplify and

do more predictive studies in that regard, I think

would help.

DR. HUSSAIN: Definitely, that is an

important point. For example, I think as we move

towards more complex materials, the material cost

is, as you saw, is already showing up, and so

forth.

Introduction of new excipients or new

adjuvants, and so forth, is a significant

challenge, and as we go towards nanomaterials,

nanodevices, and so forth, if we still have to rely

on the traditional pharmaceutical excipients, it

would be a very limiting aspect, so I think that

that is clearly on our agenda.

One aspect that I do want to mention, as

we think about this, the patient has to be foremost

in our minds, what are the unmet needs, and as we

sort of develop this, I think clearly, the patient

needs have to be kept in mind as we move forward,

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because there are many diseases, many aspects where

we don\'t have effective drugs, and so forth, so we

shouldn\'t forget that aspect.

DR. KIBBE: Marvin, are you ready now?

DR. MEYER: Yes. I was just thinking of a

simple example where the Agency I think played a

major role and really expedited drug approval, and

that was back when we were battling over assay

method validation.

The hypothesis was if we had a better way

of validating assays or a uniform way of validating

assays, things would get approved without recycling

and redoing, and, in fact, FDA then, and APS and

others, convened several workshops, had white

papers, ultimately put out a guidance, and I

suspect that hypothesis has been tested, that there

are much fewer problems in the local methodology,

so I think that is a good model, and you alluded to

that.

DR. KIBBE: Anybody else would like to

make a comment?

DR. SINGPURWALLA: Yes. I repeatedly hear

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from individuals like yourself asking industry to

share more information with you. What is the

incentive to the industry to do so, because there

is a penalty to do so? Recently, those of us who

read the Washington Post can see the number of

pages devoted to the Merck and also to Pfizer

having a similar drug going to be tested, and

things like that.

So, unless the legal pressures that are on

industry are defused or removed, industry is going

to be foolish to share all the information with

you. I wouldn\'t. It\'s like me going to the IRS and

saying look, this is how I have cheated, catch me.

It doesn\'t make sense, does it?

DR. HUSSAIN: No, I think it is not in the

context of sort of cheating, and so forth. This is

in the context of how much we know and how much we

don\'t know, to start filling the gaps where the

knowledge exists. Clearly, that is the aspect, and

it is complicated by the fact that the way it gets

entrenched into the legal and political scenarios,

those are significance challenges, no doubt about

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that.

DR. SINGPURWALLA: What is the industry\'s

response to this?

DR. MIGLIACCIO: Well, it is complicated

by obviously, intellectual property rights, which

is the life blood of a commercial business, but it

is also complicated by\--you just used the word

\"trust.\"

I will give an anecdote here. I went to

an internal FDA meeting to provide training, and

during that training, provided knowledge about

products, which normally, would not have been made

available.

The reaction was the traditional

predictable reaction, not the forward thinking

reaction, by certain elements of the audience. So,

that was a risk, that was a poorly thought-through

risk on my part.

We have to reduce the risk associated with

sharing knowledge. That is the fundamental issue

is if we share knowledge and expose ourselves to

compliance action where that knowledge is

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essentially reflecting what is the scientific

truth, and we can now measure that, we can now see

that where we couldn\'t before, and if you divulge

that knowledge and risk compliance action versus

scientific discussion, then, the knowledge will not

be transferred.

DR. KIBBE: Ajaz, anything?

DR. HUSSAIN: No.

DR. KIBBE: Anybody else? Let me just put

three things on the table and perhaps you can think

about them as how they respond to the questions we

were left with yesterday.

One is that I think I heard from around

the room that the Agency has a limited resource

base, and it truly should focus on those aspects of

the critical path that only the Agency can do, that

no one else has the wherewithal or the capability

or the information to do that.

Secondly, that we try to get others who

are even more capable of responding to certain

aspects of the critical path to take on that

burden. I am thinking primarily of industry and

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perhaps industry/academia together looking at those

aspects of it.

But the third thing that I think that the

Agency and both the industry will have to look

forward to is that the rate of technological

advance is such that 10 years from now, the

questions that you are trying to answer now will be

ancient history, and the questions that you are

running into are going to be dramatic and clearly

different, and I really look forward to a paradigm

shift in the way we approach therapy, and I would

recommend to the industry that they change their

name from drug companies to companies that provide

therapeutic agents and processes, because they

could be caught up in the same system that the

railroads did. They were railroad companies, and

not transportation companies.

I don\'t know how the Agency can respond

effectively without having some type of internal

committee that is constantly looking at four or

five years out and the technology that they are

going to have to deal with then.

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So, that is where I think the critical

path kind of initiative ought to be looking.

DR. DeLUCA: Let me just comment. I made

some notes here from yesterday, and I think that

this is based on collaboration, I think I am going

to really focus on that, and as Jerry mentioned, I

think trust. Certainly, trust is essential in

collaboration, and as we get into talking about the

science-based approach here and research, research

is a search for the truth.

I would like also to commend the Agency in

their research efforts. I mean yesterday was, I

think, I would say overwhelming to learn the type

of research that is going on and the collaboration

with NIH, so I really have to commend the Agency

for this.

I would like to also talk about the

presentation by Monsoor Khan where he talked about

critical path research and some of their efforts,

and I think Gerry Migliaccio had responded that

industry takes this approach.

I have to say that that is true from my

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experience to an extent. I know, I am involved in

the novel drug delivery area and the research in

that area, and working with a company that was

scaling up or transferring some technology, that

that approach was taken, the critical path approach

was taken, and worked with them, and they did solve

the problem at hand, but there were other things

that still needed to be done to define some of the

process variables, that once the problem was

solved, they went on, they didn\'t want to go any

further with that.

So, I think there is a limit to where they

go and I think this is where collaboration is

important, and I think there is a need to continue

on and to search those things out, and probably the

place for that is in academe.

I don\'t know if it was Jerry Collins, when

he talked about the science-based approach to

critical path issues and the research, that it is

probably essential that the research that is going

on, that it is going to be hypothesis driven. I

think this is something that many times the

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research that takes place, and if it is in an

industrial setting, may lack the hypothesis driven

type of research, and that probably I think is

important.

I guess my feeling is in hearing all the

things, and I think what Art had said, FDA can\'t

really overreach, I mean there is a limit

resourcewise, but I think more importantly is the

idea that they can\'t do it alone, so I think that

collaboration is important.

The FDA has been collaborating more with

NIH, and I think translational research issues,

taking the drug product development, that portion

of it along, but I think there is a gap there with

the critical path, in the formulation and taking it

and the manufacturing science, and I guess I think

that the collaboration has to be there between

academe, industry, and FDA, and FDA could really

set the stage for this. I think there is a very

important role.

Just to bring out my experience with the

journal, the APS on-line Pharmaceutical Science

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Technology Journal, that the submissions, we get

about 50-50 from abroad and the United States, but

about 90 percent of the submissions\--now, this is

in the Pharmaceutical Technology Journal, and you

would really think that you would get more from

industry\--but about 90 percent of the submissions

come from academe.

I have to acknowledge that probably in

about 40 percent of those, there is a collaboration

between academe and industry, so that there is a

tie-in and that it is all those being submitted

from the academic institution, the industry is

involved in it.

But I think that this kind of sends a

message, and I have tried to encourage more, more

submissions from industry, and there is

intellectual property situations involved in that,

but I think there is a need.

I know, being in academe and graduating

Ph.D.\'s, the majority of them will go into the

industry, few of them publish after they are in

industry. Before they left, they had eight or nine

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publications, and then they went in and stopped

publishing, so, I am not sure that is a good thing.

What I wanted to emphasize here is that

there is an essential need for collaboration. I

think the whole science-based approach to the

regulatory arena is great, and I have to commend

the Agency in this, but they just can\'t do it

alone, and I think there is an essential need that

this collaboration occur.

It may be that with that type of

collaboration, you know, for a long time in

academe, we have talked about the NIH and trying to

get them involved with supporting drug product

research and development to little avail, so maybe

now is the time.

Certainly, I think it is essential that

this type of approach be taken in the manufacturing

sciences, because it certainly will benefit, I

think, our society, so I think it is in the

interests of the country, so that hopefully, the

NIH will look a little bit more favorably on

supporting this type of research. I think the

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collaboration between FDA and NIH may help in doing

just this.

DR. KIBBE: Thank you.

Ken, go ahead.

DR. MORRIS: Thanks, Art. Welcome to your

last day.

A couple of things I wanted to say first

to Nozer\'s point. In the face of the data that I

think Merck generated or was generated and then

shown to Merck, I don\'t think they would need the

Agency to tell them that they needed to pull the

drug or to modify it. They are really very

responsible about that sort of thing. I understand

your point.

DR. SINGPURWALLA: The lawyers made them

do it.

DR. MORRIS: Well, the lawyers made them

do it, but the drug companies in general, the

innovators of generics, when they see problems like

that, are still I think honor bound and have

historically done a good job of monitoring

themselves with respect to public health when there

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is a clear and present public health injury issue.

But beyond that, let me just comment, if I

can, I have just five points here, relatively

short.

The first is, is that the unique

opportunity afforded by the FDA massive database, I

think is absolutely invaluable and needs to be

exploited to the maximum. I mean that, in my mind,

is perhaps the number one initiative in terms of

getting down the critical pathway with all due

deference to proprietary data, of course, as we saw

yesterday.

There are some issues I think, for

instance, tox, where the database would probably

not be nearly as good as even the sampling of the

Big Pharma companies\' databases on tox, because you

don\'t have the tox information on compounds that

never made it to filing, so they may actually have

a bigger database there, which would really help in

the really interesting work we saw yesterday on

modeling.

The second point is it look from a

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nonbiological and obviously blue collar tablet

smasher, that there is a fairly large disparity

between the amount of internal biological research

versus product development research. I am not

really in a position to judge what the priorities

in the biologicals should be. It is all obviously,

very high-caliber research.

I am not in any way commenting on that,

nor am I capable of it, but I think it does point

out the fact that there are developmental research

agendas that probably would be better handled in

part at least, or at least administered through the

Agency, that aren\'t being, and we can talk about

specifics, and have with John and you and others,

of course.

But I think that points out an opportunity

if you were on the critical path, and that is the

prioritization that I was asking about yesterday,

is that given the breadth of projects and the

dearth of resources, I think the prioritization,

particularly the internal research projects,

becomes your biggest challenge and one that I think

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could be helped by the committee, and I think has

been in part, hopefully, in these days.

It also points out, to reinforce Pat\'s

point, and this is a little bit self-serving, but

the amount of research that doesn\'t or is not as

logically done within the Agency, needs to find

federal support in terms of public health

initiatives, as well as the obvious advance of just

basic science.

To address a question that Gerry had

raised with respect to the possible putative

consequences of sharing information, there is a

mechanism that we have been sort of developing,

which is to, through blinded intermediates, to be

able to discuss general topics without filtering.

I am not talking about filtering data or

hiding data, but to bring data to light to the

Agency in a blinded manner to say, you know, is

this the sort of data that would be useful, or is

this the sort of data that would give you cause to

think that there was no particular reason to review

it, and it would just be a waste of the Agency\'s

33

time.

So, I think there are mechanisms to do

that. They are not formal mechanisms, but through

consultants and whatnot, I think you have already

got that as an opportunity, so you can\'t be too

specific, of course, because once you are too

specific, then, you have already revealed what it

is you are asking about.

Finally, with a question of metrics, I

think the suggestions you made yesterday, the

multiple review cycles I think is a great metric.

That was what the Manufacturing Subcommittee, at

Judy\'s last meeting, we talked about the idea that

in the new or the desired state, instead of having

minimal data that the reviewers have to try to

piece together into some sort of Frankenstein

rationale, if you get the rationale in a piece from

the companies with summarized supporting data to

make it a compelling argument, then, the reviewers

just have to assess the sufficiency of the

rationale as opposed to trying to piece together

one on their own.

34

So, I think the review cycles are an

excellent metric. The time to approval, of course,

is a low hanging fruit there in terms of a metric

although it is not independent, and for generics,

of course, that is compounded by the workload

itself.

Maybe you could normalize it by

normalizing the time to approval to the number of

pre-filing and pre-approval meetings, the off-line

meetings that John talked about yesterday, John

Simmons talked about yesterday.

The other one\--and I don\'t know if we have

talked about this before\--is to track FDA personnel

turnover. I think it is not a bad metric to look

at retention of the FDA reviewers themselves. I

mean it is a very high-pressure job, it is not all

that celebrated a position, but obviously of key

importance.

I think that does two things. One is it

gives us a metric of how effectively the program

works, and the other is that it gives an internal

metric for the personnel management, so you don\'t

35

burn out your best and brightest.

DR. HUSSAIN: Ken, the whole aspect of the

critical path was in a sense that review cycles

have really come down, so that review cycle is not

the rate-limiting step in the critical path. So,

there are different metrics for that purpose.

DR. KIBBE: Marvin, do you have something

else?

DR. MEYER: A quick comment. Helen was

saying last night that on the ANDA side, that the

generics are now, or shortly going to be, required

to submit all studies they did, not just the 1 out

of 12, the test.

Maybe, and this is terribly naive because

I don\'t know all of the complications, but maybe

there is some way down the line of having the NDAs

be accompanied by a synopsis, at least, of what

they tried and what failed, a one-pager perhaps.

We tried doing virus filtration this way,

and it failed because, we think it because, and

this might be attached with the NDA, but reviewed

independent of the NDA. There might be a group at

36

FDA that evaluates failures, if you will. So, some

way of getting the data to the Agency that wouldn\'t

impact on the NDA and yet would provide the Agency

with I think some valuable information.

DR. KIBBE: I am concerned that as much as

we in academia value getting all the information,

industry values having information that their

competitors don\'t have, and if they have a lot of

failures they corrected, and they know what

mistakes not to make, they generally think they

have an edge on doing it right, and they are not

really excited about turning that over to someone

else, let them make their own mistakes and figure

it out.

I think the time that we will actually be

able to share all the information about all the

drugs that have ever been approved is when Glaxo

finishes buying everybody or Pfizer has merged with

whoever is left, and there now is International

Therapy Development Company.

DR. KIBBE: Ajaz, anything to wrap up

with? Okay.

37

DR. SINGPURWALLA: Mr. Chairman, I have a

few thoughts. Ajaz, back.

\[Laughter.\]

DR. KIBBE: It\'s okay, Ajaz, you can

escape if you would like.

DR. SINGPURWALLA: Ajaz, you asked three

questions here. To be quite honest with you,

yesterday, I couldn\'t focus on these because I

couldn\'t get my mind straight as to what we are up

to and what is happening.

But subsequently, I think I can answer

some of your questions very directly.

I looked at TR Critical Path Initiative

Challenges document, and to be quite honest with

you, I think you are on the right track, and I

think you are thinking along the proper lines.

Two, three things come to my mind. Your

mention or at least the mention of design of

experiments that was discussed is one of the right

ways to go about things.

You also mentioned the use of bayesian

ideas. That is the best way to reduce time cycles

38

because you are taking advantage of all other

sources of information, but you don\'t want to use

that only for clinical trials, but you want to use

it throughout the entire process. Again, you have

highlighted it, so I think again you are on the

right track.

The one thing is you cited examples from

manufacturing. That is fine, but I seriously

consider you also look at the area of weapons

development. They face problems very similar to

yours and you may want to see what they are doing

and how they are developing their particular

processes, and the weapon development process has

much in parallel. The two communities are very

alien to each other, but I urge you to look into

what they are doing, and I think I can say that you

are on the right track. You are focusing on the

issues that I would focus about, that is all. I

wanted to reaffirm it.

DR. HUSSAIN: Thank you.

DR. KIBBE: Paul.

DR. FACKLER: Let me just offer a couple

39

of thoughts to those questions, you know, are you

on the right track. Of course, I am speaking for

the generic industry, but it is difficult to give

people help when they haven\'t asked for any, and I

can\'t speak for PhRMA, and I don\'t know if PhRMA

has come to the Agency and said, help, we can\'t

develop new drugs.

So, I think you face a very difficult

challenge trying to assist a process that maybe the

people actually doing it don\'t feel is broken. The

economics of drug development in 2004 is

significantly different than it was in 1994.

You know, if you have a company selling

\$50 billion in drugs a year, and they want to grow

by, say, 5 percent, which isn\'t acceptable by any

means, they need to get an additional \$2 1/2

billion in revenue out of the new drugs that they

are developing.

So, you know, a product that has some

marginal value, say, 50- or \$100 million that would

benefit society probably just gets put in an

envelope somewhere, and not brought out. It is a

40

problem with the situation in industry, but I am

not sure FDA is going to be able to do anything to

assist that.

Let me speak to the generics because there

was a presentation yesterday, and speaking for the

generic industry, we have communicated with FDA

where we think we need help. We have asked about

topical products, we have asked about inhaled

products, biologics, of course, are an issue, and

time to approval is a real issue for us.

So, the question was are you on the right

track, and at least from the generic perspective,

the answer is yes. I think you are trying to

overcome the hurdles that we face, that would

assist us in bringing products to the market

earlier.

I know it is not really the main thrust of

the Critical Path Initiative, but for our portion

of it, the answer is yes.

DR. KIBBE: Thank you, Paul.

DR. HUSSAIN: I think just the point

generics are equally important for us, so they are

41

part of the critical path from an OPS perspective.

DR. KIBBE: Gary.

MR. BUEHLER: Well, we have had a number

of mentions of our workload. It is significant.

We did receive 563 applications I believe the last

fiscal year, 449 the year before, and 361 the year

before, so we are increasing by about 100 a year.

It is a bit scary, but we are dealing with

it, and we are communicating with the industry

significantly on what we can do to make their

applications better and to make our responses to

them more predictable, so that they know what we

want.

As part of the critical path, and we are

trying to work in providing the information that

the industry needs to develop their products, and

this is through the dissolution methods and the

bioequivalence methods that we get tons of letters.

We got over 1,000 correspondence last

year, over half of them requesting what is the

bioequivalence method for a particular drug, what

is the dissolution method for a particular drug, so

42

we can begin to develop our products.

We are trying to get that up as a

web-based program, so that they can actually access

these methods. We have people working full time in

our office to research this information, so we can

make it available to the firm.

Now, this isn\'t revolutionary stuff. This

is stuff that we have always provided them. We

just want to provide it to them faster. We want to

make it easier for them to access this information,

and we don\'t want to get as many letters. The

letters that we get obviously take up our resource

time, and we want those resources to be put toward

application review.

We hope to be able to get these up soon.

I know I promised them I think six months ago to

the industry. Things are never as easy as you

would like them to be in the Agency. A lot of

people have to sign off and make sure that we are

not giving away the farm, and we don\'t want to give

away the farm, but we do want to give away

information that is needed by the generic industry.

43

The generic industry is a very viable,

very robust industry right now. A lot of new

players are getting into it, a lot of people want

to put applications in as evidenced by our

workload. We welcome that workload, we are glad.

This country needs generic products. A lot of

people out there can\'t afford prescription drugs

out there.

So, we welcome the work and we welcome the

challenge.

DR. KIBBE: Anybody else? Okay.

We have an opportunity now to hear from an

absolute genius. They asked me to give a talk on

visionary overview, and I will get up there, then,

I will pontificate for half an hour, and I hope you

all enjoy it.

Science in Regulation - Visionary Overview

DR. KIBBE: I need a soapbox. I have six

slides. This is to reduce some of the slide

overload that we are suffering from. You all have

copies of these slides. You can tell that the

slides are really informative because they are

44

filled with words. I look at slides and I say,

hey, there are 22 slides and each one has 180

words, how am I going to get through it, so I put

up a couple of simple slides.

First, the title was given to me by the

Agency. I looked at it and I said Visionary

Overview, I guess they think I am a visionary, why

would they think that. So, I thought long and hard

about why they think I am a visionary, and I

realized it was because I live in Pennsylvania,

which is the home of the world\'s most well known

and renown visionary, the seer or all seers, the

procrastinator for all good things, Punxsutawney

Phil, who comes out and tells you whether you are

going to have winter for another six weeks or not.

I also would like to make a disclaimer, we

do lots of disclaimers. All the ideas that I

express today are strictly my ideas, and I would

not saddle anyone in the scientific community and

industry over the Agency with any of these

cockamamie ideas. So, they are all mine and

hopefully, they will stimulate your thinking

45

without putting you completely to sleep.

So, what has the FDA and we been doing for

the last few years? I actually went out and got a

copy of the agenda for the first meeting I was at,

and there wasn\'t PAT mentioned in the agenda, but

when you looked through the agenda, you saw the

beginnings of what was I think a wonderful three-

or four-year push in an area that can significantly

impact industry\'s bottom line, and hopefully, the

industry will be in a mood of generosity and have

that bottom line, some of those savings reflected

in the cost of goods produced.

The effort I think was an opportunity for

me to view the way that scientists from industry,

both the generic and innovator companies,

scientists within the FDA, and scientists from

academia, and those consultants who serve all of

us, could get together, look at a problem, develop

a reasonable approach to it, something that would

work in the community that we work in, and really

come up with something worthwhile.

I could go on about the successes we have

46

had, but they don\'t make great news, and the news

media always wants failures and disasters to report

on, and so I will move directly into those.

First, is it the Agency\'s role to apply

science to regulation? Of course, we all agree it

is. The application of the scientific method to

goalpost generation for the industry is extremely

important, and I am going to try to look at what we

have done and where we are going, and perhaps make

some projections out.

If we are going to regulate a

science-based industry with science, then, we need

to use a scientific approach to where we are going.

We all are familiar with linear

regression, and we know that there is a certain

amount of error associated with it, but in order to

project beyond the data that we already have, we

have to have a significant amount of data going

backwards to draw a line through, so that as we go

out in the future, we get closer to the truth.

We know that the further out in the future

we can project, the less reliable the answer is,

47

but we do it anyhow, and I am going to do that.

So, where have we been in terms of

regulating the quality of drug products and

therapies in the United States? Of course, we start

in 1817 with Dr. Spalding, and he decided that we

ought to get the physicians together and say why

can\'t we have quality products to give to our

patients, let\'s set up some standards, and the USP

was formed.

So, we started the regulation of the

quality of how we treat our patients by getting the

health care providers who treated patients together

to decide what quality was and how to arrive at it.

After the Civil War, the pharmacists got

together and decided that while the USP had

standards for individual ingredients, it really

didn\'t have standards for how to mix them together

and make them useful, so they decided to publish

the National Formulary, and I was instrumental in

the first edition, and I brought my copy with me.

This is the sum total of how to make

pharmaceuticals in 1888, and compare it with what

48

we know today and how many shelves it takes up, and

how controversial each little, tiny issue is. Of

course, we also know that you have to learn Latin

to use this, so it\'s dead along with the dead

language that it is written in.

At the same time, the industry actually

regulated itself. There was a comment made here a

little while ago, which said that lawyers make them

do things. I would argue that in the current

litigious society, companies act slower to remove

drugs from the market when they have worrisome data

than they would if there wasn\'t a litigious

society.

I think they worry more about what it

means to their future class action suits to

actually admit that there is a problem until they

have all their lawyers lined up, so they know how

to defend themselves, and if they weren\'t worried

about the fact that the American public has an

exaggerated misconception of what drugs do and

work, they would act quicker.

I think the American public in general

49

expects drugs to be safe and effective, and they

don\'t recognize that drugs can be safe and

effective if used correctly, but in the wrong way,

are dangerous and shouldn\'t be used, and they don\'t

get that. They just don\'t get it.

I put E.R. Squibb down because I know a

little bit about E.R. Squibb as an example of the

leadership that the industry had back in the 19th

century. Dr. Squibb, a physician, wanted a higher

quality ether for anesthesia. This was an

extremely important drug in those days, and so he

founded a company for the express purposes of

making sure he had high quality ether.

He built it in Brooklyn, and then his

company started making other things and then he

noticed that there were other companies that were

copying his products, calling them the same thing

and putting them out there less expensively, and he

said the public might be at risk if they aren\'t

made correctly.

So, he did something unique which I don\'t

think any of the companies would do today. He got

50

all his formulas together, how he made everything,

and he published them in the Journal of the

American Pharmaceutical Association with the

proviso that if anybody wanted to make a product

that E.R. Squibb sold, they should make it the way

we make it, so it would be of the same quality, so

at least the public would have a good quality

product, and if they could make it less expensively

than we could, good luck to them.

Well, I wonder how many companies are

ready to jump into that game. At that same time,

of course, Eli Lilly was producing well over 100

generic products. It was the largest generic

manufacturer in the United States. It produced

everything that could be made that was listed in

the USP or NF, extracts, and what have you. It was

an interesting time.

Now we get into government regulation.

Now, why did the government get into regulation?

Well, it bought quinine that wasn\'t quinine and it

got upset. So, in 1848, with the troops attacking

Mexico City, their quinine didn\'t work like it was

51

supposed to, they said what\'s in here, it wasn\'t

quinine, it was something else, I don\'t know what

it was.

They said that\'s terrible, terrible,

terrible, and so we needed to find a way to make

sure that when something was labeled quinine, it

really was indeed quinine. That was the first shot

out of the cannon.

We finally had the Food and Drug Act of

1906, which really just said that if you are going

to sell something and call it a drug, and name it,

it ought to be what you call it. Right about that

time we got into the concept of misbranding, which

was putting something in something and calling it

something that it wasn\'t, and that is basically

what misbranding is.

We have a lot of meetings for misbranding

now, but the bottom line is that it is not what it

is supposed to have been.

The Agency wasn\'t really founded then, but

the government said that if we wanted to take

action against the company that misbranded a drug,

52

that it was incumbent upon the government to prove

that the drug was indeed not what it said it was,

and that there was intent to defraud. If you do

that to the government, we can\'t enforce any

quality on anybody, because we don\'t have any

information to use for it.

But I want you to remember that concept

that came about in the early 1900s, because when we

get to the end of the 1900s, we have another law

that brought us right back to that place.

So, 1938, we killed a bunch of kids in the

New York City area with antifreeze as a sweetening

agent in a sulfa drug preparation. That was the

end of a company\'s reputation, and well it should

have been, and everybody was in an uproar, so we

now have a new regulation. You will notice the

trend here - disaster, new regulation, disaster,

new regulation. It\'s kind of a recurring theme.

So, we know said, okay, it has to be what

it says it is, it has to contain what it says it

contains, and it has to be safe, but it doesn\'t

have to work.

53

Homeopathic remedies are exactly that.

They are 1 to 100 dilutions of something done 1,000

times. You end up with a bottle of water, which

they claim contains the essence of the power of

whatever drug was in the first bottle of 1,000

dilutions before. All right. So, we can claim it

works, and it contains a diluted, diluted, diluted,

fine, that is what it really contains. You can\'t

find a molecule because you have diluted more than

Avargordo\'s number, so we have products on the

market.

By the way, the Food, Drug, and Cosmetic

Act says specifically that drugs are things that

are contained in the homeopathic pharmacopeia,

which means that they are precluded from acting

against products that are in the homeopathic

pharmacopeia even though we know they don\'t work.

We are still working with things that are

just safe, but at least they are branded right, you

know. Nowadays we have people who claim that water

solves medical conditions. What the heck, you

know, 1938, that would have worked, put a label on

54

water, say, if you will bottle water and pay for it

at a rate higher than you pay for gasoline, then,

it is better for you than the water you get for

free out of the tap, and you will do better.

Well, I don\'t know, I wonder about things

like that. I have a problem my students always

complain about. I have one of those minds that

kind of wanders, and so I do that.

Let\'s get back to misspelled words and

regulation. So, in 1951, two pharmacists got

together, a guy named Carl Durham and a guy named

Hubert Horatio Humphrey\--I love his name. They

were pharmacists. One was in Congress and one was

in the Senate. Hubert came from Minnesota. He

ultimately became vice president, ran for

president, didn\'t make it.

I often wonder what would happen if the

president of the United States was really a

physician or a pharmacist, a health care worker,

what difference that would make in their approach

to the health care problems.

So, they got together and they said, you

55

know, there is a lot of drugs out there that are

pretty dangerous, that the average person really

can\'t understand, and maybe we ought to have

somebody help them figure out what to take, so they

established two criteria, prescription drugs and

over-the-counter drugs. We still, by the way,

don\'t have to have them work. You know, God

forbid, they actually should work.

We are a unique country among the

developed nations of the world. We only have two

categories of drugs. Most of them have many more

categories of different levels, and, in fact, I

like the Australian system. They are listed in the

group of things they call poisons, so we clearly

know where they belong, right? They are the poison

list.

In 1962, we finally got around to hoping

that we could figure out that the drugs were both

safe and effective, so in 1962, we said, okay, new

drugs have to be safe and effective. The Agency

was kind of curious. It said, but you can\'t tell

people that this is an approved drug, because that

56

gives you a marketing advantage over the drugs that

haven\'t been approved by us, and then we don\'t know

are effective. Hmm, that\'s interesting.

Then, Congress, in its infinite wisdom,

jumped right in there with DSHEA, and DSHEA says

that if you aren\'t really a drug, but kind of imply

that you are a drug, then, you can go back to the

1906 regulation which says that it only has to be

what it says it is, and it doesn\'t have to be

proven to be safe or effective, and if there is any

problems with it, the Agency has to compile the

data before they can make you take it off the

market. I just love that, you know, retrograde

regulation, I just wonder about the wisdom of that.

I am sure it has to do with the need that the

public has for unsubstantiated claimed herbal

remedies.

All right. Here is where we really get to

where the rubber meets the road, and that is the

cost of drugs. I grew up in a pharmacy family. My

father was a pharmacist, my uncle was a pharmacist,

I became a pharmacist because I didn\'t know

57

anything else.

I grew up in a drugstore, and when I was

at a young age, I worked in my father\'s drugstore

as a soda jerk. Some people think that I have never

gotten over the second half of that.

But in those days, the average cost of

drugs that my father filled\--he has a wonderful

ledger, handwritten in ink pen where he wrote down

the name of the patient, the prescription, the

physician, and then the cost\--and if you look at

it, you will find that the average charge to his

patient was \$1.75.

I asked him one day, being a nosy

teenager, how do we make money to live on at the

store here, and he says, \"Well, I charge \$1.75, but

it costs me about 25 cents of goods.\" So, I said I

thought that was pretty good.

Of course, nowadays, the average charge of

a prescription can be in the \$50 or \$60 range, and

the pharmacy gets \$3.50. There has been a shift

here somewhere.

At that time, Tetracycline came out. It

58

was about 50 cents a capsule. The price of

Tetracycline has gone down dramatically, but we

keep bringing out new drugs, and I think each time

we bring out a new drug, we say what was the price

that we charged for the last new drug, and we

multiply by 1.5.

You also understand that there is

absolutely no relationship between the charge for

the drug and the cost of actually manufacturing it,

and that they factor in all of the other costs to

maintain the corporate entity that creates new

drugs. So, they need to have this huge inflow of

money in order to float all of the research and the

marketing, and all the other efforts that go on,

and so that there is some disconnect.

Waxman and Hatch got together. We

recognized back in the 1980s that the cost of

health care was going up quickly. Uwe Reinhardt

has a wonderful graph that he puts up, a Princeton

economist, that shows the gross national product

and its rate of increase and the cost of health

care and its rate of increase, and then he predicts

59

some date in the future where the two will meet.

Then, he has a cartoon where he has two

physicians lying in beds in the hospital together,

prescribing for each other, and he said that is

going to be the entire productivity of the United

States is going to be this.

So, we know that there is a disaster in

the future and what are we going to do about it,

and we have a culture in the United States where we

don\'t regulate the price of drugs. We are again

unique. Very few developed countries have that

compunction. So, we try to regulate it through

competition.

So, the Waxman-Hatch Act or the

Hatch-Waxman Act, depending on whether you are a

Republican or a Democrat, came into being, and it

was a compromise that was supposed to benefit the

innovator companies by ensuring them a reasonable

patent extension or exclusivity time frame in order

to recoup the investment to bring the new drug to

the market, and established rules and regulations

for the development of generic drugs.

60

It seems to work in some areas and we hope

for the best. However, it is not going to be the

end of the issue, and if we start to make

projections out in the future, we are going to have

to do more than that in terms of cost, but it was

the first time that the FDA was an active

participant in controlling costs.

I think I see that as something going

forward. We have a problem, of course, with other

issues associated with cost, and, of course, here

comes re-importation, and we are going to get into

that in a little bit, but I don\'t want to beat a

dead horse.

My wife is Canadian and my inlaws are in

Canada, and they see the U.S. news come across that

says that Canadian drugs are bad for American

citizens, and they say, oh, and they call their

son-in-law, the expert, and they say, \"What\'s wrong

with Canadian drugs?\" Of course, i am hard pressed

to say anything about it, because there is nothing

wrong with Canadian drugs. So, that makes an

interesting argument. I think we can go down that

61

road as long as we want.

I think the next level of regulation is

going to be the line on top. People are going to

want information that shows that the next new drug

is not only safe and effective, but better. I

don\'t know how long it is going to take for

Congress to do that, but that is what is coming.

We have a history of producing lots of

drugs that might be different, but not necessarily

an improvement, where are we going to go, and I

think both the industry and the Agency should be

prepared to think about how they would handle that

situation.

Remember that we are trying to regulate

according to best science, and sometimes we lose

track of best science. There are some classic

equations that we use that we depend upon to help

us decide what is good science. One is the

Noyes-Whitney expression. The Noyes-Whitney

expression describes dissolution profile, and it

was developed by these gentlemen using a very

interesting standard material. It was a fused

62

cylinder of material.

So, their apparatus and how they did it

were standardized based on one solid hunk of an

individual chemical in the cylindrical form, so

they could accurately determine the area exposed to

the fluid and therefore, from it, determine all of

the equations. Nowadays we use a standardized

compressed tablet. I would argue that the

dissolution apparatus is probably less variable

than an individual tablet coming off a tablet run.

If you wanted to standardize an apparatus,

you ought to standardize it with something which is

less variable than the apparatus you are

standardizing. I wonder about that. I guess we

could ask our colleagues down the street what they

think about that, but let\'s go back to the basic

science and figure out what is going on.

The other one I like to talk about

occasionally is Arrhenius. Arrhenius developed a

relationship between temperature and rate of

reaction that was developed for reactions that

happened in dilute solutions.

63

We apply them, same rules, too, tablets,

ointments, creams, and lotions. We put things

aside for three months at elevated temperature, and

we say this is going to predict what is going on in

two years. We will give you two years, just send

us the real data later. I would argue that if we

went through the data that the Agency has, that we

would be hard pressed to get a correlation

coefficient much over 0.3 for that data.

The other thing is what is the rule and

regulation. When a rule or regulation gets out

there and purports to be doing something, and it

doesn\'t, it makes you wonder. We have a regulation

that says you have to do accelerated stability at

40 degrees and 75 percent relative humidity, but

you can take the humidity and temperature chamber

and you can put in it a tablet container that is

sealed with a descant in it and do the study.

That is kind of like saying let\'s see how

fast ice cream can melt in the kitchen, but you are

allowed to put it in the freezer. I wonder, you

know, I just wonder. I am just kind of curious

64

about those kinds of things. You sit around in an

academic office, you are a tenured full professor,

what are they going to do. You wonder about those

things.

I think that there is going to be a lot of

international regulation. I think that we are at

the stage where the companies are truly

international. The largest provider of generic

drugs in the United States is in Tel Aviv. Most of

the big developmental innovator companies are

really housed everywhere.

In fact, the numbers of workers at

pharmaceutical plants in the world has shifted from

the United States out. If that is true, then, we

really have to have cooperative control on quality.

I am sure that England and Germany and France want

the same high quality of drugs as we do, as the

Canadian Health Protection Branch insists that they

do.

So, we need to go in the direction of what

is truly a harmonized or internationalized

regulation of quality. We need to somehow control

65

the cost to the consumer, and if we don\'t find a

way to do that, it will be imposed on us.

One of the problems I have with all of

this is that drug costs to consumer seems to make

the news way more than the cost of a bed in the

hospital. Now, I will just ask you, how much does

it cost to be in a hospital bed. Does anyone know?

No, but you sure know how much it costs for a

bottle of Viagra\--oh, excuse me.

DR. SINGPURWALLA: I don\'t.

DR. KIBBE: Oh, there is a man with

confidence.

\[Laughter.\]

DR. KIBBE: The reason is that most of us

in the public are covered by some insurance plan

that covers the cost of the hospital bed, but we

aren\'t covered by drugs, and drugs represent 8 to

10 percent of the total cost of health care in the

United States, and if you look at it, it is much

cheaper to give reasonably expensive drugs to

patients than to put them in a hospital. But the

patients don\'t pay for it out of pocket.

66

I wonder why the huge lobbying efforts of

the pharmaceutical company isn\'t applied to getting

drugs covered by Medicare and Medicaid instead of

anything else. If they could ever do that, they

could forget about the arguments in the newspaper

about the cost of drugs.

I am sure there is lots of economic issues

associated with that.

The last three things I have are

continuous quality improvement, PAT, and

federally-funded efficacy testing. I don\'t know

whether we are going to get the right to demand

that you do an efficacy test against seven or eight

of your competitors in order to get approval, but I

think that the world deserves a chance to look at

what is those relative efficacies in an abstract or

at least impartial way.

PAT has been fun for me. I think it\'s a

wonderful initiative, it has its own journal now,

those of you who are interested in it. It has got

a forward written by\--oh, my heavens\--Ajaz. It has

some beautiful pictures in here.

67

I went through it immediately and wanted

to see if I knew anybody that actually was involved

in PAT, and there is a whole bunch of really pretty

pictures of all sorts of people that were actually

on the committee with it, if anybody is interested

in it. I thought that was pretty neat.

I think that there are things in the

horizon that really threaten the way we do business

both at the industrial level and at the regulatory

level. One of them is the development of

nanotechnology and computational power.

We are looking forward to a singularity in

computational power, a point beyond which we cannot

predict or even understand the future. In

approximately 2014 or 15, the computer on your desk

will have not only digital computational power, but

parallel processing, and will be able to think

better than you can. We will be able to process

data, come up with new ideas, and, in fact, at some

point in time, it will be the most intelligent

being on the planet, and we humans will relegate

ourselves to second place.

68

When that happens, what do we do about

health care? And let\'s look at nanobots and what

they can do. If aging is truly a degradation of

the DNA strand within people, if we can inject

nanobots who know how to count DNA strands and

repair them, how are we going to age?

If we have the capacity to scan individual

molecules and relationship in the neural net, can

we then scan down a person\'s entire knowledge base

and personality, and shift it from a carbon-based,

short term, to a silicon-based, long term holding

facility?

How many of us would be willing at the

ends of our days to become virtual us in a virtual

environment?

Where are we going? Challenges to the

FDA. In our experience over the last several

millennium, an ever- increasing rate of new

technological development. It was 20,000 years

from the time we developed hand-held rock until we

actually made a bow and arrow with a processed

rock, and the rate at which we develop things now

69

is astronomical.

We need to have improved productivity in

the industry, but that needs to be related to an

improvement in the cost of goods sold to the

American public, and the Agency needs to maintain

public confidence. It needs to not say things that

are clearly difficult to defend in the public

environment. It needs to be responsive to the

public needs and realistic, so that the public

understands the expectations of drugs.

If there was any advertising that the

Agency could do, that I think would help in the

long run, it is to get the American public to

understand that drugs are not safe, that they can

be used safely.

The American public has an unrealistic

expectation for their medications and an

unrealistic expectation of how they should feel as

they go through life, and they expect that these

little pills will do it for them, and it won\'t, and

we need to get them to stop thinking that way.

We need to maintain and improve

70

international cooperation in both regulation and

harmonization, and we need to, in the final

analysis, decriminalize Grandma. When she crosses

the border to pick up drugs, she needs to

understand that we don\'t think that she is

committing a heinous crime against society, that we

understand that the economics are driving her to

it, and we need to find a way of making it happen

for her, so that she can get the drugs she needs at

the price she can afford.

Does anybody have any questions?

\[Applause.\]

DR. KIBBE: Thank you, Dr. Kibbe, for that

exhilarating presentation. I am sorry, I just love

those kinds of things.

Now, we are going to get into some serious

stuff here, because Ajaz is going to get up to the

podium.

DR. HUSSAIN: Could we just take a break

now and then start after the break?

DR. KIBBE: I am still fired up, you know,

whatever you want to do. You know the energy level

71

after making a presentation. I really want to

complain about the lack of a soapbox. I asked for

a soapbox up there because I knew I was going to

get on my soapbox.

Ajaz wants to take a break. Let\'s try to

get back and get back to work at two minutes to

10:00.

\[Recess.\]

DR. KIBBE: We have comments on my talk

that some members would like to make, and then I am

going to be more than happy to add to my talk a few

other issues, so we might have a lot of fun today.

As is the tradition with this year\'s

committee, Nozer has a comment.

DR. SINGPURWALLA: I don\'t have a comment,

I have a question for you. The question is what

would your reaction be to the idea of nationalizing

the drug industry?

DR. KIBBE: That is a wonderful question

and I think the answer to it resides with our

colleagues over there. I know that if they ever

did that, I would volunteer to be drug czar. There

72

are a couple of issues that I didn\'t hit on in my

thing. One of them is direct-to-consumer

advertising. I think the issue of why the public

has the misconception that drugs are not safe can

be tied directly to direct-to-consumer advertising.

Many years ago, in my one opportunity to

appear on the Today Show, I was interviewed by

Debra Norville on the topic, and I was debating an

industry representative, and I said that it would

completely change the dynamics of prescribing and

using of drugs in the United States, and I think it

has.

Two days ago, I was sitting at home

watching TV, and for an hour and a half, every

single ad on TV, every single ad was for a

prescription drug, and it just has to have a

dramatic effect on the way patients interact with

their physician and how they get health care. I

think it was a mistake, but we can comment on that,

too.

Does anybody want to throw a few cents\'

worth in while we are prognosticating?

73

MR. CLARK: You mentioned something about

E.R. Squibb challenging the world to meet his

efficiency in his products that he manufactured. I

was just trying to point out that while he

challenged the world, that challenge could prove

fatal today, because today, Mr. Squibb or Dr.

Squibb would be required to freeze his

manufacturing technique, whatever it may have been,

and that while his challengers came in with new

techniques, he would be burdened with an approval

process that would slow down his ability to

compete, and we should be able to create a

regulatory environment that protects the public as

it still encourages innovation, and not just

encourages the innovation for innovation\'s sake,

but encourages applying it to the products and to

improve the entire environment.

DR. KIBBE: Clearly, he couldn\'t do what

he did then now, because the Federal Government is

in his business now.

MR. CLARK: Exactly.

DR. KIBBE: And that has happened after

74

World War II. Before World War II, the Federal

Government stayed out of everybody\'s business, and

that is a dramatic change in the way we do business

in the United States.

We need to get to the desired state\--I

recommend Pennsylvania, far less hurricanes\--the

desired state, however, is going to be defined by

Ajaz.

The \"Desired State\" of Science and

Risk-based Regulatory Policies

DR. HUSSAIN: I will do it from here. In

a sense, what we wanted to do, sort of build on the

Manufacturing Committee discussion that was

reported quite elaborately by Judy Boehlert, the

chair of that committee, but to sort of now do a

gap analysis, what we see as gaps between the

current state and the desired state from an

internal FDA perspective, what are the challenges

we face internally, and get your feedback on that.

So, what we have are three presentations,

one, Helen will sort of look at the organizational

issues, I will try to identify some of the

75

scientific gaps, and Jon will identify some of the

policy gaps and how we intend to sort of fill those

gaps.

If you could sort of give us feedback on

are we missing in our gap analysis, it is a

preliminary gap analysis right now, and then how we

proceed, and then this will be followed by

discussions and presentations by PhRMA and GPhA

perspective on how they see the progress we have

made and some of the challenges that remain.

So, that is the discussion for this

morning.

DR. KIBBE: That means you are passing the

ball to Helen.

DR. HUSSAIN: Yes.

DR. KIBBE: Let\'s see how you follow my

act.

Organizational Gap Analysis

MS. WINKLE: Believe me, in 100 years, not

only could I not only follow your act, I wouldn\'t

know where to begin, and my topic is so boring

anyway.

76

I am going to talk about organizational

gap in the Agency right now as far as the desired

state is concerned, and as Ajaz said, this is sort

of a follow-up to some of the things we talked

about at the Manufacturing Subcommittee, and I

think it is really important that we look at these

gaps and talk more about them, and sort of discuss

how we can possibly fill some of them.

I have some ideas on filling on some of

them, but I think there is a lot more that we will

need.

DR. KIBBE: There appears to be a gap in

the computational problem, too.

\[Pause.\]

DR. KIBBE: We are passing around a

transportation note for people who need help to get

to the airport.

MS. WINKLE: Is everybody leaving now?

Gosh, you could at least have given me a chance.

\[Laughter.\]

MS. WINKLE: As I said, I am going to talk

about the organizational gaps and reaching the

77

desired state, and I wanted to start off with, just

a second, showing you the organizational chart of

OPS, because I think as I talk about organizational

gaps, you need to know a little bit about what the

organization looks like, and I think you have a

good idea, but I just wanted to point out we do

have four offices.

You actually heard from all four of those

offices yesterday, but you say, in yellow, where

the CMC is done in all four offices, so almost

every part of the organization in some way is

affected by the changes that are being made by the

new paradigm and what we are trying to accomplish

with the desired gap, which complicates the issues

somewhat.

It is very important as we look at the

organizational gaps that it is multi-dimensional,

it goes across all of the organization. It is

between organizations and it is within

organizations. There is lots of gaps here and we

need to look at all of these gaps and figure out

how we are going to handle them.

78

It is outside of OPS and other parts of

CDER. We really do a lot of work with products

with devices with CBER, so we need to be sure that

those gaps are closed as we move forward in trying

to accomplish the desired state.

So, basically, what I am going to be

talking about here is what we need to consider and

resolve in our process or processes before we can

adequately implement regulatory direction and

support through applications process and review of

what we are calling the desired state.

I also want to point out as I talk, and

you will see this a lot, that the organizational

gaps that I am going to point out really intersect

with the science gaps that Ajaz is going to talk

about and the policy gaps that Jon is going to talk

about, and you probably can\'t really address any of

these separately although that is what we are

making an attempt to do here. But again as I go

through the organizational gaps, you will see a lot

of the intersections.

What constitutes the gap in OPS and what

79

are actually the process issues for implementing

the desired state, and how we will review at

different levels? This is really some of what we

need to talk about.

One of the big problems here is the

appropriate utilization and focus of available

resources. I am reading it wrong. This is why I

am having problems. It is the resources. We have

a lot of human resources. You have already heard

some of the issues that we have had with how to use

our best resources and how to focus those resources

on those issues that are most important. So, that

is really one of the things that we have as part of

the gap.

We are not always focused on those issues

which are the most important, and we don\'t always

have the science expertise available to focus on

the gaps or focus on the issues correctly. So,

this is a big gap that we have across the entire

organization.

There is a difference in products and

regulatory requirements and review processes. We

80

are regulating ANDAs, NDAs, and BLAs, and BLAs even

fall under a different act than the ANDAs and the

NDAs. So, there are some complications and some

gaps there that we are going to have to look at and

determine how best to handle.

The organizational structure, the way it

is set up really creates a really large gap in how

we are going to move forward.

I think we have made it clear in the past

that in ONDC, I know Moheb has talked about this at

different times, Dr. Nasr has talked about this at

different times, that we have chemists from the

Office of New Drug Chemistry that are located in

the different clinical divisions, so that we lack

consistency in how they make decisions often,

because it is done outside of the whole chemistry

structure, so to speak. It is done within the

Clinical Division, and we also lack the flexibility

of being able to use our staff and to utilize the

science and the staff because of these

collocations.

Actually, we have chemists in 18 different

81

teams across the Clinical Divisions, and they very

rarely interact with each other, so it really

causes a lot of complications in how we do our

work, and it will cause even more complications

when we get into the new paradigm.

I think one of the main gaps is that we

are very process driven, not science driven. This

goes back to the earlier comment by Dr. Kibbe. We

are regulating a science industry. It is a science

industry that we are regulating through process.

Some of the things that contribute to this

is PDUFA in generic drugs, first in, first

reviewed. We have a tiered approach to our

reviews. We have heavy backlogs. I think that

Gary has made that point several times to this

committee. The workloads are big, the backlogs are

big. So, that is really driving us, too, to focus

more on process than science. So, this is causing

us to really have to rethink how we want to do

things.

Part of what is adding to that workload

and to the backlog is that we get too many

82

supplements. We require supplements on little

changes that really have no significance in the

manufacturing process.

Also, part of the gap is the interaction

with inspection. We have a lack of appropriate

reviewer involvement, and we get no feedback. We

do not get copies of 483s. Once they have been in

to the industry with the observations, we don\'t

even have any correspondence in most cases with the

inspection people on things that they find when

they go out on inspections.

So, how you are supposed to really have

knowledge about the products that you are reviewing

in the future or where you can use that knowledge

that has been gathered and incorporate that into

your thinking about reviews and products, you can\'t

do, so that really creates a lot of gaps.

One of the things that is going to create

a gap in the future is the possibility of having a

two-tiered system. As we talk about the desired

state, as we talk about the things that are

required under the desired state, we don\'t have

83

regulations that are going to require manufacturers

to submit pharmaceutical development information.

We don\'t have regulations that are going to require

them to do this thing or that thing, and in some

places, I am not even sure we have the carrot to

encourage them to do that.

So, you are going to have some companies

that are naturally going to submit this stuff, or

naturally going to move toward PAT and toward other

aspects of improving on their manufacture, but you

are going to have companies that don\'t, so what we

are looking at is the possibility of having a

two-tiered system which is going to create a gap

even within one reviewer.

He is going to have to be able to look at

both tiers and make decisions, and this is going to

complicate issues a lot when we move ahead.

We use guidances to accomplish

consistency, and those guidances are sometimes very

prescriptive, and this adds to the whole gap, and

also not only are we using guidances for

consistency, they are also up for interpretation.

84

Unless they are prescriptive, they are interpreted

differently by different people, so obviously, we

have some concerns about this.

Organizational components are too

reactive, and not proactive. Now, this is caused

by workload, and the workload continues to

perpetuate the problem.

You have to be reactive because you have

so much work piled up in your In box that that is

what you have to focus on, and it is very hard to

be creative and innovative and think about those

issues and problems that you are going to have down

the road, think about, as Dr. Kibbe was talking,

new therapeutics that are coming along or new novel

delivery systems or different things like that, too

busy moving the freight from day to day.

Use of available scientific expertise and

scientific collaboration. Often within especially

in ONDC, because they are broken up according to

the clinical divisions, you may not have the

necessary scientific expertise to look at an issue,

to look at a problem, to know really what the right

85

direction is for making a decision on a product.

Also, we do not go out and use a lot of

scientific collaboration. I mean we have a lot of

SGEs, we have several in this room that are helping

us on different scientific issues of a broader

nature, but we could be taking advantage of some of

those and calling and getting more information in

the future.

There is a challenge in focusing on the

appropriate questions or what are the right

questions. Reviewers have a tendency\--and this is

not any kind of negative against reviewers\--but

they do have a tendency to look at all the data

that is provided, and we have not focused down on

what the appropriate data is, and, therefore, the

appropriate questions that we need to have

answered.

We have a lack of utilization of

appropriate tools. We could be using statistics

more, all of us, to get better answers to some of

the questions that we have around review. There

are other tools, as well, that we could be using

86

that we are not. One of the big areas I think that

causes a gap is the lack of communication between

disciplines, but I do want to add to this, there is

also a lack of communication between organizations

or components of the organization, and this is one

of the things that we need to focus on to help

close the gap.

So, I did take a look at what we had done

so far for closing the gap, because I think it is

important to emphasize some of the stuff, because

we do realize that we have some big gaps here.

I do want to upfront say, though, that

these are not all of things that we need to do. I

know that there is a lot more down the road that is

going to come along, and I am really looking for

advice from the Advisory Committee as to some of

the things that we need to be thinking more

carefully about, or make suggestions for some of

the things that we could be doing to help close

this organizational gap.

One of the things we have been doing is

making some structural changes in the organization

87

In the Office of New Drug Chemistry, which Judy

talked about yesterday for the Manufacturing

Subcommittee, we are reorganizing the Office of New

Drug Chemistry. We are actually doing away with

the collocation and making one Office of Chemistry

when we move to White Oak.

We feel that this is going to give us a

lot of consistency or at least more consistency,

and give us the opportunity to have more

flexibility as to how we look at the review

process. We feel that this is going to have some

real advantages to us.

We are also, in our Office of Generic

Drugs, we have set up a third division for doing

chemistry. The workload is so heavy in the office

that we felt like if we had more divisions where we

could spend more time and focus more on some of the

issues, that we could help in some of the gap

problems, having reviewers on inspections or as

consultants to inspection, so have complete

knowledge on products and the results of

inspections.

88

This is something that we have been

working on. We have been working with our Office

of Compliance and with our field component. We

feel like we would like to have reviewers on

inspection. We think it is very important for them

to go out and provide some of the scientific

knowledge to the inspectors as the inspections are

being done, but I don\'t think that part of the

question even came up yesterday on resources to do

this.

This is a resource issue. You are taking

people away from their desk to go and\--we have

already talked about the workload being

high\--taking people away from the desk to go out on

inspections and spend time away from their desks,

but also this is costly, and like it or not, we are

not flush with money, so we won\'t be able to do

this in every inspection.

But I do think it is important that before

the inspections are done, even though the reviewers

can\'t go out, that they provide consultation to the

inspectors and talk about some of the issues that

89

they have seen in the reviews of these particular

companies and give them some advice on what they

may want to focus on more in the inspections.

One of the big things that is really

necessary, in my mind, to closing the gaps, and

again this sort of goes across the whole concept of

the science gap and the guidance gap, and our

policy gap, as well, is that we have a lot of

questions we still need to answer and address.

This is only a few of them, but I think

there is a lot of things that we have not come to

grips with on manufacturing science and how that is

going to affect our review and what our review

process is going to be to handle these things in

the future - things like quality overall summaries.

Dr. Nasr talks about incorporating this

into the process of ONDC. We have not come to any

conclusions on this. We are still in the proposal

stage. We need to decide, if this is the direction

we want to go, what is the benefit of it to us, to

the industry, and what we really need to see in

that QOS. So, that is a question that we need to

90

look at.

What we need in the way of pharmaceutical

development information. There is a lot of

information that these companies have in the

pharmaceutical development arena, and do we want

all of that information. If we get that

information, what are we supposed to look at, what

would we focus on. We need to answer those

questions, it is very important, before we start

asking for this information.

We have to have addressed that before, I

think, companies are going to feel comfortable in

providing it. I think many companies see this as

just more information they are sending us to look

at and more questions they are going to get from

us, so we really have to develop our processes.

We also need to look at things like how

industry will determine critical attributes, so as

we look toward the desired state, that we are able

to regulate that and include those in our process,

and we need to know in all these cases what we will

do as far as reviewing these.

91

This is just a small part of the

questions, I think, that we need to be addressing.

Also, as far as closing the gap, we need

to have a better understanding of what constitutes

the design space across all products, and once we

have a good feel about that, or understand that, we

need to know when notification to FDA is necessary

for change in manufacturing.

We have not reached these conclusions yet,

and we need to have working groups, whatever it

takes, to really develop our own internal thinking

on this and work with industry to make sure that

the direction we are going is going to be useful to

them.

We need to have a better understanding of

what risk for a product is and develop a systematic

risk approach to review processes. I keep seeing

time and time again, people talk about risk

management or risk processes, and stuff like that.

I think when you talk about risk management, you

are talking about something different for every

person.

92

I mean what is in my mind, what is in

everybody else\'s mind in this room could be

entirely different, and we at the Agency need to

narrow down as far as review is concerned, decide

what that means, how we are going to use it, and

have a very, very concise program for ensuring that

we do look at this in a fair and equitable way.

Guidances. Again, Jon is going to talk

about guidances, but it is really necessary for us

to go back. This will help us close the gap, but we

need to go back and look at our guidance. We have

many guidances out there that are outdated, many

guidances that are overly prescriptive, many

guidances that don\'t fit into the new paradigm at

all.

Jon is in the process, he and his staff,

of going through the guidances, removing some,

redoing some, and looking at what guidances we will

need for the future in order to incorporate some of

the changes.

Training. This goes to the question Mel

asked, training, training, training is necessary

93

here. We have so much to train. We are doing some

training, and I will talk about some of that, but I

think it is really important and part of what we

need to do to close the gap, is determine what

really training our reviewers need and what

training is necessary for the industry, and I don\'t

think we have come to those conclusions yet.

We need to determine how we are going to

work under a two-tiered system if, in fact, that is

the direction that we go, and we need to have

developed the processes for doing that. We need to

develop an internal system for handling differences

in Review Divisions.

I met a couple of months ago with PhRMA on

a RAC Committee on a dialogue session, and this was

one of the things that came up was the need for a

dispute resolution process, some kind of mechanism

where, when there are differences in review, that

we are able to handle those decisions and get

information out as to how these issues are

resolved.

The last thing I have on here\--and

94

actually, I wrote this slide before we even had

some of the conversations yesterday\--was what is

really important is we need to have appropriate

metrics for measuring things.

Today, in the review, we measure by what

we accomplish, how many supplements we get. Well,

let me tell you when you are measuring supplements,

and that is an indication of how good you are doing

your job, you are going to want more supplements.

We have got to really back off of the

metrics that we currently have and look for those

appropriate metrics to help close these gaps.

So, some of the current steps we have

across OPS, we mentioned before that we are setting

up a working group under the Manufacturing

Subcommittee of the Advisory Committee to begin to

address many of these questions that we have. We

are also setting up some CRADAs to get some case

studies to help us, too, in getting a better

understanding of these issues and how we are going

to handle them in our processes.

ICH, too, is going to be an important part

95

of helping us handle some of our organizational

decisions especially Q8 as it looks at the desired

state and implement some guidelines on it.

We are doing some workshops. We have a

Workshop of Specification Setting and looking at

how we need to have a mechanistic understanding of

setting specifications in line with the direction

that we are going.

That particular workshop is set up in

March, but I will be upfront with the fact that I

think there is still going to be issues that come

out of that workshop where we are going to have to

look more specifically at some of the specification

areas and really dig deeper into them, so I really

anticipate more workshops than this just in the

area of specifications, but I think a number of

workshops are on the horizon in order for us to be

able to address many of these questions.

I actually think, too, one of the things

that we are probably looking at having a workshop

on is quality overall summaries. If that is the

direction we want to go, I think we need input from

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the industry and others, so that we have a better

understanding of what we need for using that type

of process and what it means to us in the industry

when we do.

We already have some collaboration with

academics. As I said, we are involved in several

CRADAs or in the development of several CRADAs. I

think these are going to be very helpful for us in

getting a better understanding of some of the areas

that we need to, or some of the questions we need

to, answer, so that we can fill some of those gaps,

and we have been doing some work with the Product

Quality Research Institute.

As I already said, we have an internal

review of our current guidances, which is very

important to helping us have the appropriate

guidances out there. We are developing a program

for team interactions for inspections.

We are sort of basing this on how we have

handled PAT and the team approach, and we are

working with Compliance in the field to develop a

better way of handling inspections and including

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the Review folks in those inspections, and also a

better way of getting the findings from those

inspections.

Training for reviewers. We have already

had a number of scientific seminars. We have

started that, especially, OGD has one every six

months or so, and those seminars have been very

beneficial to our staff in helping us have a better

understanding of where we need to go, but we need

more seminars and we need, again, really a set

training program for all of our reviewers.

We did form an OPS Coordinating Committee

within the immediate office, and actually, Keith

Webber and Gary Buehler are the chairs of that

committee, and we will be looking at all the issues

that come into OPS to try to ensure that we have

consistency throughout all of OPS on handling

these.

One of the other things that we are in the

process, I think, that will help with the gap is

finalizing the guidance on comparability protocol.

Also, in ONDC, as I said, we are really

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changing the organizational structure, but much

more than changing the organizational structure, we

are changing from a review program to an assessment

program, and that assessment program will focus on

quality attributes of the manufacturing including

chemistry, pharmaceutical formulation, and the

manufacturing process.

So, the significant thing here is that we

will be looking at much more the chemistry, the

CMC, and that is where the assessment program is

focused.

We have the proposed QOS. We have also

implemented a team approach. We are establishing a

peer review process. We have already done this on

a limited basis to provide more scientific input to

our scientists in their review processes, and

helping everyone have a better understanding and

sharing the knowledge that they learn from the

reviews.

We are implementing a Quality Systems

approach. One of the things, too, that ONDC is

doing, is they are developing a mock NDA under the

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new paradigm, under the desired state paradigm, so

that they will have a better feel for some of the

questions and issues that can come up, and they are

looking at reducing supplement requirements.

OGD has reorganized, as well. As I

mentioned, they have an additional Chemistry

Division. They are looking at changes in the

supplement review and evaluation to determine if

some of the supplements can be eliminated.

They have also taken on the team approach

on some applications, so that they have better

utilization of scientific expertise and ensure

consistency across similar product areas, and they

are also looking at efficiencies in review to

eliminate redundant or non-essential review

activities. So, they are very much involved, too,

in some of the things that we need to be focused on

in order to eliminate the gap.

OBP, which is, of course, our newest

review organization, is looking at supplement

requirements to determine where we can eliminate or

reduce supplements.

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Some additional steps. I think we need to

involve stakeholders in the review of guidances.

Maybe under the Manufacturing Subcommittee we need

a group that looks at some of the guidances. I

don\'t know how we need to do this, but I think it

is a step we need to do.

We need to determine how to handle the

two-tiered approach, if we do it at all. I have

mentioned this before, and I think it is going to

be important to involve industry and others in

doing that.

We need to have external workshops,

develop a dispute resolution process. One of the

things, too, besides looking at regular GMP

inspections, we really need to look at better ways

to handle pre-approval inspection process.

I would really like to see reviewers more

involved in making some of the decisions on whether

to do pre-approval inspections and to set better

criteria for getting those done plus participate on

the inspections if we feel they are necessary, and

develop appropriate metrics. These are things we

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haven\'t started on, but are obviously necessary,

and I am sure there is others.

Just to finish up, observations and

conclusions. I think we need to continue to

address and analyze the organizational gap issues.

I think they are going to be really important to

us, to have determined what they are and to resolve

how we are going to handle them in the future in

order to move in the direction that we need to do

to be able to regulate under the desired state.

One of the things I think that is very

important that we need to think about is culture.

When I talk about culture, I am talking about the

culture within FDA, and I am talking about the

culture outside of FDA.

There are a lot of changes that need to be

here. I realize that the culture is always a

different area of thing to handle. I thought

Jerry\'s example was an excellent example of how the

culture is a problem in some of the things that we

are trying to do, and this is one of the things

that we have got to manage and figure out how best

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to handle.

All of this, all of this, the changes in

the organizational gap will take time, and we need

to be dedicating the time to make it happen.

Also, as I said, a lot of this depends on

resolving some of the science gaps that we have.

We need to include stakeholders in making some of

the decisions and developing some of the

procedures. We need to work closely, I think, with

the stakeholders or we are really not going to have

the answers that we need.

The training of reviewers is important,

and the thing I think that is going to be something

that we have got to be open to is that as we move

forward, we are going to see other gaps that we

haven\'t anticipated, and we are going to have to be

ready to fill those.

That is all I have. Thank you.

DR. KIBBE: Thank you, Helen.

Should we take questions or you want to

move to the\--

MS. WINKLE: Let\'s go through all of it,

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yes.

DR. KIBBE: I will hold my really tough

and incisive questions until later.

Scientific Gap Analysis

DR. HUSSAIN: Last night I had a phone

call and I couldn\'t answer that, but this morning,

at 7:00, I had another phone call from a company

which recently got an approval for an inhalation

product, and they were ecstatic. They had submitted

a complete development pharmaceutics report, and

that process went extremely well. This was a

one-cycle review approval for an important product

including all the development report.

So, I think that is a wonderful example

that shows ONDC has already moved and things are

moving in this direction already. We probably will

make a case study out of it, and so forth.

Anyway, I would like to sort of focus on

the scientific gaps. I will use some background

information. I know a number of members on this

committee who are new, so I thought I will spend

some starting with the basics.

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I think, as Dr. Woodcock had come to the

Manufacturing Committee, her articulation of what

is quality has really come to almost fruition, and

she is publishing this article soon. The

definition of quality is fundamental as we move

forward, and there are some challenges as we move

forward.

Good pharmaceutical quality essentially

means an acceptably low risk of failing to achieve

the desired clinical attributes. That is the goal

of achieving quality.

The challenge has always been, and you

heard many of the discussions yesterday, saying the

weakest link\--and the weakest link is what we have

to strengthen and address\--how do we link

measurements and risk?

I think what we believe quality by design

approach that we are developing under ICH Q8 is a

way to help that. It is a multivariate model. It

is characterized during development. You have to

think about, when you think about quality by

design, the clinical is a confirmation of that.

105

That is the fundamental aspect that I think is

going to be a significant challenge in how we

achieve that.

At the same time, you have to remember

that development is only one part of it. You

essentially have to make sure you have a quality

system.

The final link between product and

customer-driven quality attributes really means you

have a good quality system for manufacture that

brought us consistently also, that requires

integrated product and process knowledge on an

ongoing basis, because you don\'t stop learning at

the time of approval. In fact, you learn quite

significantly after manufacturing status.

You have to assure ongoing control, and

you have to enable continuous improvement.

In summary, I think Dr. Woodcock

articulated this at our ONDC scientific rounds on

October 6th. The future definition of quality

should be probabilistic in nature. That is the

fundamental aspect, and we are not there yet.

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Science management, risk management, and

quality management are critical aspects, and I

think we really would like to be leaders in this,

and I personally believe that we are.

But let me take a look backwards from

beginning with the end in mind. Since we started

the PAT Initiative, the cGMP Initiative, our focus

has been on looking at the entire system, and we

have been looking backwards from a manufacturing

end to the entire discovery development product,

and it is what do we learn from that.

But before you look, before you measure,

it is always good to make sure your measurement

system is good, so you get your eyes checked. That

is the symbol there.

The reason I was so sensitive to that is I

think the dissolution variability from a

manufacturing end, we really fully appreciate it

when we are putting that white paper together, that

today, companies don\'t have the ability to document

lower variability than that of the calibrated

tablet, and which is made with the conventional

107

method, and so forth. So, that was I think a stark

reality that a lot of us fully understood during

this process. Art mentioned that, and so forth.

So, what are the challenges here in the

sense the challenge is organizational

communication, and knowledge sharing and

information sharing. If you work in silos, the

boundaries between organization, which I call

interface, the quality of the interface between

functional unit, that means the effectiveness and

efficiency of the process, the interface can be

handoffs between functions, and often is in need

for better coordination, and that is what we

learned through our GMP Initiative.

The rapid and broad movement of

information and knowledge sharing is necessary for

process optimization between organizations, within

any organization itself, so we have to move from

technology transfer to knowledge transfer.

But just toward the stage, reliability is

a phrase that we often don\'t use in

pharmaceuticals, but reliability has a very

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distinct body of information, body of knowledge

associated with that.

So, if you look at this figure, you have

performance, you have life, shelf life, and you

have a desired specification on both sides, on the

performance.

The first, Figure A is good performance,

but poor reliability because the performance

changes significantly over time, and the

variability of the spec changes, too.

The second one is good performance and

good reliability over the life.

The third is poor performance below spec.

So, I think the key is when we think about

performance, we are thinking about performance of

the shelf life, the bioavailability, and so forth,

remaining unchanged throughout the shelf life.

Just to keep that in mind.

In the current state, today, chemistry,

manufacturing, controls, design information

available in applications is limited and varied.

Our reviewers have a high degree of uncertainty

109

with respect to what is critical and what sort of

process controls are necessary.

Our reviewers have significant doubt on

the level of process validation and process

understanding. So, they have no option but to

focus on in-process and product testing. So, in

the pharmaceutical manufacturing from an

engineering sense, testing is control, but in an

engineering sense, control is very different. It

is a dynamic method. We don\'t do that.

Risk coverage post-approval is a

challenge, and supplements are a means for risk

mitigation. That is the way we have approached it.

Traditional use of market standards\--these

are the pharmacopeial standards\--as release tests

are not effective for process understanding and

continuous improvement. In fact, by definition, if

you have attribute data or so-called zero

tolerance, continuous improvement is impossible by

definition. That is the definition in QS 9000,

because we can only have continuous improvement

when the product is already in spec.

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If you have zero tolerance criteria, by

definition, the product is not in spec. So, that

is the fundamental thing. Also, we understood and

wrote about that in our Manufacturing Science white

paper.

We have variable test methods for physical

characteristics, less than optimal systems

perspective and approach, low efficiency and high

cost of drug development and manufacturing, and

continuous improvement is difficult, I would dare

to say not possible.

So, the success of the cGMP Initiative was

to get a consensus desired state statement, so I am

not using the exact words that we developed. They

are modified and the desired state statements

adopted by ICH, these are the ones. Product quality

and performance are achieved and assured by design

of effective and efficient manufacturing processes.

Since we are looking back from the

manufacturing side, manufacturing goals are kept

first.

Product specifications based on

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mechanistic understanding of how formulation and

process factors impact product performance, and an

ability to effect continuous improvement and

continuous \"real time\" assurance of quality.

Now, let\'s start looking at this in the

sense what are the gaps and how do you fill those

gaps.

Information and knowledge for regulatory

assessment and decision process based on the

desired state is information related to quality and

performance and how the design impacts that. So,

we need to know impact of formulation and process

factors on performance.

We need information to judge and develop

specifications based on mechanistic understanding.

We need information to evaluate and facilitate

continuous improvement, and continuous \"real time\"

assurance of quality.

The focus is on design, and if you are a

formulator, especially one trained a few years ago,

or if you have been in the design business, this is

simply logical extension, so this is nothing new

112

about this, but if you are not, then, you have to

think differently the design process.

Design is about doing things consciously,

and not because they have always been done in a

certain way. It is about comparing alternatives to

select the best possible solution. It is about

exploring and experimenting in a structured way.

So, that is what design vocabulary brings to us.

So, in the context of drug product

development, design is about doing things

consciously, so you start with the intended use.

That is the fundamental issue. You cannot forget

the clinical use of the product that you are

designing. That includes route of administration,

patient population, and all other things that

impact on the intended use.

That intended use defines for you what the

product design should be. You have options to

select, and you select a product design. That

design leads you to design specifications, and

those design specifications define the

manufacturing process and its control necessary to

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develop those design specifications back to deliver

the intended use.

So, you have product performance, design

specification that reliably and consistently

deliver the therapeutic objective, and you have

manufacturing capability, ability to reliably and

consistently deliver the target for a design. This

is straightforward, logical, no rocket science, and

we have been making and doing this for 100 years.

So, that was the basis that we said we

will develop the ICH Q8, and ICH Q8 document, which

will go to Step 2 in Yokohama, I am confident about

that, will essentially bring this type of

information.

It will not deal with the drug substance

manufacturing part of it, but it will start with

drug substance characterization.

So, it will bring in characterization of

components of drug product. It will bring in

aspects of manufacturing compatibility, and so

forth. Much of this information is sort of missing

or varied in the current submission, and we are

114

hoping, although the sections in CTD-Q (P2) are not

ideal, we have to live with that because that is

how everything goes in green, we felt that the

sections provide enough room for bringing all the

information to bear on that.

So, we have made significant progress, and

I think the draft 4 we are working on has captured

most of this.

What is the importance of design thinking?

Design thinking makes the user paramount, ensuring

that services we end up will do the job they are

supposed to, as well as delighting the customer.

Design thinking and methods provide new

routes to better public services that meet people\'s

needs and deliver value for money. That is the

key.

We have been making tablets for 100 years

or more. It is a design problem. We essentially

have not used the vocabulary, we haven\'t brought

that in. Tools, such as pre-formulation

characterization, and so forth, literally have

become \[inaudible\], but that information often is

115

missing in our assessment.

So, if I distinguish between conventional

and novel design for the sake of distinction in

terms of how we use prior knowledge, the key aspect

of this design and quality relationship is utility

of prior knowledge. For similar drug products, you

have probably more prior knowledge, and for novel

designs, you have to rely more on the experiments

you generate, but prior knowledge is the key.

If you are going to come with a new tablet

formulation, and you have 300 similar tablet

formulations on the market, how much more

information do we need? If you leverage the prior

knowledge correctly and characterize your drug

substance in a way to say all right, this is the

way it is, you can leverage that knowledge.

Level of mechanistic understanding will

depend, will vary. Pre-formulation programs, many

good pre-formulation programs get to the mechanism

of degradation, get to the mechanism of absorption

including Bioform Classification System,

characterization, that is the fundamental. That

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defines literally every aspect of the manufacturing

process and other things.

So, if you have that information, if you

will not be mechanistic completely, but you have

valuable information, that moves forward.

The challenge I think is to think about

design during drug development. As you develop

your characterization and your development program,

you have to keep in mind the ability to reliably

predict performance, confirm as you progress.

Every experiment you do next, say, a scale-up, is

adding to your knowledge base, is a means to

evaluate the predictability of your prior

knowledge, and so forth.

So, if you think about designing the

entire development project from a design

prospective, and capturing your predictability, you

actually have an opportunity to move forward very

quickly in terms of regulatory aspects, as well.

So, level of understanding increases over

time, and I think we have to recognize that.

Structured empirical approach is often necessary

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because you often are not mechanistic.

Use of prior knowledge to identify and

select a design space for characterization is

fundamental, and I think Ken Morris mentioned this

yesterday. People often jump into design of

experiments without knowing what design space they

want to explore.

If you miss the prior knowledge, you

actually increase your workload, you increase your

cost by not being intelligent enough to say what

are the critical variables upfront, and sort of

exploring the design space. You cannot approach

this in a blinded fashion.

For example, now, if you have multiple

number of variables that you have to study,

obviously, you cannot study all of them. That is

where risk comes in. Prior knowledge and risk

assessment is the way to address that, for example,

failure mode effect analysis would be a means to

say all right, these are the critical variables, at

least these are potential critical variables, these

are the ones we will select and move forward.

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So, initial conditions for screening

experiments and then experimental conditions are

then dependent on this prior knowledge and risk

assessment.

Impact of formulation and process factors

on performance, why can\'t we leverage and be more

intelligent about our clinical trial material

itself, and how do we design clinical trials,

because that is where the connection between

quality and clinical comes together, and I will

show you an example as we go.

Similarly, with shelf life. If you are

getting mechanistic understanding, and so forth,

prior knowledge and shelf life, I think is a

wonderful opportunity which we don\'t utilize today.

Just to give you an example, these are

standard procedures in industry. Here, is a work

from Amgen in a sense how do they address the large

number of variables as they go through process

characterization, pre-characterization experiments,

is to bring the prior knowledge to bear on this.

So, process characterization studies start

119

with pre-characterization work, screening

experiments, interactions, and combinations of key

parameters leading to process redundancy.

They sort of covered that with a formal

risk analysis. So, these are standard procedures,

and in many, many aspects, the formulation

development process has built in robust approaches,

but it is not formalized, it is not well

understood.

What is a robust design? A robust design

is not removing the source of variability, but

designing a process or product to reduce the

variability.

A very simple example that in

pharmaceuticals we have, is we know magnesium

stearate is a wonderful lubricant, but it has a

drawback of affecting dissolution, we know that.

Half of the formulations that we have in

our submissions actually have a robust design built

in. They will use a smaller model on sodium lauryl

sulfate. That negates the negative effect of

magnesium stearate. We have known that as

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pharmacists, formulators, and so forth, a long

period of time, but we never captured that as a

knowledge base.

If you are making a tablet, you are

compacting. Compaction has an effect on

dissolution. If you have right amount of

disintegrating agent, you remove the effect of

compaction force. It\'s as simple as that. That is

what a robust design principle brings to bear on

that.

What is troubling often is, if you look at

the SUPAC guidance, and if you look at the way we

have regulated, the way we have done experiments

often is to define our input or independent

variables in terms of equipment. Say, for example,

if you look at the SUPAC guidance, we say equipment

of same design and operating principles, you can do

this, and so forth.

That is not a quantifiable. It is an

identifier. So, we know that performance of a unit

operation depends on material characteristics,

particle attributes, equipment design, and

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operating conditions.

Instead of sort of defining of input as

equipment A, equipment B, and equipment C, and then

doing a design experiment, if you are smarter, you

will say all right, what are the forces acting on

the particle irrespective of the equipment design.

That removes that and improves your ability to

generalize. So these principles have been there

for 60 years.

Let me explain, in a sense, I think the

key aspect here is risk-based specifications.

Here, is an ICH Q6A decision tree. Let me walk you

through this.

What specific test conditions and

acceptance criteria are appropriate for a

conventional or immediate release dosage form?

Now, Professor Nozer corrected me before,

so I will correct myself again. He said this is

not a decision tree, this is an event tree.

Question 1 is: Dissolution significantly

affects bioavailability? That is the Question 1.

If the answer is yes, develop test

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conditions and acceptance criteria to distinguish

between unacceptable bioavailability.

But if the answer is no, you go down. Do

changes in formulation or manufacturing variables

affect dissolution?

If the answer is no, go down. Adopt

appropriate test conditions and acceptance criteria

without regard to discriminating power, to pass

clinically acceptable batches.

The first question is how do you know

dissolution significantly affects viability. Most

NDAs, not all, have a simple test that they do. It

is called a \"Related bioavailability study.\" They

will compare a solution with a solid dosage form,

and often you see they are superimposable. That

means dissolution is not rate limiting. So,

dissolution is not likely to affect that.

Do changes in formulation variables affect

dissolution? Yes, all of them do, most of them do.

If the answer is no, for heaven\'s sake, if

you can find a formulation that doesn\'t have that,

but you still put a dissolution test. The question

123

should be why, why do you need that dissolution

test?

So, some of the questions, how, why, and

what really have not been addressed adequately, and

our dissolution specification setting is one, two,

three, these were your three batches, this is your

specification. Often, it is limited to that.

I want to remind you that variability is

inherent, and I did include a paper in your packet.

This was published recently from Cambridge

University and Pfizer.

It said if you don\'t account for

variability and you assume that meeting

specification means you are bioequivalent, that may

not always be true. In fact, if you do this

analysis, if your specifications are not set right,

you have a 50-50 chance whether you are

bioequivalent or not, or whether you meet

specification or not.

So specifications for dissolution are not

likely to be the ones ensuring bioequivalence. It

is the entire control process that does that, but

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we focus so much attention on just one test, we

miss the whole point.

Let me come back to this decision tree. I

think in a quality by design thinking, this is what

are my questions. So, dissolution significantly

affect bioavailability is a product design issue.

You start with your pre-formulation, your biopharm

classification, the solubility, permeability, and

all that aspect, and you have an anticipation

whether it will be affected or not, so when you do

your related bioavailability study, you are

conforming your past prior knowledge.

So, postulate-confirmed based on mechanism

or empirically, and that can apply to the question

dissolution significantly affect bioavailability or

do changes in formulation affect dissolution or

not.

But Jurgen points out, the key question is

we have a mind-set 80 to 125, and that is the magic

number. Where did that magic number come from? I

think this is where the clinical relevance comes

in, what is a relevant acceptance criteria to judge

125

whether an acceptable bioavailability is there or

not, and that is a clinical pharmacology question.

That is where we link to the clinic.

If you have a good PK/PD assessment, and

so forth, you have far more information available

to make a more rational judgment, and that is the

question there.

So, design of manufacturing and controls,

and the question is how reliable those are, do

changes in formulation and manufacturing variables

affect dissolution? If the answer is yes, Are these

changes controlled by another procedure and

acceptance criteria?

If the answer is yes, we come back and put

a dissolution test. My question is why? If the

dissolution test itself is variable, and so forth,

why would you want to put another test? You have a

series of tests, and so forth, your chances of

failure keeps increasing.

So, the questions that we need to ask are:

How good or how reliable are your design and

controls that you have put in place for particle

126

size, morphic form, and so forth, to address these

conditions?

So, overall risk-based CMC would ask why

for these questions, but also, so what? If

dissolution is not rate-limiting, the question

should be so what, why do we need a dissolution

test, and so forth.

So, this is how it all sort of comes out.

So, quality by design thinking brings an overall

CMC systems approach, for example, link to morphic

form, particle size, stability failure mechanisms,

and so forth, to address this in a systematic way.

Continuous improvement is not possible

today, because any movement is a change. This is a

direct cut-and-paste from our SUPAC guidance.

Level 1 change, definition of change is this

category includes process changes including changes

such as mixing times and operating speeds within

application/validation ranges.

If you need to have validated those

ranges, any movement within that is a change today.

So, it requires to be reported. If you change

127

outside those ranges, you not only have to report

it, but then you have to do a Case B dissolution,

which is a profile comparison, and the supplement,

and the stability, and so forth, so today, it is

not possible.

Our law and our regulations provide

provisions for those approaches, and this is a

Section 506A of the Act and 314.70 that we issued.

We are required to make decisions based on

potential to have an adverse effect on identity,

strength, quality, purity, or potency of the drug

product.

We have used the phrases \"substantial,\"

\"moderate,\" and \"minimal.\" They are not very

useful, they are not probabilistic, and I think

that is where we have to work at.

But also, if you look at CFR 314.70, there

is a provision no change means no reporting beyond

the variations already provided in the application,

and that is where the design space comes in.

So, what is this design space? The design

space is simply a space of knowledge or information

128

where you know you will not affect your

bioavailability, you will not affect your

stability, and you will be in specification, but

you are improving the manufacturing efficiency, you

are improving the manufacturing process through new

equipment, better controls through process

adjustment in response to incoming input variables,

and so forth.

So, that is what continuous improvement

is, and Box defined this years ago as evolutionary

operations.

So, that is how ICH Q8 information that

brings reliability to your deliver design

information, ICH Q9, which will develop the failure

mode effect analysis and risk communication, too,

all of them come together to define a design space

for continuous improvement, and that design space

will depend on the company\'s information that sort

of comes about.

You will know which area is the change,

which area is not a change, and that is the map of

Maryland, a weather map, so you shouldn\'t be in the

129

red area. That\'s about it.

Yesterday, Steve showed this slide that I

had developed for thinking about the entire system,

how do you connect the dots. I am not going to get

into that, but I think the key aspect there is the

knowledge space, and the knowledge space in

relation to the clinical knowledge space and in

relation to the manufacturing knowledge space all

have to come together to sort of address this.

A personal learning that I had going

through the GMP process is a better appreciation

for quality system. I am still an academic at

heart, and when you put me into a documentation

mode, I get nervous, and great mounds of paper is

something I want to avoid.

The quality system that we have worked out

in the GMP Initiative is actually quite nice and

simple. It says say what you do, do what you say,

prove it, and improve it. Those are the fundamental

principles.

So, say what you do to FDA, is your

pharmaceutical development information that you

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share with us? If you say this is all I know, so

that is what you are going to get. If you say this

is how much I know, and so forth, you get benefits

from that, but then you have to do what you say

consistently. You have to prove it, and if you are

unable to prove it, you have to ask why, and you

have corrective actions.

If you are unable to ask why, unable to

answer why, then, there is a risk profile that

increases. And prove it is more optional, there is

continuous improvement in innovation sort of comes

in there.

The challenges, I think in pharmacy, in

pharmaceutical education, we have been doing this

all along. What has been missing is a formal

structure and communication tool.

I draw some similarity here. If I look at

what has happened in chemical engineering, and now

I think chemical engineering is going through

soul-searching activities to redefine themselves,

but this is how chemical engineering evolved.

It started with industrial chemistry, unit

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operations, material and energy balance, chemical

engineering thermodynamics and control, applied

kinetics, process design, transport phenomena,

process dynamics, process engineering. Now, they

are in molecular transformation, multi-scale

analysis, and systems view.

So, they went from industrial chemistry to

unit operations, to chemical engineering science,

to system engineering.

Industrial pharmacy is still industrial

pharmacy in the U.S., not as well in Japan, China,

Europe, it\'s a pharmaceutical engineering degree

literally. So, we are still in that, and I think

we can catch up on that, going to bring some of

those principles.

It is important to do that, it is

important to bring a systems engineering

perspective because not only we have to deal with

the traditional goals of quality, the GMP

Initiative offered new, non-traditional goals, that

is, risk-based, flexibility, robustness,

scalability, continuous improvement, innovation,

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and efficiency. These are typically

non-traditional goals.

The characteristics of these goals are

complexity and uncertainty associated with that. The

relationship between goals and characteristics

that we are seeking is knowledge and information

centric relationships.

There are fundamental issues there,

because if you don\'t get to this, our quality

system will continue to be a paper chase exercise,

and not really get to the heart of it, because we

don\'t want to be lurching from fact to fact, from

one quality system to another. Unless this process

is in the same sciences there, this will not

happen.

I will skip that and focus on where we

are. My assessment is this. This is not rocket

science, this is straightforward and simple for

those who have been in this area for quite some

time. For those who are not, there is a need for

education training.

There are signs that I see. The phone

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call this morning from a major company, and, in

fact, I should have asked that I can share the name

or not. Their positive experience with the

development report already in a four-cycle review

is a good example that our folks can manage this

process well, but consistency and making sure it

happens consistently is a challenge.

So, the immediate education need that I

see going through the PAT training, and so forth.

Now, for a broader training is introduction to

statistical quality control. That is fundamental.

We are missing that, and I emphasize it is not

biostatistics. There is a distinction between

statistical quality control and biostatistics,

hypothesis testing, and where we keep missing that.

I meet with the PhRMA Statistics Group,

and so forth. It comes back we are missing the

quality dimension here. We have to understand

variability. We have to focus and put training

programs on molecular pharmaceutics and

biopharmaceutics.

We have gone to the molecular level in

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most of those areas. Engineering principles is a

key aspect. Risk assessment and communication

would be a program. All of this will come together

quite nicely with the ICH Q8/Q9 training program

itself, but I think we would like to add some

additional training.

I know Ken has been working with us quite

constantly on focusing on what the right questions

are for the review process, but I think we can put

a more formal training program on all of these

aspects.

I would like to say systems approach and

thinking is important. Unfortunately, most of the

training programs that we go through, our BS/MS/BA

programs actually takes us away from systems

thinking to focus as narrowly as possible, and so

forth, but in an applied area in the regulatory

setting like this, systems thinking is important.

Unfortunately, I go and talk about Deming,

many people in the industry have never heard of the

name Deming. I think we need to introduce people to

Deming and others.

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Team building and communication will be

the key.

I will end my talk saying that coming

together is a beginning, keeping together is

progress, working together is success.

The GMP Initiative brought us together. I

think the PAT Initiative took us further, and a

smaller group is actually making progress.

I am fairly positive. I went through a

quite depressive cycle in some of the challenges,

and so forth, but I am fairly positive that I think

we are on the right track, and we will achieve this

rather quickly.

Policy Gap Analysis

MR. CLARK: I am going to deliver a talk

about something of the policy gap, but what I will

really be talking about is a guidance development

process and some changes that we have done there.

My talk will be quite pedestrian and quite short,

which I hope to be some relief.

I noticed in the agenda, at 10:30 we were

supposed to break, but now it\'s after 11:00, and

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were this agenda an application, we would be found

in violation of an agreement, and if we showed a

pattern of being late, well, we might just be under

a consent decree. So, I think we are at some risk,

so I will move us along and try to get us back on

the path of righteousness, and such.

I want to point out that somebody

mentioned earlier today about failure, about

failure data, I am sorry I didn\'t quite catalog who

it was that brought it up, but the failure of data

to point stayed in my mind.

One of the things that we will be talking

about in Yokohama in Q8 is what role that plays in

an application, and to help define a design space,

is there a place for us to use that in an

evaluation of an application, and if you have

determined where your system fails, can that offer

you some relief as to where you operate. I wanted

to just bring that point up as I start in this

speech.

In the GMPs for the 21st Century, some CMC

guidance documents are out of synchronization with

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that rollout that you all have seen by now, but the

guidance process that developed these documents has

strong and weak points, and one of the main

strengths of this is the technical input from our

staff, from our review staff.

One of our weaknesses is in the

decisionmaking process for actually moving the

documents from step to step and getting them out,

which causes it to be very slow.

I would like to really dwell on the

strength. One of the things that we need to take

away from our previous guidance development process

is that these deliberative processes are well

meaning, and these people are highly trained, and

they are experts at what they do. At every step,

they are trying to articulate the things that are

on their minds and how to get applications approved

in the best way.

They may have become proscriptive and

prescriptive, but that is not a failure in their

attempts to articulate the best way to get an

application approved.

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We believe that there may be a better way

to articulate that point, and obviously, with the

rollout, and you compare the rollout to the

documents that we have on our guidance page, there

is the gap, and most people know that, that are

familiar with the two sets of documents, so I will

move on from there.

The draft cycling that was the weak point,

I will point out this is the old draft cycling, and

you will see that there was a CMCCC working group

assigned from a CMCCC committee body. That CMCCC

would define a group to work, and we will call that

the body for now, to develop a document.

They would go ahead and develop a

document, and this might take six months, and it

might take two years, and it might take five years,

but they would develop an articulation of the areas

of interest for that document.

They would then proceed to take that and

go through each review team, through some kind of a

hierarchical structure in the organization. Those

review teams would then have comments, not unlike

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the public comment system, and those comments would

go back to that review group, and they would

redraft the document, which might take another year

or two.

Because these people are not dedicated to

that task, they are also reviewing drugs, they are

also involved in a lot of other efforts like ACPS,

and they are also involved in guidance development.

So, they go back to the review teams, goes

back to that CMCCC body, and then it goes back up

to the working group or back up to the committee

for review, and then from the committee, it goes

to an OPS editor.

Now, that process, those steps might take

as much as six months, it might be a year. The OPS

editors then have a go at making sure that the

legal language is current with the desires of our

legal staff, and they might pass it on to the legal

edit if their suggestions are minimal, and so on.

If not, if the suggestions are strong and

get into the body of the document to a large

degree, it might actually go right back up to the

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body and have to go all through all that stuff I

just mentioned all over again, and were I

mean-spirited, I could go through it a second time,

but I won\'t.

Well, you go to the legal edit, then, it

goes out to public comment. Then, you have public

comments dockets come back. You might have 1,000

comments if you are lucky. It might be a couple

inches thick if you are lucky, and it might be a

foot high if you are not so lucky.

If that happens, well, it will happen,

then, you have to catalog all those comments,

address each of them somehow, address them by

groups or individually, and then if you have to

make substantial changes to the document in order

to address those comments, go back up to the top,

and if I were extra mean-spirited, we could go

through this whole thing again.

I think you can understand that that could

be a laborious process, and that is my excuse for

why guidances take so long to get out of the

Agency.

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When somebody says that a guidance will be

available soon, they may think it is going to be

available soon, because they think they are near

the end of the process, or what they don\'t maybe

not understand is that there is an iteration that

they hadn\'t predicted. So, that is something we

have been dealing with over the years.

This is a slide that puts into words some

of what we just discussed, but it also points out

that there is a rapid change in FDA thinking over

the last couple of years. It leaves slower efforts

to catch up. The guidance development is, in fact,

a slower process.

There is an investment of time, and the

documents may be slow, but they have a lot of

momentum. You have that many people working that

hard, that many smart people working that hard over

that many years, and the document gets momentum.

The guidance content and the new direction

are managed actually by two different groups. We

have this OPS policy direction setting group, which

had some involvement from the reviewers and staff,

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but the guidance content was being managed by the

review staff directly with reciprocal input from

the higher end, the OPS level.

We have taken some actions to try to

remedy the situation. We have moved coordinating

and decisionmaking from the CMCCC working group to

an OPS office level group, and have created the OPS

CC\. Helen mentioned that a little earlier. They

have a lot of tasks, one of which will be to help

us coordinate these guidance documents.

It will move guidance content management

up to OPS with some lookback down to the review

level when we need that expertise that is at the

review level.

We disbanded the CMCCC as such, as words.

Of course, we have the same people wearing hats

with new letters on them, OPS CC, but it has a

different function, and I will show you that in the

next slide.

The mandate through OPS CC is to recruit

technical input from scientists when we need it.

The new process looks something like what

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I have on the board now, where you have OPS CC

actually managing the creation of the documents,

getting science input from selected teams, getting

input back to OPS CC. Then, you have a smoother

process on the high end of that document formation

process. So, we hope that that will shorten things

up a bit up there. It might take 10 or so years

off the process, which should improve things.

The OPS edit and the legal edit have never

really been hugely time-consuming except that they

can cause reiterations, but it is that iteration

that we have tried to smooth out. Of course, the

public comment isn\'t changing. We still have the

dockets and dockets management.

We are trying to synchronize the effort,

but there are a number of techniques we intend to

use to synchronize the effort of guidances with the

rollout of the two-year effort in the GMPs for the

21st Century.

One is, of course, obviously, a revision

of drafts. We have drafts out there. We have

public comments that are available for many of

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those drafts, bring those in, and we might actually

put out for a second draft some of these documents,

because we may incorporate public comment, we may

incorporate some of the new thinking, and if the

document is substantially changed, we may not go

from draft to final. We may go from draft to

public draft to get more comment.

Another option is the withdrawal of

documents. I would see that option mainly for

finalized guidance documents that just have become

obsolete, and perhaps no longer do any good for us,

so we may actually consider withdrawing some of

them. We have done this in the past, and we may

seek to do it in the future.

Another effort is enforcement discretion.

We may actually use guidance to bring into line

more of our practice where sometimes a practice has

found its way into regulation, where the regulation

will require you to do something that we really

don\'t necessarily believe is constructive at this

point anymore, and we may use guidance to iterate

an enforcement discretion over some terms to

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address some of the regulation requirements. That

would pretty much be viewed as a precursor to

actually revising the regulation itself.

There is also a consideration of options

in OTG other than guidance. The question and

answer format where we have a simple question and

we want to answer it with a paragraph and

hopefully, it doesn\'t turn into a chapter, we post

it on public Internet, try to keep it simple.

It would go through our guidance

procedure, but hopefully, be much quicker, and not

try to address a large range of things, but just to

keep it to one topic, keep it simple.

We also want to look into a Manual of

Policy Procedures, to expand that. I don\'t believe

that we have actually exploited our Manuals of

Policy and Procedures enough to articulate what we

would like our internal staff to be doing, have it

in an if/then format, directed toward OPS staff.

What is nice about the Manuals of Policies

and Procedures is that they are publicly available

once we are done, and they are rapid. They can be

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rapid to get out, and we have more flexibility in

what we say in them.

Back to guidances in particular. We

really would like to have a more risk-based

approach expressed in the guidance, reverse recent

tendency toward proscription and prescription,

which I think that if anyone has read some of the

recent drafts, you can see there is a difference

between what was published in 1987 and what we have

been publishing in recent times, and that they tend

to be much more detailed and much more instructive

as to exactly what you should be doing.

We try to get up to a higher level and try

to rely more on the science for the specific issues

to drive the decisions that are made.

The manufacturer should choose the

technology and the approach to problem solving

where we should be evaluating more of the science

behind whether or not the quality, the ongoing

quality is short, and as Ajaz put up there earlier,

what is the acceptably low probability of not

meeting the clinical intent.

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Focus efforts on assurance of reliable

product quality, and not on technology.

Input into our processes is one of the

things I would like to propose here, is for this

body to seriously consider, creating a fact-finding

group to help us with guidance processes.

Is there a potential gain from formation

of this fact-finding group to help us determine how

we move forward to the desired state?

Some of the questions that fact-finding

group would be asking or asking and answering would

be: Do we need all the guidances that we have now?

Where are they incongruent? Provide advice as to

what guidance industry needs as we work toward a

new regulatory paradigm, and what should be the

prioritization of those documents if we have any of

them at all.

So, I would like to propose that this body

be engaged in that effort at some level to be

deciding who would be on that body and, of course,

it would be within the rules of the advisory

committee system.

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That is the end of my talk. Since I am

the last of the three, I guess I will stay at the

podium and be the target for the questions.

DR. KIBBE: It depends on how much time

the other two speakers will need and how much time

we allow for questions. We can always come back to

the topic after the lunch break, but if there are

some quick questions, we can handle, Nozer?

DR. SINGPURWALLA: Not quick. I have lots

of questions for Ajaz, and I am sure he expects

those. So, perhaps we should postpone them until

another avenue, or I can privately communicate.

DR. KIBBE: No, we will get to them. I

want them on the record.

Go ahead.

DR. MEYER: Just one quick comment. I

like the idea of a question and answer format in a

public Internet, frequently asked question kind of

thing. I think that would save the Agency some

time. It will be easy for the sponsors. You won\'t

have to deal with repeat questions, so I think that

would be a step forward to have that.

149

MR. CLARK: Thank you, Committee, thank

you, Dr. Kibbe.

DR. KIBBE: Meryl, go ahead.

DR. KAROL: I have heard throughout this

morning about the risk-based approach towards your

changes, and I wondered what do you have in mind

for training and education of the personnel in

order to make them knowledgeable about risk-based

approaches?

MR. CLARK: The training of the personnel

is really an ongoing thing. It isn\'t really a here

it starts and here it ends. We have the people

involved. We have a peer review system that Moheb

has set up where they come together after they have

finished a review, and they present it to their

colleagues.

We, from the Policy Groups, we go in and

we listen. We have comments. We steer them, we

try to steer them toward the things that have been

done well, and to bring that out. A lot of the

practices that are involved in a review of an

application are, in fact, risk-based practices, and

150

sometimes a reviewer just doesn\'t bring that up to

the surface and make that well known.

Part of our role in that particular venue

is to point that out, to say, well, you took a

risk-based decision here, we would just like you to

bring that up to the surface and make it the theme

of the document as opposed to going down into the

technology and making that the backbone.

So, it isn\'t really a big stretch for

these people to grasp onto it. They are all very

highly trained.

We do have training programs in mind. We

haven\'t really implemented a lot of them upfront

yet, but the goal is to have a top-down approach.

Dr. Morris has been involved at some level at

helping us train managers into the thinking and to

work that down through the management levels.

We have gotten down to the team leader

level at their last presentation, but the rollout

did take up all our resources up until just now.

So, we will be re-initiating that effort.

DR. KIBBE: Jurgen.

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DR. VENITZ: A few comments, one more

fundamental comment to Jon\'s presentation that has

to do with my favorite word, and that is risk. You

talk about how risk is being assessed, and you have

emphasized primarily the probabilistic component,

that you have tried to predict the likelihood of

something happens.

Well, risk has a second component, and

that is a judgment, how bad is what you measure, or

how potentially bad can it be. I think one of the

things that you will face is within the Agency, is

this culture of always assuming the worst, anything

that happens we can assess whether that happens

often or not is bad.

Well, risk really requires you to make a

judgment as to how bad or how not as bad it might

be. So, I am just pointing that out, risk is not

just measuring probabilities, but it is also

assigning utility values to those probabilities.

Two small comments to Helen\'s

presentation. I would encourage, especially with

all the changes that are occurring, that your staff

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participate in all those industry meetings,

particularly the pre-IND and the end of Phase II

meetings, because I am pretty sure that is where a

lot of things are being discussed that are relevant

to the change in GMP and PAT, and what have you.

As far as the briefings are concerned, you

might consider something like a question-based

review where not the entire material gets reviewed,

but you are actually focusing in on things like

source variability on things that are potentially

at risk.

DR. KIBBE: Thank you, Jurgen. What we

really were hoping for is if you had a quick

question, because I want to get the next two things

out. If you have got a long discussion, we will do

it right after lunch.

Let\'s go ahead and get Mr. Ahmed to talk

about the FDA Critical Path Initiative, a generic

industry perspective.

Generic Pharmaceutical Association Perspective

MR. AHMED: Good morning, everybody.

Sorry for this delayed presentation. I

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know a lot of you must be looking for a break, but

just bear with me. It\'s not that bad. It will be

fairly short because I am presenting from a generic

perspective, and clearly, the Critical Path

Initiative does not really look into the generic

industry the way other presentations or the

Internet on the FDA web site.

First of all, I would like to thank Helen

and everybody at the Agency for providing GPhA the

opportunity to present their view regarding the

Critical Path Initiative.

Gordon actually asked me to do this

presentation on behalf of GPhA. I am from American

Pharmaceutical Partners, which is a direct

injectable manufacturer. We have a proprietary

drug under review right now at the FDA.

What I am going to talk about, first, is

what is the overview of generic industry, what part

the generic industry really plays in the health

care system in the United States, the Critical Path

Initiative concept, the benefits of the Critical

Path Initiative to both the generic industry, as

154

well as the innovator companies.

I think one of the most important

component of the U.S. health care system is generic

industry, as you can see. Fifty-one percent of the

prescriptions dispensed in the United States were

generic drugs. This data is based on the 2003 IMS

data. I am sure the utilization of drugs will

increase as time goes by.

About 8 percent of overall cost of

prescription drugs is contributed by the generics.

There are several off-patent products which still

don\'t have any generic competition, and that is

really hurting the consumer in a lot of respects,

because these products have been off patent for a

while, and I will elaborate on those as I go on.

When we reviewed the Critical Path

Initiative, we found that it really provides

significantly improved tools for evaluating

basically safety, efficacy, and characterization of

the drug substance like the product/manufacturing,

because I think this is a very bold concept

proposed by the Agency, because over the last

155

15-plus years I have been dealing with the Agency,

this is really a breath of fresh air, because I

still hear that titration is a better method than

is HPLC, because it\'s in the USP, so this is really

very good thinking on the part of the Agency.

We have got to get out of that mode,

because, on the one hand, we hear from FDA good

science, good science, good science. We file an

application and provide a better method to the

Agency. There is now we like potential metric

titration because in the USP, your HPLC method or

LCMS method is not good.

So, I think this is a good shift. At

least from our standpoint, we think that science

really holds a lot more promise and can hoe a lot

more ground than regulations.

We like FDA\'s approach. We like the

collaborative approach. I think it is important

that we involve the academics, the patient groups,

the industry, as well as the regulatory bodies,

because really at the end of the day, all of us

have the same function, which is to protect the

156

American public and to provide a service, because

the drugs used by folks is really for people who

are unfortunate, because they have to use those

drugs, so we have to make sure that we provide the

highest quality product, which is the most

efficacious and has the lowest side effect.

The desired outcome meaning yes, faster

approvals. Again, a little bit of a misnomer

because just to give an example, we filed for a

CB30 to extend expiration dating for a very

critical product.

It took FDA 60 days to first acknowledge

that we filed the CB30, and then it will be another

six months before we make a decision, so what is

the point in filing a CB30? That is what I really

wanted to bring to Helen. If we want the desired

outcome to be faster, let\'s please be more

pragmatic, because if it is built around the system

the way it is right now, the desired objective is

really very far away.

Again, the primary emphasis is on

discovery, and it really helps pharma, and clearly,

157

we are a big proponent of that because what pharma

produces eventually has the opportunity to become a

generic, so we are imploring the Agency to work

with pharma to enhance drug development process and

give the pharma folks faster approvals.

From a generic industry perspective, I

think the Critical Path Initiative is also very

helpful, and I request Helen and Ajaz and everybody

else to really think it hard because the generic

industry represents a big opportunity for the

American health care system, as well as for the

Agency itself.

We would like to be part of this

initiative because there are lot of opportunities

where we can minimize the pains we go through on a

daily basis, as well as you folks.

Again, the goal here is to have timely

submissions as well as timely approvals, so the

consumer can benefit. As you know, the prices,

when the product becomes generic, almost within the

three months, the price of the generic drug is

almost 90 percent less than the innovator product,

158

so very clearly it helps the American public

significantly from a financial standpoint.

Again, we very earnestly request the

Agency to really look into providing guidance to

MDIs. As all of you know, it took seven years for

Albuterol to become generic. We don\'t want to go

through that scenario again. There are still a lot

of products which there is no guidance for.

The products, especially the transdermal

products, which have no guidance, the inhalation

products, there is still no guidance, and also,

again, I don\'t want to take anything away from

Ajaz\'s PAT Initiative, but in the entire PAT

Initiative, there is no mention of sterile

products, and currently, in the United States,

about 20 percent of prescription drugs are sterile

products, which includes parenterals, which

includes inhalation products and topical products.

So, I would really again urge FDA to look

into how they can help the sterile product

manufacturers in terms of providing guidance and

reducing regulatory burden. Clearly, we are

159

looking for better collaboration with FDA. We

would like to be partners with FDA in every respect

we can, but again it\'s a two-way street.

Sometimes we get a lot of resistance from

OGD in terms of pestering them too much or in terms

of arguing on scientific issues, so we really would

like to have a more collaborative effort.

As part of GPhA, I would really urge FDA

to look into it in terms of what our objective is,

to make the safest product, but apparently there

are some scientific disagreements at times, and we

want to minimize the pains we go through in terms

of the review process.

Lastly, I would like to talk about the

21st Century Pharmaceutical GMP Initiative. I

think it\'s a step in the right direction, but there

are a lot of issues we really need to look very

hard at. One of the issues is inspection.

There is so much inconsistency in the

inspection process, and to give you an example, an

inspector going to a sterile manufacturing facility

in New Mexico really does not even cover one-tenth

160

of what is covered in the Chicago District.

So, like we are from the Chicago District

and we get the highest scrutiny, I can tell you

that for a fact. Susan Bradley basically really

keeps us on our toes, but there is so much

inconsistency as I go from district to district.

Please look into this because this really hurts the

generic manufacturers especially because of the

patent issue, and things like that.

The other think is I keep on hearing the

Science-based Initiative, Science-based Initiative,

but we are still getting questions from the

reviewing chemists, which is really a total waste

of time for us and you both, the reason being that

we cannot change basic science, and nobody can

change basic science.

But to give you an example, not too long

ago I got a request from a reviewing chemist asking

me to provide a chromatogram for mannitol where the

quantitation was 229 nanometers, and I picked up

the phone and called the reviewing chemist and I

said, \"Please, mannitol has no pi bonds, they are

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all sigma bonds,\" and I \[inaudible\] off any sigma

bond which the electrons could be transferred to

sigma star at 220 nanometers.\"

He said, \"I still want to look at the

chromatogram.\" So, please, please be open-minded,

please listen to the folks who really do this for a

living. They know the science. They would not

present data which does not make sense.

So, that is part of the 21st Century

Pharmaceutical GMP Initiative. Let\'s be

open-minded, let\'s discuss with the industry,

because we folks, we put a lot of time and effort

in terms of manufacturing batches, testing batches,

and we want to produce the highest quality product

and to have the minimum risk.

However, we need to be very open-minded.

We need to depend on science rather than

regulation.

Thank you.

DR. KIBBE: Judy has a question.

DR. BOEHLERT: I have a comment. I am

going to help you out. You said you had a problem

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with USP methods, titrations. Well, I have several

solutions for you.

First of all, USP would love to get your

HPLC method. Second of all, USP allows the use of

alternate methods, so as long as your HPLC method

is equivalent to a better titration, you may use

it.

Now you have got the FDA to deal with.

They are talking about risk, and they are talking

about science. I would hope that the FDA would

look at a submission favorably if you have

demonstrated that your HPLC method is equivalent to

the titration method and the compendium, and you

can go forward.

I know you probably do get questions along

those lines, but I think we need to move past that

and ask the right questions.

MR. AHMED: Judy, what happens is that

they say yes, HPLC method is better assurance than

equivalence data, so what is the point? If you are

showing equivalence data, then, what is the point

of using HPLC method?

163

DR. BOEHLERT: Well, because you don\'t

have to do the titration, and you really do get

better data with the HPLC method.

MR. AHMED: That is what my point is.

DR. BOEHLERT: Titration might be a great

method for releasing product, that you might want

to use HPLC particularly during development to

learn more about your product.

MR. AHMED: And like we are providing a

stability indicating method, and we are telling the

reviewing chemist, please, titration cannot predict

the stability indicating nature of the product, and

still we are asked to provide comparative data.

So, that is what my point is.

DR. BOEHLERT: I know that that happens,

and it happens to the pioneer industry, as well as

the generic industry. We need to get past those

questions that really aren\'t meaningful and deal

with really the scientific issues and look at what

the risk is of some of these decisions that are

made.

MR. AHMED: Exactly.

164

DR. BOEHLERT: So, no, I support what you

are saying.

MR. AHMED: Thank you, because we know FDA

has very limited resources. We don\'t want to waste

your time in terms of providing meaningless data.

DR. KIBBE: Thank you.

MR. AHMED: Any other questions? Thank

you.

DR. KIBBE: Gerry, you have the last word.

Pharmaceutical Research and Manufacturers

of America (PhRMA) Perspective

DR. MIGLIACCIO: Three weeks ago, the FDA

released their final report on the 21st Century

Initiative. This morning, Helen, Jon, and Ajaz

talked about some gaps to achieving what was

defined in that final report.

That final report did a very good job of

defining the desired state, and I am not sure how

many of the committee members have gone through the

entire report. I had 12 hours on a flight to

Tokyo, and I couldn\'t get through it all, but it

does a very comprehensive job of painting the

165

desired state. Yes, there are gaps in the FDA and

yes, there are gaps in industry.

In the time that I have, I am not going to

give PhRMA perspectives on every element of the

final report. What I will do is touch on certain

elements of it.

I want to reinforce what Helen said

earlier about culture change, make a couple of

general comments on the report, and then talk about

three of the documents in the final report, the

Quality Systems guidance, the risk-based inspection

model, and the ONDC risk-based quality assessment

system, and then finally, summarize before lunch.

Three years of culture change. It\'s a

two-year process, but we have been working on this

for a lot longer than two years. In fact, I

contend that we have been working on this for three

to four years, and the culture is changing.

It is changing, it\'s gradual, in some

cases it is dramatic and others, but there has been

in this unprecedented period of communication and

learning for both the industry and for FDA, and

166

that has really been driven by the, first of all,

having a shared vision of what the desired state

is, maybe not always agreeing on how to get to the

desired state, but at least having the shared

vision of where we wanted to get to, and having

open communications about that.

PAT was the model, and much has followed

based on the model.

We, in industry, are moving from a fear of

data to a passion for process understanding. Now,

let me describe that fear of data. I grew up in

this industry, I have been in it for 25 years, and

I remember the days in the laboratory where I did

some testing that was not required by the documents

in my NDA, and getting reprimanded for doing any

testing that was not required and where I did not

have a clear understanding of how I was going to

deal with the data.

Well, we are getting much better now, we

are using much more sophisticated tools at

converting data into knowledge, and therefore, the

fear of just data generation is going away, and we

167

are also learning very rapidly that that data, if

converted properly into process understanding,

process knowledge, can tell us a lot about our

processes, can tell us where the variability is,

and can help us remove that variability where it is

excessive.

The next point, science, not blind

compliance, is winning the day more often. I am

seeing this both internally and I am seeing it

during inspections by FDA, that there is much more

discussion. There is much more discussion about

the science, and I certainly, from my perspective

in the industry, and I see my colleagues, as well,

in other companies, they are using the science to

make decisions much more frequently than simply

sitting back and saying I am not going to take a

risk, blind compliance, this is what the Agency

expects, and just ignore the science. So, that is

going away.

I think you are finding in many companies,

innovation is accelerating, and a lot of it has to

do with the open dialogue and the encouragement of

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the Agency obviously in this area.

Interactions during inspections are

changing, and I think some companies have seen

dramatic changes, others subtle changes, but Helen

talked I guess yesterday about the dispute

resolution process, and I think that the

discussions leading up to the guidance, the draft

guidance, have had a significant impact on the way

both our firms and the FDA investigators approach

an investigation or an inspection.

We are far more willing to put much more

scientific knowledge on the table during an

inspection. Why? Because basically, the dispute

resolution process says that if you are going to

dispute a scientific issue, you have to use what

you have presented during the inspection, so we

want to make sure we get that information out.

Most of used to sit there and say, all

right, we will wait to see if the investigator puts

it on the 483, and if they put it on the 483, then,

we will provide a written response to dispute it.

Well, now, we are dealing with it during

169

the inspection, and now the investigators are

taking the time to look at the science, and they

are calling in outside help when they need it to

review the science, and we are seeing more and more

issues resolved during the inspection, or shortly

after the inspection with the district.

So, I think the dialogue about dispute

resolution has taken us 90 percent of the way to

dealing with scientific disputes.

So, some general comments on the final

report. I think this is a Churchill quote. \"This

is not the end, it is the beginning.\" The

infrastructure is in place, but we have a lot to

do.

We applaud the magnitude of what has been

accomplished, and not so much the volume of work

that was accomplished by FDA with assistance from

industry and academia, but the rigor.

If you look at these documents carefully,

it is not individuals sitting around and putting

their own thoughts on paper, but bringing in

experts from various fields, including risk

170

management, and ensuring that the documents had the

technical content that was required to achieve the

objective.

We obviously, in both industry and FDA,

need to continue to work together to make sure that

what is in those documents is fully understood

throughout the Agency and throughout industry, and

modified as appropriate, and then implemented. So,

we have a lot more to accomplish.

Let me now turn to three of the documents

that were in there.

First of all, the Quality Systems

guidance, and this is the Quality Systems guidance

for industry. We were very pleased to see the

Quality Systems document for use within FDA. We

think that is going to contribute to their

operation significantly, but the guidance for

industry is very comprehensive, and we think it is

of great utility.

I know many companies are already using it

to benchmark themselves, to look at our own Quality

Systems and say how do we match up against this

171

document.

Now, there are some key issues in the

document, and PhRMA will be commenting on this

document and many others. I am just trying to

point out some high-level issues, but certainly

process understanding, what level of process

understanding leads to flexible continuous

improvement in the regulatory environment? It\'s a

key issue and I think both Helen and Ajaz pointed

that out this morning.

We believe that it is imperative that

these concepts be addressed on the global level.

Somebody pointed out earlier today, most of us are

in global businesses, the FDA guidance on Quality

Systems, we believe really lays that starting point

for ICH discussions on the proposed Q10. So, we

really believe that this needs to go on a global

basis and can contribute globally.

There are some parts of the guidance that

we need to ensure we look at, potentially revise.

We need to move away from some of the current

compliance systems, and get us into a Quality

172

Systems mode. So, I will just give you one

example.

The guidance calls for the trending of

data, encourages the trending of data as being part

of a good Quality System structure. The problem is

some of the data we generate for compliance

purposes provides no value on a trending exercise.

How do you trend \"none detected\" or below

level of quantitation? How do you trend data that

is rounded down to a point where it no longer has

any meaningful benefit to gaining process

understanding? And why trend data that is

generated that has no relationship to critical

quality attributes or critical process parameters?

Our current specification system drives

the collection of that data. So, we talked about

specifications earlier. I think this workshop in

March is going to help us move these discussions

forward, but our current specification system has

to evolve. It has to evolve so that we are

collecting meaningful data on things that are

critical to quality.

173

Now, let me move to the risk-based

inspection model, certainly a solid step forward to

allow FDA to focus on higher risk sites. We do

question some of the elements of the algorithm, and

we think they require further discussion.

Again, as I raised at the Manufacturing

Subcommittee meeting, and Judy talked about

yesterday, the concept of volume is problematic to

us, because if you have a manufacturing facility

that makes two or three products at very high

volume, actually, they understand those processes

much more than a facility that may make 20 products

at lower volumes, and they are probably much better

controlled. Therefore, the risk associated with

high volume is probably, in many cases, much lower.

So, the use of a strict volume metric in

the algorithm is problematic, and we would like to

discuss that.

But our most serious concern is about the

transparency of the system. These are words from

the risk-based inspection model document, and what

they say is that the FDA brought in experts, and

174

the experts have established risk weightings for

various processes, products, unit operations I

assume, we don\'t have that information, and that

has all been used to determine the risk factors or

the risk level of various sites, but they don\'t

intend to publish or disclose that information.

Now, when we started this three years ago,

we said one of the key objectives was that we

understood where the risk was in this business, and

that both industry and FDA focused on the high

risk.

Another document that was issued in the

final report is this defining the customer in a

regulatory agency, and we are, the industry is, a

customer in certain case of the Agency, especially

when it comes to their guidance documents and

position papers.

If you look in the middle, when FDA

develops guidance documents representing the

Agency\'s current thinking on a particular subject,

we provide clarity and understanding to firms.

Well, there is no clarity and

175

understanding on what the FDA considers high risk

in manufacturing coming out of this document.

Also, in the final report, the FDA will now be

using a Quality Systems approach to improve the

predictability and consistency. Again, there is no

predictability here.

We believe that industry and FDA have to

have a mutual understanding of what processes, what

unit operations are considered higher risk. We

believe experts in industry should have the

opportunity to discuss and potentially debate what

is considered higher risk by FDA, so that both

industry and FDA can focus their resources on what

we mutually agree are higher risk.

We think transparency is essential here,

and I truly believe this is a win-win-win, a win

for FDA, a win for industry, and a win for the

patients if we all agree and focus on what is high

risk, but if it\'s not going to be published, if we

are not going to understand whether the FDA

perceives certain facilities as high risk, we are

going to do our own risk assessment, and it may be

176

different. It may be different, and I don\'t think

that is going to be an effective use of anyone\'s

resources.

So, we feel very strongly that

transparency here is essential, and we hope FDA

will continue the dialogue with us on this specific

model.

Finally, the ONDC risk-based assessment,

quality assessment system, it represents a very

profound change in the organization and review

process. You heard a lot about that both yesterday

and today. We support the objective strongly, but

a lot of work is required to achieve the end state.

Now, on the PAT Initiative and then on the

GMP or the Drug Quality Initiative, the FDA

demonstrated a willingness to put the leadership in

place and the resources in place to make it happen,

and I think this two-year report is an evidence of

that.

The question we have, a question that will

we have the same commitment of leadership and of,

in this case, review availability, to deal with

177

this initiative, and as importantly, will industry

have the same input into this process as we had

into the PAT and the general Drug Quality

Initiative over the past two to three years. So,

it is a key issue for us.

There is this potential that this proposal

creates this expectation. I think, Judy, you said

something about this yesterday in your summary of

the Subcommittee meeting, that there is going to be

a significant increase in the knowledge provided

upfront.

We will be providing different information

and more knowledge, yes, not necessarily more

information, it is going to be more knowledge.

But again, there will be a greater degree

of process understanding, but it still will be

limited with the original NDA submission. It will

be sufficient to establish that we have a robust

process, but process understanding is a continuum

and will accelerate post-approval.

So, you know, you are going to get the

design space in the NDA, but that design space may

178

be limited. It will expand tremendously in the

first one to two years of commercial manufacturing.

We believe FDA should work through ICH to

establish a global partnership for the risk-based

quality assessment system. Right now the

assessment systems in Japan, the EU, and the U.S.

are very different, and we certainly should not

exacerbate the differences by moving forward with

this initiative without including our global

partners.

One area which we understand the

motivation to go to the pre- and post-marketing

approach in the quality assessment system, but it

does require some further evaluation.

As I said just a few minutes ago, process

understanding significantly increases during the

first one to two years of marketing, and potential

for continuous improvement is really the highest

during that period of time, and there is certainly

a value in having the reviewer who reviewed the

original NDA involved in those initial continuous

improvement changes.

179

As I said, you have got a limited design

space in the NDA, and that design space is going to

grow exponentially in the first couple of years.

Having to shift gears from one reviewer to

another may be somewhat counterproductive. So, we

think this requires further discussion as to is

there an appropriate time frame where the handoff

goes to postmarketing.

Helen talked this morning about two

systems, potentially two review systems, one where

you have the science process understanding in the

application, one without. The problem is that

process understanding is not a yes or no answer,

it\'s a continuum.

So, every application, Company A may

believe in this concept of manufacturing process

and process understanding, but Company A\'s NDA for

product X and for product Y will have different

levels of process understanding.

How will a reviewer determine where the

application is in that continuum and how it should

be addressed? Key questions we think need to be

180

addressed between FDA and industry as we move this

quality assessment system forward.

So, to summarize at two minutes before

noon, Mr. Chairman, the infrastructure is in place,

but some modification is required. We are very

pleased with the two-year report. We think it is

extremely comprehensive and really helps us focus

on that desired state.

The culture is changing, it needs more

changing, but I think the steamroller is moving and

I don\'t think it is going to stop either in

industry or in FDA.

The desired state is on the horizon, we

are starting to see it in little bits at

manufacturing sites and in research and development

sites, you are starting to see the desired state

coming to fruition, and I think it is not as far

away as some might think.

Thank you.

DR. KIBBE: Thank you. I see by the clock

on the wall that we are in plenty of time to

actually get up and go to lunch. We have no

181

individuals who seek time during the open forum, so

that we will return and at 1 o\'clock we can

entertain questions and comments about all of the

speakers that we have heard prior to lunch break,

and then we can jump right into the information and

presentations in the second half of the day.

I know that there are some members of the

committee who need to get out of here by 3:30 or

4:00 and we are going to try out best to make sure

that the bulk of the work is done before they have

to leave, and I appreciate your attendance.

\[Whereupon, at 12:00 noon, the proceedings

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

182

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. KIBBE: I see by the clock on the wall

that we should be turning on our equipment, so we

can start recording the wonderful brilliance that

is coming forth from these meetings.

We agreed before we went to lunch that we

would spend some time responding to this morning\'s

activities and give an opportunity for those with

extensive comments and questions to discuss the

issues, and I know, Nozer, you are ready.

Committee Discussion and Recommendations

DR. SINGPURWALLA: This is to Ajaz. Would

you like to sit down while I ask the questions, or

would you like to stand? You will stay here.

DR. KIBBE: It\'s safer, you are further

away over there.

DR. SINGPURWALLA: Anyway, I enjoyed your

presentation. The ideas again are visionary and

stimulating, and the comments I want to make are

purely to improve upon what I think is something

positive.

183

The first question I want to ask you is a

particular viewgraph that you put up in which you

said the future definitions of quality should be

probabilistic in nature. This is a comment

attributed to Janet Woodcock, although I am pretty

sure you may have had the thought.

What do you mean by that? I subscribe to

the view, but I would like to see what you want to

say to it.

DR. HUSSAIN: I think, in part, that sort

of follows a continuum of our discussions at FDA

Science Board, and that is the IPAP RS debate also,

is we often establish acceptance criteria, and so

forth, in a more deterministic type of thinking in

the sense of we don\'t utilize variability as a

means of decisionmaking, and our criteria are 75 to

125, that\'s it, and no unit outside that for a

given sample, so it\'s an outgrowth of that thinking

to saying that at one level, to say let\'s utilize

the statistical distribution variability in making

decisions.

That is one level of that, but

184

probabilistic also is linked to the risk-based

aspect, and risk is probability for harm and

consequences of that, and I think to bring that

level of thought into how we approach quality.

DR. SINGPURWALLA: I think this requires

much more thought and discussion, but I was curious

as to what you had in mind.

On your viewgraph 7, you have those

3-dimensional illustrations of critical parameters,

reliability, and life, shelf life is what you had

in mind. I could not get the essence of what it is

that you were saying there, and the main reason I

am raising this particular issue is next time you

present it, you may want to rethink as to what it

is that you want to communicate, and I didn\'t get

the message.

DR. HUSSAIN: The message was in the sense

I think when we often think about shelf life as a

point estimate or as a endpoint determination

perspective, and so forth, and what I liked about

that viewgraph was it brings in the variability, it

brings in an understanding of variability from that

185

context and how variability changes.

So, that was an illustration, and so it

provides a means to think about reliability and

shelf life together. So, that was the

attractiveness of that viewgraph.

DR. SINGPURWALLA: You mean the

reliability of a drug?

DR. HUSSAIN: Product.

DR. SINGPURWALLA: Of a product.

DR. HUSSAIN: Yes.

DR. SINGPURWALLA: Well, when we normally

talk about reliability of a product, it is the

probability of it either living to some life length

or doing it or performing satisfactorily or not, so

you had a similar notion of reliability in mind?

DR. HUSSAIN: Yes.

DR. SINGPURWALLA: Let me go to your

viewgraph No. 24. I want to introduce a new

concept based on that viewgraph. This is on page

12\. Perhaps I am going to introduce a new buzz

word, which you may find attractive in the future.

Are you ready?

186

I think that buzz word may also apply to

some of Gerry\'s presentation. You are talking

about substantial, moderate, and minimum as not

being probabilistic. You said something to that

extent.

DR. HUSSAIN: We haven\'t defined the

probability aspects to that.

DR. SINGPURWALLA: I want to introduce you

to the following. You perhaps know that in our

presidential debates, President Bush used the word

\"fuzzy math,\" and I think now Kerry is talking

about \"fuzzy calculations.\" But there is a body of

knowledge called \"fuzzy sets,\" and fuzzy sets are

those whose boundaries are not sharply defined.

So, the idea of substantial, moderate, and

minimum would contribute to what is called a fuzzy

set, whose boundaries are not sharply defined, and

I think Gerry said something, I forget exactly

where, but he was also alluding to a fuzzy set.

Now, what I am recommending to the FDA and

to the drug industry and whoever else is listening,

that the notion of fuzzy sets may be very useful

187

here, particularly with your nasal sprays

thresholds, with the idea of a threshold. You

cannot have a precise threshold. You cannot say

that if something is more than 4 inches, it is

good, and if it is less than 4 inches, it is bad.

The boundary is fuzzy.

There are ways by which you can endow

probabilities on fuzzy sets, and I would like to

alert you to that particular body of knowledge, and

I would like to alert you to looking into it as a

possible venue for the kind of problems that you

are working on.

This is very recent, very new. The idea

of fuzzy sets has been around. Control engineers

use it, but to make it precise, and to endow

probabilities on it is something very, very new,

and the last issue of the Journal of the American

Statistical Association has a paper with discussion

on that particular topic. I urge you to look at

it.

The last comment, and this is a comment,

on your last slide, on immediate education needs.

188

First, I want to say what else you need into this

package. You really don\'t need introduction to

statistical quality control. What you need is

introduction to statistical process control,

because when you take quality control, it goes back

to acceptance sampling, and you are really

interested in a process.

You say you should understand variability.

I think the point is if you understand variability,

variability goes away. Once you understand it, you

know what to do with it, and therefore it vanishes.

What you really need as far as an

educational component is some training and

appreciation of what do we mean by uncertainty, and

how do you work with uncertainty. I think that is

an important component. Once that is understood,

all other issues, process control, biostatistics,

non-biostatistics, all those become very clear.

The last question is how do you plan to

implement this immediate education needs, what are

you going to do, hold workshops?

DR. HUSSAIN: No, I think we have

189

different mechanisms to sort of training. We

actually have formal training programs that

actually go on, on a regular basis at a

training\--we used to have what I think we called

staff college. There are aspects of that. There

is an Office of Training and Communication, which

is thinking of a course on design of experiments,

and a whole series of courses which are sort of

built in. People can take them whenever they have

time, so these are ongoing.

But immediately what we have been focused

on is workshops, internal seminar series, and so

forth. We are starting in a step-by-step fashion.

As we move towards the final guidances, for

example, we generally have a training around the

guidance. Much of that we also get captured there.

But my thoughts are I think we need a

portfolio of courses that are available every

quarter or every semester, or whatever, that people

can take on a regular basis, so we need a

curriculum that is available for our staff whenever

they choose to take it, and so forth.

190

DR. SINGPURWALLA: My reaction to these

things, available on a semester-by-semester or

quarter-by-quarter is that they fail. What you may

want to do is have special courses like this

throughout the FDA, not just your organization,

provided they agree that this is what is needed,

and have them, you know, once, and maybe twice, and

then stop, but then require that the people who

should need that exposure go.

If you keep it optional, somebody says,

well, I know statistics, I know what r-square is, I

don\'t need to take a course. That is where the

tragedy is, that everybody thinks they know it.

So, I propose that you design something specific

and go through that.

Again, I am not volunteering since I made

the suggestion.

DR. KIBBE: Do you have a suggestion for a

college that they could take all these courses at?

DR. MORRIS: Someplace in Indiana maybe,

Notre Dame.

DR. KIBBE: I was hoping for Pennsylvania

191

myself.

DR. MORRIS: Pennsylvania, okay.

Actually, the University of Hawaii I think would be

good.

I actually had a couple of comments I

think that go across Helen\'s, Ajaz\'s, and Jon\'s

talk, but I want to preface it by saying that in

the time I have been spending with you all, it

occurs to me that there is a lot that is right,

right now, with the reviewers and the reviewing

process that we don\'t want to lose. I don\'t get

paid any extra for that, by the way.

In that sense, the idea of a two-tiered

approach doesn\'t really seem to have legs to me.

In a sense what we are saying is, is that the

reviewers would have to be somehow two tiered, and

that is really not the way they review.

What we talked about at the last

Manufacturing Subcommittee was the idea that when

companies can provide a rationale with supporting

data, that that automatically registers as a level

of understanding as opposed to when the reviewers

192

have to develop a rationale based on the data that

they have available, but at the end of the day,

they are still looking for rationales, still

looking for flags in terms of safety and efficacy

and rationales.

So, I don\'t really see that there is a

real need for that. I mean we can certainly

comment on it, and probably should hear from Paul

and Gerry on it.

I have a couple of other comments, but go

ahead.

DR. HUSSAIN: No, I think that has been a

concern, and this was an extensive topic that we

discussed at the London meeting of ICH, especially

working group meeting on that. The language we

have crafted, I mean that took a long time to

craft, to say there won\'t be any two systems or not

tiers at all, in the sense it is a smooth

transition.

But the reality is you will have much more

varied types of submissions.

DR. MORRIS: Absolutely.

193

DR. HUSSAIN: But that is managing that,

and so forth.

DR. MORRIS: And I agree, but I think in

that sense, you know, there were a couple of

things. You know, the evaluation of the

Pharmaceutical Development Report that you had

mentioned, Helen, and really it should create less

questions if you assume that most questions come

from the lack of a presentation of a rationale, so

hopefully, we will realize some efficiencies from

that.

Similarly, Ajaz, I think the review of the

critical variables and attributes should be

improved by the Development Report, the P2 and the

CTD, as well.

I guess this point you had made in your

presentation, as well, I can\'t remember if it was

Jon or you, Ajaz, but the idea that there are

already in industry, the scientific expertise. It

is a question of how they are organized and linked

in terms of communication.

I think the same is true in the Agency.

194

There is a good bit that is already in place, that

just needs to be wired, and that is really all I

had to say.

DR. KIBBE: Melvin, did you have

something?

DR. KOCH: I had a comment or question for

Jon. It had to do with the new process or actually

even the old process in terms of creating, say, a

draft or a guidance, and after you go through the

legal audit, the public comment, and eventually

have a final draft, I am just wondering if there

isn\'t\--maybe I should ask the question\--is there

anything that happens before the final draft in

terms of explaining how the comments were used?

I know they all show up on a docket, but I

know with the most recent PAT final guidance, there

were questions that those who are hoping to use it

have, mainly because there is some part of it which

seems to refer back to doing things the way they

used to be, and there is a little bit of inhibition

initially in how to use it.

I am just wondering, in the process, you

195

mentioned something called a public draft, and if,

say, after the public comments are taken, you know,

the almost final draft shows up for some quick

response.

MR. CLARK: The comment that we receive

when\--this is true of the old process and true in

new, as well\--public comments received are treated

as if they are FOIable whether they are or not.

So, there is a documentation of comments, an

indication of how they are collated, and the

response to them if they are grouped together as a

group or individually depending, that is up to the

group whether they group them together or not.

The FOI rules, they shift a little on me,

I am not sure what level they are available, but we

treat them as though they are. It\'s a public

draft, it was not meant to be any different than

the current draft that we now publish. We provide a

Notice of Availability in the Federal Register and

then it is provided on the web. That draft is what

receives the public comments.

What I was referring to, the main crux of

196

what I wanted to have accomplished here was to

involve this body in evaluation of prioritization

of guidances in general and where we would need

them.

In other areas where we talked about this,

it had come up that we needed to have a better way

of looking at whether or not we needed a guidance

in certain instances, because our methods for doing

that now usually involve public workshops, very

driven by the FDA, and perhaps we should include

some more outside opinion as to where we would need

guidance.

DR. KOCH: I guess I was wondering is

there a process for revision and/or interpretation

of a final guidance?

DR. HUSSAIN: No, I think the policy in a

sense, we do not plan to sort of outline how we

address the comments, only for regulation changes

that is a requirement. For guidances, comments,

essentially, we don\'t share that information.

MR. CLARK: If we receive some indication

that there are interpretations of the guidance that

197

aren\'t going the way we anticipated, this is a

point of having a question and answer associated

with that document or with that topic.

DR. KOCH: Right, and it is in that

context. Anyway, we maybe could talk at some point

in terms of some specifics.

DR. KIBBE: Pat.

DR. DeLUCA: I just want to comment, and I

guess I best comment using Ajaz\'s slide, the cGMP

Initiative. It is on page 14. It has been my

experience that most times in the pre-IND, pre-AND

product development process development, that these

is a hesitance at actually getting too innovative

or pursuing new things and trying to improve a

product with the idea that, oh, well, after it is

marketed, then, we will do this, which I don\'t

think in my experience that it happens very often.

So, I like this. It is because you have

in the circle here that after you get to improve

it, and there is a slot there for continuous

improvement and innovation, and I think I may have

said this before at previous meetings that I think

198

even after postmarketing, that there should be

vigilance in trying to improve the process, and

sometimes you have to try to change both in order

to do one or the other.

I am certain, seeing here that the

expertise certainly exists in the industry the

expertise exists here, and kind of encourage that

it looks like the mentality may even be moving in

that direction, too.

So, that is something that I would

encourage as the desired state, that postmarketing,

that there is this effort, continued effort to

improve the product and the process.

DR. KIBBE: Gordon, you have a comment.

DR. AMIDON: Yes, I have a comment on two

of the slides that Ajaz presented. I mentioned one

to you at lunch, Ajaz. The other was\--

DR. KIBBE: Just give a page number.

DR. AMIDON: On page 11 in your

presentation, the top slide. Interpretation and

Optimization of the Dissolution Specifications for

a Modified Release Product with an In Vivo-In Vitro

199

Correlation.

I am not sure what implication the authors

were making with the dissolution passed, the

bioequivalence passed and the dissolution passed,

bioequivalence failed, but my question would be

what dissolution did they do.

The impression I had from your

presentation was it was suggesting that dissolution

was inadequate in predicting bioequivalence, and it

obviously wasn\'t, but that is because they did the

wrong test, the dissolution test.

So, this implies to me that we need to

really be more specific when we are talking about

dissolution, what is the test, did the test reflect

what is going on in vivo, because if your in vitro

test reflects your in vivo process, that has to

predict what is going on. Otherwise, there is

magic in between.

DR. HUSSAIN: I think the theme of that

paper was twofold in the sense to evaluate\--if you

have the handout, it is part of that\--the team was

to evaluate the linkage between in vitro

200

dissolution and in vivo bioequivalence and how

variability or random variability sort of plays

into that.

Authors looked at what they call a

non-optimal specification and an optimal

specification, optimized specification based on in

vitro correlation, then essentially simulated with

random variability built in, in vitro, as well as

in vivo, what is the likelihood of finding failed

dissolution, so that has been that analysis.

DR. AMIDON: I didn\'t mean for you to have

to defend the paper, and I will have to take a look

at it, but there is something wrong here in my mind

at least based on this one slide, because if your

in vitro dissolution reflects the in vivo

dissolution process, it will predict

bioequivalence.

DR. HUSSAIN: No, that is the whole point

here in a sense. The point here, all we can do

with the current dissolution methodologies are the

mean values. We have no idea on the variability.

So, once you factor in the variability, then, you

201

see these aspects. That is the crux of that.

DR. AMIDON: The second comment would be

on just the previous page, page 10, at the bottom

of the slide, which I did mention to you at lunch.

I am confused whether this is a flow chart or an

event chart of something.

The very first step, does dissolution

significantly affect bioavailability, I mean the

answer, I have problem with the answer \"No,\"

because I can make a tablet no matter what the drug

properties, it will not dissolve and disintegrate,

so dissolution always affect bioavailability, it is

a matter of how much.

I guess my broad comment, and I will make

this again later in my presentation, is that we

need more research on dissolution particularly in

vitro to in vivo. That is where we have the big gap

in our scientific understanding today.

DR. HUSSAIN: I think this is an ICH Q6A

decision tree, and now looking back after years of

this, I do want to give credit to Professor Nozer

Singpurwalla that he really pointed out this is an

202

event tree, not a decision tree, and I actually

before that had not paid attention to that fact.

Now, when we look at it after years, some

of the questions really don\'t make sense.

DR. KIBBE: Michael.

DR. KORCZNSKI: This is just a comment

related to the past two days of discussion. I

think we really heard some excellent data being

generated from the FDA labs, and I might add, after

spending a number of years in the industry, I wish

some of my retired colleagues could have heard the

discussion. I think they would have marveled at

the progress being made scientifically.

A thought comes to mind. I think this is

a very significant question. I have tried to

distill a significant thought here. Can innovative

drugs, as a result of where we are going and the

data we are seeing, eventually be reduced in scope

relative to clinical trials and without a loss of

patient safety or efficacy?

Just to kind of encapsulate that, if,

indeed, you do have some very excellent innovative

203

types of assays at the preclinical level, such that

they perhaps might even mitigate to some degree or

reduce Phase I studies, because they are so

thorough and better predictors, and then if you got

to that stage, could there be a consideration of

collapsing Phase I and Phase II clinicals into one

clinical trial basically, then, with all the data

that we saw from the ICSAS staff, the computerized

data, is it possible in some way to network with

sponsor companies, such that more drugs could

probably be placed in an orphan drug clinical

pathway as opposed to the current conventional

Phase III.

So, long term, there are some real

opportunities, I think, in condensing and

collapsing that costly and lengthy clinical trial

procedure, and the data to a large extent that is

being collected.

Just another two items. One, we talked

about innovative drugs. I think what is going to

be important, this is kind of futuristic, would be

the identification of target sites for disease

204

states, and very important with the development of

these nanomolecules and small peptides will be the

delivery systems. What will be the micro delivery

system to the host site especially as we talk about

gene therapy?

So, the development of that technology has

to occur in concert with the development of the

molecules, so we are going to have the molecules

and not the means to deliver to disease state host

sites.

So, that is just an encapsulation. Thank

you.

DR. HUSSAIN: On the last point, I think

there has been an amazing growth in that particular

area, vehicles, nanovehicles, nanodrug delivery

systems, and so forth, and we hope to publish a

paper soon on the topic of dendrimers and then how

dendrimers can sort of shrink promers \[ph\], and so

forth, so there has been wonderful progress even on

that side, on the delivery part of it.

DR. KIBBE: Anybody else? Okay. So, we

kind of beat that into the ground, and we got that

205

under control.

We need to move forward. I see that

Lawrence is getting ready to go. He has two sets

of presentations, and he agreed that if we would

just do exactly what he says in the first set of

presentations, he would be really fast on the

second set.

Pharmaceutical Equivalence and Bioequivalence

of Generic Drugs

The Concept and Criteria of BioINequivalence

Concept of BioINequivalence

DR. YU: Good afternoon. This afternoon

we have to deal with two topics. One is follow-up

topics which we have presented this committee six

months ago, and a second topic, introduction topic,

is called Bioequivalence of Locally Acting GI

Drugs.

Let me go through the first topics of

bioINequivalence, concept and definition, which

this topic, as I said, was presented to you six

months ago on exactly April 14, 2004.

The bioavailability is defined as the rate

206

and extent of drug absorption. Regularly, we use

the Cmax as a surrogate for the rate absorption and

the AUC, all to the exact area under the curve used

for the extent of the drug absorption.

So, the bioequivalence is defined as

absence of a significant difference in the rate and

extent absorption, and many other things, for

example, become available at the site of drug

action when administered at the same molar dose

under similar conditions in an appropriately

designed study. So, this is basically the CFR

definition.

With bioequivalence, we usually use 90

percent confidence interval for AUC or the extent

of absorption, or Cmax rate of absorption between

80 and 125 percent.

The passing bioequivalence criteria or

confidence interval allows market access.

Certainly, we have to, for example, generic firm

have to meet other quality standards. If you pass

the confidence interval, or we call the

bioequivalence for generics, this means the generic

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approvals, for innovators, this means demonstrated

to be marketed formulation to be equivalent to

clinical formulation.

Those concepts are well understood, well

developed, widely used.

The question remains why do we need to

define bioINequivalence? It is because FDA

receives studies, as we discussed six months ago,

receives studies that attempt to reverse a previous

finding of bioequivalence, in other words,

companies, whether innovator companies or generic

companies out there, to conduct a study, say, the

generic products or products on the market, in

fact, is a bioINequivalent.

The bioINequivalent definition is not very

well defined. In many cases, to be scientific

term, those studies actually should be defined as

failed to demonstrate bioequivalence to be exact.

That is part of reason when you define the criteria

of a bioINequivalence, when you define the concept

and criteria of bioINequivalence.

The question certainly, what should

208

bioINequivalence mean? Bioequivalence leads to

market access, bioINequivalence leads to market

exclusion. That is what

bioequivalence/bioINequivalence basically means.

Now, come back to say look at the results,

what does it specifically mean when I said failed

to demonstrate bioequivalence, failed to

demonstrate bioINequivalence, bioequivalence or

bioINequivalence, those concepts.

In the center, the top one is demonstrate

bioequivalence just because the confidence interval

for this study is within the bioequivalence

interval of 80 to 125 percent.

The bottom one is demonstrated

bioINequivalence, I use BIE here, it stands for

bioINequivalence. Now, the middle one, basically,

the left side or right side, we have fail to

demonstrate bioINequivalence and fail to

demonstrate bioequivalence. This basically is

because neither, whether either outside of the

confidence interval, outside of bioequivalence

interval, 80 to 125 percent or not completely

209

inside.

Now, since the April discussion, I

received several phone calls and also we had a

discussion within FDA with my colleagues, some

question came back that by definition of

bioINequivalence may be too far. Some people

suggest maybe use mean of the point estimate,

confidence interval, while the suggestion was that

if you use the point estimate or mean ratio outside

or above 125 percent, it should be defined as

bioINequivalence.

Now, certainly this makes a lot of sense.

However, if we look at it deeper, statistically, it

is not. Let\'s look at an example here. The top

one, obviously, it failed to demonstrate

bioINequivalence. Now, failed to demonstrate

bioINequivalence could have been for many reasons.

One of the reasons you would think is not enough

subjects, for example theoretically, they should

have used 100 subjects or 50 subjects, and this

study only used 10 subjects.

Because of the small number of subjects,

210

it makes the confidence interval of the final

results much wider, therefore, end up you have a

failed to demonstrate bioINequivalence. We see we

cannot use this result, failed to demonstrate

bioINequivalence as definitive answer, is because

if you use large number of subjects, there is two

possibilities as you can see here.

Could be bioINequivalence completely below

the 80, outside of the bioequivalence confidence,

either below 80 or above 125 percent.

There is another possibility that even

though the study, this is a small number of

subjects study shows bioINequivalence, in reality,

they could be bioequivalent, as you show here on

the left side, right side or left side. So, the

right side one is because once you use large

numbers of subjects, could give you a definitive

answer, you end up even though the study itself

fails to show bioINequivalence, but at the end you

have two outcomes, and that is the power that could

be demonstrated bioINequivalence or demonstrated

bioequivalence.

211

That is part of the reason we say we may

not be able to use these results to have a

definitive answer to make regulatory decisions.

The objective is the same which we were

discussing back to April 14th, to develop a

bioINequivalence criteria that are scientifically

sound, statistically valid, fair to all parties,

and easy to use.

I want to remind you that the comments or

conclusion draws back to the last discussion. The

first question, back to April 14th: Does the ACPS

agree with the distinction between demonstrating

bioINequivalence and failure to demonstrate

bioequivalence?

The answer was yes. That was the

conclusion reached back to April 14, 2004.

The second question: Does the ACPS

recommend a preferred method for evaluating the

three pharmacokinetic endpoints for

bioINequivalence?

There are many sub-questions. Here are

the comments which were discussed.

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The committee agreed on a general

understanding of bioINequivalence to move forward

by recognizing this is not a simple matter. In

addition, the members felt that there is an

important concept, especially now it applies to

entire regulatory scenario. There was no consensus

at this point as to a final criteria pertaining to

the three pharmacokinetic endpoints.

We will present you today our

recommendations based on those discussions and hope

we can follow the comments or discussion.

DR. MEYER: Could we ask a question before

we get confused with statistics?

DR. KIBBE: Okay, great. Why don\'t we ask

the question before we get statistical.

DR. MEYER: I like to approach things in a

very simple manner. If you could get slide 7 back,

Lawrence.

It strikes me that you are trying to use

phraseology to fit a subsequent statistical

analysis, and I am wondering if there isn\'t a

simpler way to go about it. I am kind of, of the

213

school that you are either pregnant or you are not,

and if you haven\'t taken the test yet, you can\'t

say. So, that is basically where I am going to go.

I am going to number these 1, 2, 3, 4, 5.

I think we can all agree that No. 1 is

bioequivalent, and No. 4 and 5 are bioINequivalent,

just as you have shown.

DR. YU: Yes.

DR. MEYER: I say No. 2 is

bioINequivalent, not failed to demonstrate

bioequivalence, the pregnancy/non-pregnancy thing.

I say that because the mean is well outside 80

percent, and increasing the numbers may shift the

mean one way or the other. You shifted it, of

course, to the left to make it worse.

I would say maybe it will stay the same.

All I know is that the means are terrible, and the

confidence limit kind of extends over to acceptable

range, but in my view, if somebody came to me with

that data and said I ran the study on 40 subjects,

should I do 80, I would say no, reformulate.

If they came to me with a confidence level

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that lopped that over, I would say, yeah, do an

added number.

So, I think the N problem, which could

expand confidence limits, can be solved by

requiring anyone that dose a bioINequivalence study

to fix their N at the same as the person that got

the approved ANDA. So, if it took Teva 485

subjects to do their study, then, I think Pfizer

ought to do 485 subjects if they are going to try

to prove that Teva is no longer bioequivalent for

some reason.

No. 3, I would say that fails to

demonstrate bioequivalence by the current

standards, but it also fails to demonstrate

bioINequivalence, because the means are well below

125\. That is a wash.

You can\'t tell one way or the other,

therefore, whoever is doing the study can\'t make a

claim of bioINequivalence, because there is

ambiguity in the data. That is a much simpler

approach than trying to come up with a new metric

of 3 parameters or 1 parameter or what have you.

215

DR YU: Indeed, Marvin, you have excellent

questions. That is true, I guess, we have too many

discussions on this topic.

Well, come back to your question, is that

does fail to demonstrate bioINequivalence, top, No.

2, is actually demonstrated bioINequivalence here,

that is the question.

Indeed, you point out it probably could be

bioINequivalence if the sponsors, whoever conduct

the study, you have sufficient power, was

sufficient in number of subjects.

I guess the question comes back under this

scenario, that for top one, which is clear,

demonstrate bioequivalence, and the bottom one is

clear, demonstrate bioINequivalence, however, for

No. 2 or No. 3, this does not

necessarily\--especially for No. 2\--if we receive

the data, this does not necessarily suggest, we are

not going to take any action whether or not you

look at it, simply because you fail to show

bioINequivalence, therefore, we are not going to

take a look at it, we are not going to take any

216

action, that is not the case.

Certainly, this case, if you submit it to

the Agency, and the study is well conducted, well

powered, we have to look at all of the scenario and

then to draw a scientific decision, or I guess what

I am saying is top 1, and top 4 and top 5 give us

definitive answer, top 2 and top 3, we have to look

at it case by case. We cannot draw very decisive

conclusive decisions is part of the reason you have

assumption here, you have a sufficient number of

subjects.

If you don\'t use a sufficient number of

subjects, say, you only use 1 or 2 subjects,

certainly, we were not able to say you have

demonstrated.

I hope I answered your question. I guess

we answer your \"if\" questions.

DR. MEYER: How about fixing the N at the

same as the ANDA submission used?

DR. YU: That is one of the options, yes.

DR. KIBBE: You are responding to a

question that I don\'t think the Agency is asking.

217

You are responding to a question that a sponsor of

one of those studies would ask in order to get the

study to do what it wants to do.

Then, you are saying, well, the Agency

should say if they did this, then, they probably

would show this and what should we do about that.

The difficulty for me in this whole scenario is

that the failure to demonstrate bioequivalency

doesn\'t necessarily prove bioINequivalency, and if

a product is already on the market because it has a

bioequivalency approval, what level of information

do we need to reverse that decision.

I agree with Lawrence, those two in the

middle wouldn\'t justify in my mind as a regulator a

change in the previous decision, whatever it was.

Okay?

DR. MEYER: If the orange one, No. 3, was

done under the same conditions as the ANDA holder.

DR. KIBBE: If it was done under the same

conditions as the ANDA holder, I wouldn\'t reverse

my decision on anything.

DR. MEYER: That is an exaggeration

218

perhaps because let\'s say it\'s 127, you can\'t get

real excited about that. No, it would have to be

125, but let\'s say it was 145.

DR. KIBBE: What I am saying is we already

have a product that passed once.

DR. MEYER: Right.

DR. KIBBE: That study doesn\'t help me

decide to reverse that decision.

DR. MEYER: The product has changed.

Remember, Gary Levy published The Clay Feet of

Bioavailability or Bioequivalence Testing. You do

it once on a hand-picked lot against one lot of the

innovator product, a fresh lot of yours, and one

you have selected maybe out of 12 of theirs, and

then somebody else comes along with an older lot of

theirs or vice versa, and no longer are you

bioequivalent.

DR. KIBBE: I understand the argument. I

am just saying that, as a regulator, I wouldn\'t

change anything I have got on the books based on 1,

2, 3. Okay?

DR. YU: I guess I will make one more

219

comment. When you conduct bioequivalence studies,

you look at availability, you look at the power,

you look at the subject. You are basically always

saying here that the bioequivalence criteria is 80

to 1 to 25 percent. Agency never defines how many

subjects you use. You could have used 24, 48, 96,

500, for example, for clinical endpoint studies.

So, when you define the number of

subjects, then the confidence interval could be

variable, one way or another. You define one, and

you have another criteria.

I think that for the bioequivalence

criteria, we define the confidence interval instead

of define the number of subjects.

DR. KIBBE: Go ahead, Nozer. We are

having a lot of fun here.

DR. SINGPURWALLA: I think it is always

fun when committee members disagree, but something

bothers me about this whole concept.

DR. YU: That was not the\--

DR. SINGPURWALLA: That was not the

question, I understand.

220

DR. YU: That was not the question.

DR. SINGPURWALLA: I understand, that was

not the question.

DR. YU: If we don\'t want to live with it,

I guess the decision will have to be made.

DR. SINGPURWALLA: I am sorry, my comment

here is you are building a castle on sand, I think

this whole idea\--

DR. KIBBE: Or clay, right?

DR. SINGPURWALLA: Whatever you want to

use, it\'s a castle that cannot hold up. What you

have done is you looked at Cmax and you looked at

AUC, and if the Cmax and AUC are not significantly

different, you say there is bioequivalence. Not

true? What is it then?

DR. KIBBE: If you are going to give an

answer, Don, you might as well get on a microphone.

MR. SHERMAN: Lawrence showed a quote from

the regulations on the definition of

bioequivalence, and it said rate do not show a

significant difference. The word \"significant\" in

that sentence does not mean statistically

221

significant, it means significant the way the word

is used in the English language, substantial,

important.

DR. SINGPURWALLA: Then, my comment

becomes even more acute. The whole thing should be

relooked, revisited, because I kind of agree with

Lawrence about those two, and I agree with our

chairman about the two middle ones as demonstrating

failure to demonstrate, then demonstrating. I mean

I wouldn\'t change anything, but I think the whole

concept of doing all this through this particular

vehicle of setting confidence limits and looking at

the little tail falls here or there seems

completely capricious to me, and you may want to

revisit this whole topic.

DR. KIBBE: We have been revisiting this

since 1970 at least.

DR. SINGPURWALLA: I was not there.

Change the paradigm.

DR. KIBBE: We are not revisiting the

paradigm.

MR. SHERMAN: I just want to correct the

222

notion that you look at Cmax and AUC and you

approve products as inequivalent if there is not

statistically significantly difference. That

hasn\'t been true for decades.

DR. SINGPURWALLA: So, it has been

nonsense for decades.

MR. SHERMAN: You are entitled to your

opinion, sir.

DR. YU: We will move on to the next

topic. Thank you.

Criteria of BioINequivalence

DR. LI: Good afternoon. My name is Qian

Li. I am from Office of Biostatistics in CDER,

FDA. I am going to present a statistical criteria

for evaluating bioINequivalence using multiple

endpoints. I know there have been citing for using

one endpoint, but I decided to move on to talk

about multiple endpoints.

Before I start to talk about the criteria,

I would like first to discuss the question why we

need to use multiple PK endpoints to assess

bioINequivalence.

223

To answer this question, we need to

understand that for systematically delivered drug

product, bioequivalence established by comparing

the rate and extent of drug absorptions. The rate

and extent are usually represented by Cmax, AUCt,

and AUCinfinity.

In statistical terms, Cmax, AUCt and

AUCinfinity, I refer to as PK endpoints. For

bioequivalence assessment in generic drug approval,

it has evolved to use AUCt, AUCinfinity, and Cmax.

As Lawrence has mentioned before, that you have to

prove that 0 to 3 PK endpoints to be equivalent in

order for the generic drug product to have market

access.

Now, for bioINequivalence, it can be

established if one of the PK endpoints are

inequivalent in truth.

Now, in reality, we do not know the truth,

so we have to perform statistical analysis to test

all the PK endpoints. That is why we need to

assess multiple PK endpoints. I hope this is clear

to everybody now.

224

Now, this is the outline of my

presentation. I will give a brief review on the

criteria for bioINequivalence using one PK endpoint

and then present strategies for assessing

bioINequivalence using three PK endpoints, and I

will discuss available approaches and then present

power comparisons of those approaches.

Then, I will discuss FDA\'s recommendation

of using the three PK endpoints in assessing

bioINequivalence.

Now, let\'s first look at definition of

bioequivalence and the inequivalence using one PK

endpoint.

We use the ratio of geometric means Mu

T/MuR

to define bioequivalence and INequivalence. Mu

T

represent the geometric mean of the test product,

and the Mu R is the

geometric mean of the reference

product.

The bioequivalence is true when the ratio

is between 80 percent and 125 percent. We call

this bioequivalence interval. Outside this

bioequivalence interval is defined as

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bioINequivalence region.

Now, to test the bioINequivalence, the

null hypothesis is the bioequivalence interval.

The alternative is the bioINequivalence regions.

Similar to bioequivalence test, we will perform

two, 1-sided test, as well for bioINequivalence

assessment.

The null hypothesis for 1-sided test is to

have the ratio reached and equal to 80 percent, and

the alternative is less than 80 percent. There is

another test that now is less than or equal to 125

percent, and the alternative is driven 125 percent.

We can claim bioINequivalence if one of

the two nulls is rejected. We perform the test on

the significance level of 0.05. Now, this is the

equivalent to form 2-sided 90 percent confidence

intervals.

The criteria to claim bioINequivalence is

when the 2-sided 95 percent confidence interval

lies completely outside the bioequivalence

interval.

I would like to remind everybody here that

226

using 2-sided 90 percent confidence interval for

bioINequivalence test, the error rate is not always

protected at 5 percent level. This is different

from bioequivalence test.

If we have a reasonable conducted study,

say, it\'s a 2-sequence and a 2-way crossover

design, and the subject is more than 20, and the

within-subject standard deviation is less than 0.7,

then, we can safely control the error rate to 5

percent, however, if the subject sample size is

less than 20, we have large variance for the test

statistics, then, the error rate may not always be

controlled at 5 percent. In this case, we might

have to consider to use 2-sided 95 percent

interval.

Let\'s move on to the definition of the

bioequivalence and the inequivalence using three PK

endpoints. As mentioned before, the three PK

endpoints is Cmax, AUCt, and AUCinfinity.

The definition of bioequivalence is the

cubic region in this 3-dimensional diagram.

Outside this cubic region will be the

227

bioINequivalence region.

For the criteria for bioequivalence

assessment using three PK endpoints is to require

all 3, 2-sided 90 percent confidence interval for

the ratios of our geometric means has to be

reaching the bioequivalence limit.

Now, the error rate of wrongfully

rejecting bioequivalence using this criteria is

protected at 5 percent level.

Now, for bioINequivalence assessment using

three endpoints, we are looking for a strategy that

can control the error rate of wrongfully rejecting

bioequivalence at a rate of 5 percent.

Also, we want to control the error rate

under all correlation structures because we do not

know the correlation structure of the three PK

endpoints.

Now, to develop those strategies, we

assume the variances of test statistics are not

large.

Now, there is a common misconception when

assessing bioINequivalence. The common

228

misconception is that to claim bioINequivalence,

when one of the three PK endpoints satisfies the

bioequivalence criteria, which is the 2-sided 90

percent confidence interval is outside of the

bioequivalence interval.

Now, we will not accept this kind of

approach to assess bioINequivalence because it will

inflate error rate of wrongfully rejecting

bioequivalence. The error rate can be up to 15

percent if three endpoints are independent, can be

about 8 percent if the three endpoints are highly

correlated. We consider that approach is quite

liberal.

Now, people may want to think about we can

use quite tough criteria, which is to claim

bioINequivalence if all the three PK endpoints

satisfy the bioINequivalence criterion, which is

2-sided 90 percent confidence interval outside of

the bioequivalence interval.

These tough criteria will tightly control

the error rate under all correlation structures,

however, it won\'t provide good power to demonstrate

229

bioINequivalence, therefore, we are not

recommending to use this criteria either.

What we would like to recommend are the

following strategies. The first strategy we

present here is to pre-specify one of the three PK

endpoints for bioINequivalence test. For example,

if you decided to use AUCt to test the

bioINequivalence, then, you can perform analysis on

this endpoint only, ignore the other two.

The requirement for this strategy is that

you have to pre-specify this endpoint in your study

protocol. Otherwise, you could end up switching

endpoints, which may inflate error rate, which we

don\'t like to see that.

Now, this strategy is ideal for situations

when one knows that one specific PK endpoint is

more likely to show bioINequivalence than others,

but it may have poor power if you misspecify the

endpoint.

Another strategy we would like to

recommend is called Bonferroni corrections. There

are many versions of Bonferroni corrections. One

230

example of using Bonferroni correction is to use a

2-sided 96.7 percent confidence intervals for three

endpoints instead of 90 percent confidence

interval.

If one of the three 96.7 percent

confidence interval fall in the bioINequivalence

regions, we will say the bioINequivalence is

demonstrated.

This strategy is ideal for scenarios when

one knows that one PK endpoint is more likely to

demonstrate bioINequivalence than others, but do

not believe that all the endpoints have good power

to demonstrate bioINequivalence.

Another strategy we would like to discuss

here is to use three confidence intervals with

different lengths. This can be considered a

variation to the approach that requires all the

three endpoints to satisfy the bioINequivalence,

which is the very tough criteria. This criteria

will control the error rate no more than 5 percent.

One example of this criteria is to use 94

percent confidence interval, 98 and 96 percent

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confidence interval for the three endpoints instead

of all three, 90 percent confidence intervals.

This approach is ideal for situations when

one has no idea which PK endpoint has the best

power, but you know that all the three endpoints

could show bioINequivalence.

To support what we have discussed for the

three strategies, I would like to show you some

power examples for several scenarios for the three

strategies.

We calculated power under two correlation

structures. The first scenario is that only one

endpoint has good power to demonstrate

bioINequivalence. One example is that AUCt has

only 5 percent power, AUCinfinity has 20 percent

power, and Cmax has the best power, which is 90

percent.

In this case, if we choose pre-specified

strategy, we could have a power between 5 percent

and 90 percent, so this example clearly shows that

if you know Cmax is the endpoint that could give

you the best power to demonstrate bioINequivalence,

232

then, you should choose the strategy to pre-specify

Cmax in your protocol.

In this example, Bonferroni correction

also can give you quite a robust power, but the

varying confidence interval approach is not as good

as the other two approach.

Now, for second scenario, which is all

three endpoints have reasonable power to show

bioINequivalence. Now, here, one example is AUCt

has 60 percent power, AUCinfinity has 70 percent

power, and Cmax has 80 percent power.

Now, the per-specified approach give you

60 to 80 percent power. The Bonferroni correction

will give you about 64 to 72 percent power, and

under the varying confidence interval approach, we

will give you about 70 percent power.

So, in this case, if you feel that all

three endpoints could demonstrate bioINequivalence,

then, varying confidence interval approach might be

a good choice.

This scenario is that all three endpoints

have equal power. All has 80 percent power. In

233

this case, if you know exactly that all has 80

percent power, then, you can choose pre-specified

approach, but this is probably unlikely known to us

before we do the experiment.

Now, in this approach, Bonferroni

correction will give you decent power, but varying

confidence interval will give you probably the best

power if you don\'t know that all the endpoints has

equal power.

This leads to the summary of our

recommendations on using three PK endpoints for

assessing bioINequivalence. When one knows which

endpoint is more likely to show bioINequivalence,

Strategy I should be used, which is to pre-specify

the endpoint in study protocols and use the

endpoint to test bioINequivalence. For this

approach, you should use a two-sided 90 percent

confidence interval.

When one knows that one endpoint may have

good power, but do not believe that all of them,

all of the endpoints have good power, then, we

suggest to use Strategy II, which is the Bonferroni

234

correction.

One example of Bonferroni correction is to

use a two-sided, 96.7 percent confidence interval.

If you believe that all three endpoints could have

reasonable power to show bioINequivalence, then,

Strategy III should be recommended.

The example of Strategy III is to use 94

percent and 98 and 65 percent confidence intervals.

Thank you.

DR. KIBBE: Questions? Go ahead.

Committee Discussion and Recommendations

DR. GLOFF: Art suggested over lunch that

I say something this afternoon to earn my keep

here. I have a question, it is probably an

uninformed question, so I apologize for that.

Is there any provision in all this to look

at the results for the reference product relative

to the results for the reference product that were

obtained either by the company that submitted the

ANDA in the first place or prior results submitted

by the holder of the NDA?

DR. LI: To my knowledge, I don\'t think

235

so. I don\'t know.

DR. YU: I guess the bioequivalence

confidence is defined 88 to 125 percent, so that is

the criteria we use. Under certain circumstances,

when, for example, the variability is significantly

high, we will get clinical studies. We will look

at the availability, how much they impact the

confidence interval, but the criteria still remains

80 to 125 percent.

DR. GLOFF: Well, I am sure you probably

have thought of why I am asking that question. A

prior speaker made the comment that when a generic

is being developed and submitted, that they could

hand-pick the lot that the generic company uses to

compare to and hand-pick the lot of the innovator

product.

I am sitting here thinking, well, why

couldn\'t the innovator company do the exact same

thing to try to demonstrate that the two were

bioINequivalent or were not bioequivalent, and I

don\'t know if the Agency came to that conclusion,

what they would then do for sure, but I am

236

concerned about that, that you do that, and then

where are you.

DR. YU: I guess the information for

bioavailability, bioequivalence, as clinical

pharmacology sections, it is available in the

public domain, so any sponsors, any companies out

there, you can request, go through Freedom of

Information and get those information from FDA

before you conduct any studies.

DR. KIBBE: Go ahead, Ajaz.

DR. HUSSAIN: I think the question that is

being asked is how do we relate one study finding

to what happened in the previous one. I mean that

is the fundamental question.

We actually don\'t do that. We often don\'t

do that. But I think that is an important point,

and I have tried to look across different ANDA

submissions, especially when Gordon Amidon was at

FDA and we did a lot of the data mining for our BCS

classification, we looked at all that.

I think there is value to that, but often

we find that absolute numbers that you see in terms

237

of percentages is fine, but the absolute values

that you see depends on the assay variability, and

so forth, differences, and so forth.

But I think no matter what you see, one

study, the second study being done to show

bioINequivalence in the first study, there is an

aspect of selecting the thing, and that has been

discussed as Marvin said, profoundly by the father

of biopharmaceutics, Garrett Levy, so that is part

of the systems.

DR. KIBBE: Jurgen.

DR. VENITZ: I have a question on Slide

11\. This is where you were discussing using the

three PK parameters and you are commenting that you

don\'t recommend that because there is not adequate

power. I would like for you to explain that

statement to me.

DR. LI: This criterion to require all

three endpoints to show bioINequivalence, the

bioINequivalence criteria for one single endpoint

is 2-sided 90 percent confidence outside of the

bioequivalence region.

238

So, if you remember our previous talk, we

showed a power of showing bioINequivalence. It is

pretty hard to show bioINequivalence for one

endpoint.

DR. VENITZ: How do you define power?

DR. LI: Power is the probability to show

bioINequivalence if bioINequivalence is true.

DR. VENITZ: So, you are ignoring the fact

that you have a previous study that says the two

products are bioequivalent, in other words, your

power is only defined post hoc after this single

experiment that you are trying to address?

DR. LI: No, the power is not defined by

the experiment. It is a probability which you

don\'t know actually, you do not know.

DR. VENITZ: But you do have prior

information that two products are bioequivalent,

right?

DR. LI: Right, you could have. What has

driven power is how far the bioINequivalence away

from the bioequivalence interval. The further away

from bioequivalence interval, you have back-up

239

power, and also it depends on how many sample size

you use, which is sample size basically reduce the

variability.

DR. VENITZ: But don\'t you then ignore, as

I said before, in your power, the way you define

power, the fact that you have prior information?

You are just basing it on a single experiment. You

already have an accepted study that says those two

products are bioequivalent, and now you are saying,

well, I need more power to show that they are

bioINequivalent. Isn\'t that kind of a

contradiction?

DR. LI: I didn\'t see the contradiction.

What I am trying to explain to you, that to use

three endpoint to show bioINequivalence\--

DR. VENITZ: Is hard.

DR. LI: \--is harder.

DR. VENITZ: Right.

DR. LI: Because the power is lower.

DR. VENITZ: And I am saying you already

have evidence to suggest that they are

bioequivalent, shouldn\'t it be harder.

240

DR. LI: Well, no, if the drug is truly

bioINequivalence, if you design your study

properly, you should have good power to show that,

but if you choose this criteria, you probably won\'t

have good power. You could choose the better

criteria that give you better power.

DR. KIBBE: You are beaten.

DR. VENITZ: Okay.

DR. KIBBE: She is talking about

statistical power of the individual study presented

to her.

DR. VENITZ: I am talking about the

overall power to rule whether something is

bioequivalent or not in the totality of the

information that you have, not just the specific

study, which is what you are talking about. You

are talking about a specific study where you look

at the three parameters individually, you correct

it or all three of them.

DR. YU: I guess, Jurgen, you are

absolutely correct. Actually, we have many, many

debates and discussions, Qian knows that, talk

241

about when the statistic versus you have a prior

knowledge about bioequivalence or bioINequivalence

or quality.

Certainly, what we are trying to address

here is actually, you have five potential options.

One of the options is you have no prior knowledge

whatsoever. That is one of them we have to present

as a complete picture, we are not recommending

this.

One of the options, we say\--all the option

scenario out there, I guess, one of the scenarios,

in your mind, you have a prior knowledge that is

impossible, but for the completion of the picture,

that was presented.

DR. KIBBE: We have got Ken and then Paul,

Nozer, and me, and Marvin.

DR. MORRIS: A quick comment.

Irrespective of whether this is innovator or

generic, I think the fact that you can hand-pick

lots that are this different says more about the

process that is being used to make our products

than it does our testing for bioINequivalence. I

242

think this was Levy\'s point either directly or

indirectly is that it is probably more to the point

that we need to control our processes to the point

where Jurgen\'s observation becomes the rule in a

sense.

DR. KIBBE: Paul.

DR. FACKLER: Part of the problem, I think

is we are trying to do an exact science here where

the whole issue is so variable, it is out of our

control. If we run the same study in the same set

of subjects twice, we will get two different

results, the same drug product, the same people,

and it\'s different.

The variability is just unmanageable, so a

generic company will take a lot of innovator

product and a lot of generic product and run it in

a certain number of subjects, and that number is

calculated to give us 80 percent power. Four out of

five times, those products will statistically

appear to be bioequivalent, and one out of five

times they won\'t, they are not bioequivalent.

It\'s statistics, and we should not spend

243

too much time trying to get an exact measurement

here of what bioequivalence is, nor what

bioINequivalence is. I think the question is

really when is a product not going to perform for

the patient who is taking it, and we have

arbitrarily said 80 to 125 works, and there is some

anecdotal evidence over the last 25 years that the

generic products on the market work.

So, I would just caution the committee to

be careful defining when you would want to pull one

of those products off the market.

DR. KIBBE: Nozer.

DR. SINGPURWALLA: Well, first is I think

you have done a very thorough, detailed analysis

given a badly defined problem. You have done very

well. Thank you.

Now, I am going to comment. I am going to

ask you two questions. You have this AUCt. How do

you pick the t?

DR. LI: The t is the time point that you

can still identify the drug concentration in your

blood.

244

DR. SINGPURWALLA: It\'s the last.

Is it possible that for one t, you will

arrive at one decision, and for another t, you will

arrive at another decision, which goes back to what

Paul has been cautioning us about?

DR. LI: Uh-huh.

DR. SINGPURWALLA: That is one comment.

The last comment is your last viewgraph. When you

say \"recommendations,\" you have three bullets.

When one knows this, you do this. When one know

this, you do this. When one knows this, you do

this.

Well, what do you do when one knows

nothing?

DR. LI: Actually, this is a very good

point. If you see my example, the 3 example, if

you know nothing, actually, Bonferroni correction

give you quite reliable robust power even it is not

the best power for that situation, but it give you

pretty good power, we might recommend this, and

actually, this probably will be the default

approach for us to review if the sponsor didn\'t

245

specify any approach.

DR. SINGPURWALLA: So, maybe you should

put a fourth bullet, if you know nothing, do this.

But now let me go back to the main

discussion that has been spawned by Carol\'s

question. I think both Jurgen and Ajaz have been

dancing around the issue, and not coming out right

and saying what is on their mind.

Basically, what is on their mind is if you

have prior information, which you do have, what do

you do, and really what we should do is not address

the problem in the manner in which this is

addressed. No criticism intended to you of the way

you have done it. You have done it very well.

I think you should formulate this as a

problem in making decisions. You either declare

bioequivalence or you declare non-bioequivalence,

and the declaration of one or the other is a

function of what risks it may entail if you make

the wrong decision, so that takes care of Paul\'s

argument that there is so much variability.

You make decisions in the face of

246

variability, so that would recast this whole

problem, reformulate it, and readdress it. It\'s a

serious issue, because really, what you are all

doing is building a superstructure on something

that is not carefully defined.

Thank you.

DR. KIBBE: Marvin, do you want to jump in

or do you want me to jump in?

DR. MEYER: Well, let me just comment. In

my experience\--and there is probably exceptions

certainly\--if I had to pick a parameter to show

bioINequivalence, I would go with Cmax. That tends

to be a lot more variable, wider confidence limits,

so I think you could probably go a priori with Cmax

and use Strategy I if you wanted to do that.

You are saying if I do that, then, the

confidence limits has to be totally outside of 80

or 125.

DR. LI: Right, yes.

DR. MEYER: Otherwise, you can\'t tell

perhaps.

DR. LI: Yes, it is exactly the picture

247

Lawrence showed you before, and if you feel

uncomfortable, I think there is a second picture

that has failed to show bioINequivalence.

Actually, I would like to come to answer

that question from a statistical point of view.

You like to see, you know, the picture, if the

confidence interval overlap to about bioequivalence

interval, which is the second case.

DR. MEYER: I am really more worried about

means.

DR. LI: The mean is outside the

bioequivalence. Let me tell you about the

statistical concerns. If we claim, be clear, this

is bioINequivalence, then, you end up to make the

error that is a modern FAQ \[ph\] event, which for

statisticians, we do not like to see this happen,

and if you have the confidence interval completely

outside of the bioequivalence interval, then, we

are comfortable that if you would claim this drop

is bioINequivalence, we won\'t make error more than

5 percent.

I know for pregnancy test, you could claim

248

that lady not pregnant, even 51 percent sure, and

you could make a 49 percent error, but for

statistical decision, for regulatory decision, we

cannot make more than 5 percent error. That is why

we define it has to be outside the region.

DR. MEYER: I guess I worry about too much

rigor in that. Let\'s say the point estimate was 60

percent, pretty bad, and the confidence limit,

because of high variability, went over onto 80.2

percent.

You have a bioINequivalent product, there

is no question about it. You are not going to fix

that by anything other than reformulation, but

because of variability, you managed to slop that

righthand tail over above 80.

DR. LI: What if people tell you the study

is conducted using only five subjects, and you see

the point estimate is 60 percent, and you have a

confidence limit, you know, almost everywhere, can

you claim this is bioINequivalence?

DR. MEYER: No, that is why I think you

ought to fix N, too, to avoid that kind of an

249

issue, and maybe even fix the mean must be less

than the mean ratio in the ANDA.

DR. LI: If we fix, that will lead to

stagnation \[?\] of bioequivalence and

bioINequivalence. Maybe we will fix our approach

after the problem is redefined.

DR. YU: I do not see actually any

difference. I personally perfectly understand your

concern. For example, there are two scenarios we

can talk about to this figure, which figure No. 2.

One of the scenarios is point estimate is 79, the

confidence interval is 78 versus 81. Another

scenario is the point estimate is 60, confidence

interval is 40 to 80, for example.

Under these two scenarios, from

statistical perspective, we cannot give you a

definitive answer, however, the first scenario, do

you know the drug. Certainly, we can definitely

use prior knowledge with respect to safety and

efficacy of this drug, and we will make a

scientific decision.

The first case, you might have to think

250

about it, because this drug is still on the market,

you are perfectly okay, and you will make a

scientific decision on the second case. Obviously,

we will not close eyes and say let it go,

definitely not, and chance to be pulled to the top

of the company is high.

Even the first case, we will inform the

company, we will discuss with the company what to

do with that case. Certain case, the probability

to be pulled is higher. I would not say 100

percent definitely as the first case, that

bioINequivalence case, this case, certainly we will

take a look at it and discuss it with our

clinicians within FDA, discuss it with our sponsors

outside of FDA to take a proper action as issues

occur.

I hope this answers your question. Thank

you.

DR. KIBBE: Let me just throw a few random

thoughts in on the table with the intention of

keeping us all past our flights, so everybody

misses their flight.

251

First, if a product has already been

established as bioequivalent, it has been on the

market for a while, and we have a lot of confidence

in the product, then, I think to pull the product

off the market, we have to make a clear and

distinct argument that the product is indeed

failing to live up to the criteria that was

established for it.

It is hard for me to imagine a product

that got on the market with a bioequivalency study

where the mean values were, say, 97 percent or 103

percent of the mean, the innovator, and well within

the confidence interval, and all of a sudden you

are going to find a lot that is going to be a

disaster.

However, it is possible. If that is the

case, then, you have before you two experiments

with opposite results, and in most laboratories

that I have been involved with, when you have two

experiments with opposite results, everybody looks

at each other and says we have got to do it again,

we can\'t just leave it like this.

252

So, no matter what you do as an agency

setting up guideposts for the innovator to come

forward with a bioINequivalency study, I think then

the Agency says thank you very much for a second

piece of information, and we now must resolve the

discrepancy, not by trumping their study with your

study, or trumping your study with their study, but

doing the critical study, which is now the Agency

should go out in the marketplace and buy 100 of

each of the products off the shelf somewhere, maybe

St. Louis, maybe Kansas City, somewhere.

I would be afraid that if we went to

Canada, we would get much higher quality products,

and we want to stay with the quality level here,

and do the third study, and then say, okay, your

company did it with whatever biases that might have

been involved in the selection to get on the

market, and your company did it with whatever

biases or not that you had and to show that it was

off market, and we did it, and now we have the

definitive result, and we have to limit the number

of times you can come forward and do this with us.

253

So, we have done the third study.

Otherwise, I think it is really one of those he

trumps you, and you trump him, and if they come

forward with a bioINequivalency study that seems to

pass the criteria, whatever you pick, and I come

and give you a second bio study with the product

and say, look at that, it really is good, what do

you do?

Let them trump and trump and trump, and I

know the CROs are all saying oh, shut up, let them

do it, because we can do these studies, you know,

once a month, it would be okay, but it is not going

to get you the final answer.

There is a couple of other things that you

might want to keep in the back of your mind. Drugs

which are non-linear, are easy to manipulate.

If you do a study with dilantin at 50

milligrams per patient, and you get a bioequivalent

result where one is just slightly higher than the

other, then, get a group of patients and give them

400 milligrams, and you will run that mean right

off the table, and what would be an insignificant

254

difference at a reasonable therapeutic level would

not be a insignificant difference at an elevated or

above normal therapeutic level.

There is lots of things we can do, so that

if we are going to get into this, I would go with a

nice tight bioINequivalent study, and we can argue

the value of the statistics, but that can\'t be the

end. That absolutely cannot be the stopping point.

That is just one more piece of data, as

Jurgen correctly points out. We already have data,

now we have new data, and to resolve it, we have to

have an impartial arbiter, and the Agency has to do

its own biostuff.

Gordon wants to disagree with me. Go

ahead.

DR. MEYER: Actually, I think that is a

good idea, but I think that given the resources,

that there is no reason that an innovator can\'t be

expected to do a study properly. They will get

inspected on the first one anyway, the first

bioINequivalence study, they can be inspected on

the second one. They are not going to risk their

255

reputation by messing around with the data, so I

don\'t think the Agency, I mean that would be

impractical for the Agency to have to run out and

do a confirmatory study.

DR. YU: We come back the April 14th

discussion, and I think all of us heard Gary made

the presentation back in July that our submissions

this year increased 25 percent, and then we talk

about risk management, we talk about where we put

our resource in, and all we are doing for this

bioINequivalence type is Agency have defined the

criteria for bioequivalence, we want to define the

criteria for bioINequivalence to make a

clarification out there.

That\'s all come back because in the

literature, scientific literature, people tend to

conduct a bioequivalence study, now the confidence

interval is 79 or 126, claim as bioINequivalence.

We say this is not scientifically valid.

So that is the whole purpose is wanting to give a

clear definition with respect to bioequivalence

versus the bioINequivalence, as well as a fail to

256

demonstrate bioequivalence and a fail to

demonstrate bioINequivalence.

Then, from here, you are absolutely

correct, when we see a study like that, if we

cannot\--we are trying to put our resources in the

NDA reviews. Just in case this happened, cannot be

very clear, there is an ambiguity in the gray area,

certainly, Agency will have to put the resource

whether we like it or not. I think we agree.

Thank you.

DR. KIBBE: Go ahead, Gordon.

DR. AMIDON: I am not going to disagree

with you, Art, but the question I have regarding

the scenario where a product is bioequivalent and

on the market, and another company comes in showing

potential bioINequivalencies, has the product

changed.

If we had a good dissolution criteria in

evaluation, we would have some underlying possible

more scientific hypothesis to make rather than run

out and test another set of products.

So, I think it comes down to dissolution.

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DR. KIBBE: Just so you know, bayesian

dissolution.

DR. GLOFF: One quick comment on what

Gordon just said. He said has the product changed,

and my question would be, and if so, which of the

two products has changed. It is not necessarily

just the generic.

MR. BUEHLER: Well, Lawrence made a good

point, and this is a resource issue for us. We

haven\'t gotten that many challenge studies

recently. When we do get them, they are usually

out by, like Lawrence said, a little, 127, 79,

something like that, but the letters that accompany

them are very profound.

They are big public health issues, they

are always presented as huge issues, and, of

course, we have to look at these, we have to

address the issue and resolve the issue because I

agree with Gordon, we don\'t want generic products

out there that are bioINequivalent. That is a

problem for that particular product, it\'s a problem

for the entire industry to have products where the

258

American public can\'t have confidence in those

particular products.

We want to know about those products, and

we want to know when products are truly

bioINequivalent, but we don\'t want to have to deal

with all of these studies that come that are just a

hair out one way or a hair out the other.

We like rules in the Office of Generic

Drugs, and we are sort of bound by our rules, and

however, you know, they are criticized by some

statisticians, we do have our 80 to 125 rule, and

we stick by that very rigidly, and to not do that

would mean a tremendous creep, you know, a

tremendous I think lack of confidence in the

generic process.

Is 79 okay? Well, you know, sure, okay,

79 is okay. But what about 78, what about 77? You

can to down, you can go up, and the next thing you

know, you have a confidence interval you can drive

trucks through.

So, that is why we are very particular

about rules, and in this particular case, you know,

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this is what we are trying to get for

bioINequivalence, is some kind of a rule that

companies won\'t send these in if they know that we

are not going to deal with them.

If they know that our rule is it has got

to be this far out or this far over\--

DR. KIBBE: Let me ask you a question.

The ones that you have gotten, would they have

passed this rule that you are putting\--

DR. YU: The one we have right now\--how

many addition we have? Probably 41 additions

already back and forth, four or five people

involved with the lawyer and the scientist

involved. The case we have, we hope we resolve

very soon, but this case submitted to us back to

\'99, I think, submitted again in 2002, and you can

see how many resources we are putting in, more than

two years already passed.

The issue is this case we are here, the

confidence interval is\--I have got a lower one\--the

top one is 126.

DR. KIBBE: And it\'s Cmax.

260

DR. YU: It\'s Cmax.

DR. KIBBE: So Marvin is right.

DR. YU: Oh, it\'s always Cmax.

DR. KIBBE: Of course, it is. Would this

proposed rule have said upfront that you haven\'t

established your case?

DR. YU: Absolutely, yes. You can see

that, two people for two years.

DR. VENITZ: Can I make an observation and

then give my recommendation? First, I agree with

Nozer, we are trying to squeeze a bayesian problem

into a frequentist scenario, but given the fact

that we have been hearing this time and last time

that those are the rules that have been in effect

for 20-plus years, that we don\'t find people dying

on the streets, or they might be working actually

in terms of providing safe and effective generic

products, you are stuck with the system the way it

is right now.

So, I way I tried to approach it, not

being a statistician, we have a body of evidence to

suggest that the generic and the reference product

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are bioequivalent. That is the reason why it got

approved in the first place.

I assume as part of your review, you are

going to look for things that might have changed,

creep in either the product or the reference

product.

So, now you have a claim being made that

seems to contradict that, and then, in my mind, the

burden of proof is with the person or the

organization that files that claim. So, the burden

of proof to me means that it has to be difficult

for them to overcome what you already know, so I

personally would go with the toughest off your

recommendation, and you have excluded my favorite

one, which is all three of them have to pass:

Cmax, AUCt, and AUCinfinity have to pass, because

that is toughest route.

If you can overcome that, then, I think

you can argue, well, that is about as much evidence

as you need given the fact that you already had

pre-existing bioequivalence. Then, you have enough

to overrule.

262

So, I would recommend what you didn\'t

recommend, that all three parameters, all three

metrics have to pass in order to conclude

bioINequivalence.

DR. KIBBE: What do you recommend, Marvin?

DR. MEYER: I might say I am going to

apologize for not being a statistician\--I once said

pharmaceutical scientists all apologize for not

being statisticians, but statisticians don\'t

apologize for anything. I think that probably

applies here.

DR. KIBBE: I will let you comment on that

later, Nozer.

DR. MEYER: Under Strategy I, Lawrence,

prespecify one of the three PK endpoints, and then

analyze that. Now, if you do a PK study, you are

going to have all three at hand. Why don\'t you

just do Cmax and then do AUC, and then do

AUCinfinity, and look at the data? What is the

problem with doing that?

DR. YU: Let me explain that first, that

the criteria, when we define, statistically

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significant or not, is 5 percent of criteria. If

below 5 percent, statistically significant; above,

it is difficult to say.

For you to not prespecify anything, you

conduct a study, the chance to be wrong is higher

than 5 percent. In fact, change on one slides, I

believe it could be high, like 14 percent.

DR. MEYER: Isn\'t that if you use all

three?

DR. YU: If you use any of three. You

don\'t not prespecify any of them, they are just

looking for one. For examples, these are the

slides, the error rate could be 14.7 percent. If

that is the case, scientific speaking, is too high.

Certainly, scientific speaking will look at a case,

you just present it and make a scientific decision.

DR. MEYER: But if you pick one and pick

the wrong one, you also have a chance of being in

error, which isn\'t in there somewhere.

DR. YU: That is correct. You are

absolutely correct, Marvin. Actually, you

understand very well in my judgment. If you

264

prespecify and if you use AUC, the wrong one, you

could have a probability power. The power could be

5 percent to 90 percent, however, you just said you

have a prior knowledge, so most likely you have

probably picked the correct one.

Now, let\'s put the stack back. Indeed,

there is a company out there. Pick the wrong one,

but even the wrong one you pick, for example, you

pick the Cmax. The case I will talk about is very

theoretical.

You pick up a Cmax, but it end up an AUC,

you show the confidence interval, for example, 60

to 79. This is certainly the case is,

statistically speaking, you do not see, the error

could be a lot higher, but this does not mean we

are going to close eyes, the Agency will not take

an action, probably not, absolutely not.

We certainly will investigate. As we

said, we look at a formulation change for both

innovator and the generic side. We look at all the

scenarios. We will have a bunch of people sitting

in the conference for many hours, probably many

265

meetings, and discuss with many parties and trying

to make the best decision for the public.

DR. MEYER: Let me just say that if you

pick an area under the curve, you are not getting

any information about rate, because area under the

curve can be quite independent of rate.

If you pick Cmax, you are getting

information about rate and amount, and also

information about how different your population is,

and lots of that kind of information, because Cmax

has bounced all over the place especially when Cmax

has also moved around Tmax, and the Tmaxes aren\'t

constant, so your Cmax from one patient is going to

be happening at half an hour, and then the next

patient\'s Cmax is going to be happening at one

hour, and you are going to have lots of fun.

I really think Jurgen is right, that you

need to establish a criteria that looks at all of

the three parameters for bioINequivalency, because

we look at all three parameters for bioequivalency,

and pre-existing information has to be trumped

effectively. I still like the idea of doing a

266

third study.

DR. YU: Thank you.

DR. KIBBE: Nozer, do you want to comment

on his statistics?

DR. SINGPURWALLA: Oh, he was absolutely

brilliant. I am disappointed he went into

pharmacy.

DR. KIBBE: Pat, go ahead.

DR. DeLUCA: In your diagram, Lawrence,

you know, to me, there is only one here that

demonstrates bioequivalence, the others are not

bioequivalent, so however you turned them, the

other four are not bioequivalent.

But the question I would ask, in

determining that the product was bioequivalent, you

need Cmax and area under the curve.

DR. YU: Correct.

DR. DeLUCA: If they came in with just

Cmax or just area under the curve, you wouldn\'t

have approved that as being bioequivalent, is that

right?

DR. YU: Absolutely.

267

DR. DeLUCA: So, if they just had one that

wouldn\'t be, you wouldn\'t approve it if they just

had one. So, I can\'t see why, then, if you are

looking at a product that is bioINequivalent, why

you can\'t just use Cmax.

You can just use one of them to me,

because they had a pass, both of them, at the

start, so if they didn\'t have both of them, they

wouldn\'t have passed bioequivalence, so why isn\'t

one enough? Why isn\'t just Cmax enough to show

bioINequivalence?

DR. KIBBE: Paul.

DR. FACKLER: Just one quick point. The

generic has to pass Cmax, AUC zero to t, and AUC

zero to infinity under fasting conditions, under

fed conditions, and for capsule beaded products,

under sprinkle conditions.

So, for some products, it is nine

parameters that need to pass, for others, it is

six, and for a relatively small group of products,

it is three. I just put that out there for what it

is worth.

268

DR. KIBBE: Marvin.

DR. MEYER: You asked for a

recommendation. In the spirit of harmonization, I

would suggest that Lawrence\'s figure there is

perfect, that under standard conditions, no

monkeying with the confidence limits, not 86, not

three different ones, keep our 80 to 125, 90

percent, and declare the two bottom ones

bioINequivalent, and therefore bad, and therefore

need investigation, and the rest of them are all

either unknown or bioequivalent.

DR. YU: Thank you. That is actually what

we are recommending.

DR. KIBBE: Anybody else want to jump in

on the consensus recommendation wagon?

What do you think, Carol?

DR. GLOFF: I have a question for Marvin.

Do you mean that all three parameters need to fall

outside?

DR. MEYER: No, this could be any of the

three parameters, any one of the three exhibiting

either of the two bottom ones, bioINequivalence.

269

DR. SINGPURWALLA: I would like to make a

comment from mathematics. To disprove a theorem,

all you need is one counter example, so if you want

to show bioINequivalence, all you need is one

violation. If you want to show bioequivalence,

then, you may have to go and do everything else.

Does that rhyme well with your view,

Jurgen?

DR. VENITZ: I am not sure because I still

think that the hurdles that you have to overcome to

get an approved generic on the market, not just

looking at Cmax, I mean the other things as you

have heard, and it may just not be a single Cmax,

it may be other things.

Given the fact that, as you have heard me

talk about earlier this year, the 80 to 125 percent

is really an arbitrary goalpost. I do believe that

the burden of proof should be high for somebody to

get this reversed, to get an approval reversed.

DR. SINGPURWALLA: But the burden of this

proof need not be so high.

DR. VENITZ: Think about what

270

bioequivalence means. It basically means you don\'t

have enough evidence to reject a null hypothesis,

to use statistical lingo. You are basically trying

to prove the impossible. You can never prove that

something is equal. So, you are just bounding.

You are saying, in my mind, I put arbitrary bounds

on, and say, well, as long as it fits those bounds,

we consider it to be bioequivalent.

So, to disprove that, I think you have to

disprove it on all the three metrics, the metrics

that you used in the first place, to get approval.

DR. KIBBE: The argument that you are

making is that because the criteria says that all

three of these parameters have to meet the criteria

to get approval, doesn\'t necessarily mean that we

shouldn\'t require all three to meet the criteria to

get unapproval.

By saying okay, in the original

submission, all they had to do is fail one to not

get approval, that\'s fine, but now we have an

already approved product, and we are doing a test

to show that it is not equivalent, so I would like

271

to see it demonstrated that it is not equivalent on

the same three parameters, and if it can\'t do it on

all three, then, it has failed that test, just like

it would have failed originally to get approval by

failing one of the three, and that is my argument.

DR. SINGPURWALLA: Off the record. To

really look into this issue, it is a much more

serious issue that what meets the eye. There is a

rule that has been set up, and you have to live

with that rule, I agree with you, but what is to

stop the FDA from looking to the future and

changing the rules?

DR. HUSSAIN: I think that point is well

taken, and, Helen, actually that is exactly what my

new instructions were from her, so we will take

this further into discussion, and so forth.

I think this was very valuable, and I am

not fully sure exactly that we have come to a

conclusion on this yet.

DR. KIBBE: Jurgen and I have come to a

conclusion. Marvin\'s conclusion is slightly

variant, but not too much.

272

DR. MEYER: But I am retiring.

DR. YU: I guess that we are back to the

April 14th situation where there is 1 versus 3.

DR. HUSSAIN: Lawrence, I think it is time

to stop the discussion.

DR. KIBBE: I think the Agency has to step

up to the plate. We have given you the best advice

we can.

DR. YU: Okay. Thank you.

DR. KIBBE: I think it is appropriate at

this stage, since my schedule says we are taking a

break, to take a break.

We are breaking 15 minutes early. We will

give you 10 minutes. We expect you back in your

seat at three minutes to 3:00, and at 3 o\'clock, we

will have our discussion about the locally acting

gastrointestinal materials, and we will wrap that

up in short order because Gordon has the exact

answer we need right here.

\[Recess.\]

DR. KIBBE: Ladies and gentlemen, the

clock on the wall says it is three minutes to 3:00,

273

and as it is my tradition, I will remind you to

gather and begin.

We have one more topic area.

Lawrence, are you going to set the topic

up? You have got three minutes.

DR. YU: Yes, I will. Actually, I can

finish within two minutes.

Bioequivalence Testing for Locally Acting

Gastrointestinal Drugs

Topic Introduction

DR. YU: The bioequivalence testing for

locally acting drugs was I think presented to you,

and I saw the comments. Well, today, we are going

to discuss the real issue of bioequivalence testing

for locally acting drugs. I will introduce this

topic, and Gordon from the University of Michigan

will give the talk on Scientific Principles, and

Robert Lionberger from the Office of Generic Drugs

will give you specific examples.

Again, bioequivalence is defined as the

absence in the rate and the extent of drug

absorption.

274

As I said yesterday, the pharmacokinetic

measure for bioequivalence method for systematic

drugs is well understood, well used. We have

pulled many, many products.

The issue remains for locally acting

gastro and GI drugs. The part of reason for that,

because the plasma concentrations may not be

relevant to locally delivery bioequivalence, for

example, a topical, nasal, inhalation, which I

presented to you yesterday.

The point we want to make sure that the

dissolution controls the delivery to the site of

action, whether it\'s the jejunum, jejunal ileum, or

colon. The drug concentrations in plasma are

downstream from the site of action, unlike for

systematic drugs, the drug ending systematic first,

then, get the side effects action, for example,

heart and liver, and so on, the heart and the

brain.

For GI acting drugs, there is no alternate

absorption path because already they have to be

absorbed from the gastrointestinal tract. So,

275

bioequivalence approach the Agency has used, for

example, the clinical study of vancomycin,

pharmacokinetics study is sulfasalazine, the in

vitro study is cholestrylamine.

What we want is want to develop a

scientific basis for the choice of BE method,

bioequivalence method, which we need your input on

role of pharmacokinetic studies, role for in vitro

dissolution studies, role of the clinical studies.

With that short introduction, Mr.

Chairman, I finished it within two minutes, I turn

the podium to Gordie.

DR. KIBBE: Thank you, Lawrence.

Dr. Amidon.

Scientific Principles

DR. AMIDON: Thank you. I am glad we are

recovered from that discussion of statistics. I

know I get glassy-eyed. I think Qian Li did a

great job, and then we turned it into chaos, but

that is our job, I guess.

MR. CLARK: Chaos theory is our goal.

DR. AMIDON: What you received in the

276

handout was the unedited version of my

presentation, because it was done before I knew

what Lawrence and what Rob were doing, so I am

going to skip a lot of the slides that I have

because points are already being made, and talk

about the highlights, the essentials of my point,

and I will give you the executive summary right

now.

First, bioequivalence is the question of

dissolution. What else is it? The same drug in

different products. Once the drug is absorbed, it

is the same except in the unlikely scenario, there

is maybe a competitive metabolism inhibitor or an

excipient that might alter permeability. Evidence

for that is limited in vivo in humans.

So, bioequivalence is a question of

dissolution. That is where the science needs to be

done. So, the bottom line for GI drugs, for all

drugs, is that we should put more emphasis on the

science of dissolution and what I think of as a

bioequivalence dissolution test. So, that is going

to be my bottom line, big picture conclusion.

277

The subconclusion for GI drugs is that I

think what we need is a bioequivalence dissolution

test with some type of in vivo test, perhaps not a

confidence interval test, maybe a point estimate

and an interval requirement, say, between 90 and

110, so that we don\'t have this confidence interval

issue.

You could argue do we need the in vivo

test. I think in some cases, we do not, and

probably we need to go drug by drug for locally

acting drugs, and Rob will talk about specific drug

examples.

One of the issues in setting up a policy

issue is try to be very general, and you get into

trouble because some things aren\'t generalizable

very easily. So, I think we will have to regulate

GI drugs, of which there may be a half a dozen that

are very important, more on a drug-by-drug basis,

or maybe classify them, I don\'t know.

So, that is the bottom line. Dissolution

is what we should be looking at, and a dissolution

test plus an in vivo test, perhaps a point estimate

278

would be enough.

I am going to skip over most of these

slides, because the points are already being made.

The one point that I will make, that I

make all the time, and I think is generally

accepted, at least no one has argued, is that I

think bioequivalence is maybe the single most

important regulatory standard for virtually all

products on the market today.

That is, products on the market today, are

on the market because of either proven or assumed

bioequivalence. If not, what could we say about

the clinical? We have to make that connection, the

connection between the product in the bottle and

the label is bioequivalence.

Yes, of course, we have to have the

potency, the impurities, and we have to have the

standards, but bioequivalence, so this is I think

one of the most important issues in drug regulatory

standards in the world today, because it pertains

to all products. My interest, of course, is in

oral products.

279

There is some caveat in the Orange Book,

just to point out kind of the legal basis. If you

look at where I think the most up-to-date

definition of bioavailability and bioequivalence,

it is in the preface to the Orange Book.

It has been revised periodically over the

years, I think no one has noticed it, because they

slip kind of changes into the Orange Book, it just

comes out, and life goes on. Right? Is that what

you do?

At any rate, for locally acting drugs, it

says, \"Where the above methods are not applicable,

e.g., for drug products that are not intended to be

absorbed into the bloodstream, other in vivo or in

vitro test methods to demonstrate bioequivalence

may be appropriate.\"

That is where we are at here with GI

locally acting drugs.

Again, I am going to skip through these.

You have seen this. Rob is going to use this, so I

am going to skip it, the disconnect for locally

acting drugs.

280

Now, classically, we do Cmax, AUC, of

course, and AUCt, and we have confidence interval

test, but if the levels in blood are very low, we

have a problem, so we have a practical problem.

So, I am going to come back to the

paradigm for bioequivalence. I think of the

paradigm of bioequivalence today as being the

following, starting at the top. Similar plasma

levels, similar pharmacodynamics, similar efficacy

to the label. I mean that is the implication,

similar pharmacodynamics.

Then, similar in vivo dissolution, similar

plasma levels. For oral products, I think maybe

for all products, but certainly for oral products,

similar in vivo dissolution. When we think about

the physiology of oral absorption, the drug

dissolves and is spread along the gastrointestinal

tract and absorbed. We think of absorption as into

the intestinal mucosal cell.

Subsequently, systemic availability is

later, and there is more stuff, drug stuff, you

know, liver in between. That is part of the

281

complication, we are doing bioequivalence based on

plasma levels, which is systemic availability. We

are doing a systemic availability test which is

distant for GI drugs from the site of action.

So, similar in vivo dissolution, similar

plasma levels. So, then, where the science is

today is in vitro dissolution. We need to be more

rigorous in how we do dissolution when we use it

for bioequivalence materials.

We think that there is no reason why we

cannot establish better dissolution methodologies

that reflect the in vivo dissolution process. I

think that would have a number of implications

including accelerating the drug development

process, because when you are making a product and

then testing it in humans, you would like to have a

good idea you are going to succeed.

In order to do that, you have to have a

dissolution test that reflects what is going on in

vivo. So, I think better dissolution can be a big

step in advancing and accelerating drug

development.

282

So, that means doing something. Often now

today, we have what we call biorelevant dissolution

media or biorelevant dissolution. I think we need

to use that term carefully because, you know, to

take some natural surfactants and a little bit of

phospholipid and put it in water and shake, you

either have a drug delivery company or you call it

biorelevant dissolution media, but what is it?

There is no evidence that it is relevant to the in

vivo dissolution process.

So, we need to establish that connection

between the in vitro dissolution methodology and

the in vivo dissolution process, and I think that

is where there is a big gap in our knowledge today,

not just for GI drugs, for all drugs.

So, my point here is broader than just GI

drugs, but similarly, if we had confidence in an in

vitro dissolution test, that is all we need to do.

That is all we need to do. So, we should be

focusing the science on that dissolution test.

I am preaching too much here, so I am

going to skip most of my slides, but I have to show

283

at least an equation. I noticed that on my badge,

they had MA. It took me a while to remember that I

had a Masters in mathematics, and I was impressed.

The FDA is so thorough in their

investigation of my background, you know, every

year I have to fill out all these conflict of

interest things. They actually put MA. That is

the first time that has ever happened, so I have to

compliment the FDA and their thoroughness in

investigating my background. But I did pass, and I

am here.

Anyway, this is the equation of

bioequivalence, but I am not going to talk about

it.

We talk more about the physiology of

gastrointestinal tract and product disintegration,

dissolution, and spreading along the

gastrointestinal tract. That is where the

investigation is. That is where we need to do more

investigation.

Again, I am skipping most of the slides.

So, to kind of come to the conclusion on

284

the bioequivalence for locally acting drugs. I

mean obviously, plasma level is downstream from the

site of clinical effect, which is local. The local

site of action is in the GI tract.

So, dissolution and transit in vivo

controls the presentation of drug to the site of

action. So, this is where plasma levels are

probably less good than a good dissolution test.

Now, we could, with intubation, measure

concentrations along at least part of the

gastrointestinal tract, not easy to do, and, yes,

you have got tubes in, so it is not normal. You

could argue is that feasible.

Now, I think most locally GI drugs are low

permeability, but I now would want to caveat that,

I am not sure that is the case. There is certainly

low systemic availability in general, and that is

probably more the issue, because that makes the in

vivo test plasma levels more difficult to measure.

So, for locally acting drugs, in vivo

dissolution is the key determinant. So, for the in

vitro dissolution test, we should cover the range

285

of in vivo variables.

So, here is the hypothesis. If a product

dissolves, two products could be the same

manufacturer, but they just did some reformulation.

If those two products dissolve at the same rate

under all in vivo conditions, such as pH, 6.5, 7,

7.5, maybe a couple more if you want to be really

rigorous.

That means that the two products will

perform the same regardless of what the pH profile

is in an individual subject. That is what we have

to ensure, and I think we can do that better with

an in vitro test than an in vivo test.

Now, might want to debate do we want to do

6.5, 6.75, you know, but we need to first accept in

principle that a dissolution test is a key crucial,

I would say an essential component of setting a

bioequivalence criteria for a GI drug, because I

think that is the case.

Now, one place we could start is that

biowaivers for Class I drug, if a GI drug is a

Class I drug, high solubility, high permeability,

286

and rapidly dissolving, it is all over, it doesn\'t

matter.

In this case, the GI drug would be low

permeability or certainly low systemic

availability, it may or may not be low

permeability. So, I think that is the equivalent

to extending biowaivers to Class III drugs\--I am

sorry\--that is Class I drugs.

What we are talking about for low

solubility drugs or particularly low permeability

drugs would be extending biowaivers to Class III

drugs, which has been proposed. I don\'t know if

there is any examples, and maybe Rob will talk more

about that.

I think for pH, we want to look at

dissolution as a function of pH. The one product

that I am going to show just some data on, I think

Rob is going to show the same data, so I will be

quick, is mesalamine. It is in enteric coated

dosage form.

The question would be do we need

surfactants or not, and that would depend on the

287

drug, because if the drug is poorly soluble, then,

we get into the spiro-relevant \[ph\] dissolution

media, and that is a bigger question.

So, I think we should require a

dissolution test for bioequivalence in the

bioequivalence criteria for acceptance criteria for

GI drugs, that we need to consider the pH and time

that the drug will spend in the stomach and in the

gastrointestinal tract. I can propose those if you

want to discuss them.

I think what is more important is

accepting or at least advising and recommending to

the FDA that in vitro dissolution testing should be

part of considering the bioequivalence requirement

or testing for a local GI drug.

You would have to use the similarity, you

know, the 10 percent difference or F2 comparison

for dissolution profiles.

The dissolution test actually is a

difficult criteria, I think. Mesalamine, I will

show just a few slides on that, but mesalamine is

an enteric-coated, local acting drug, and are some

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dissolution profiles done by Jennifer Dressman, now

at Frankfort, published in European Journal of

Pharmaceutics and Biopharmaceutics, but here are

different products and simulated gastric fluid.

Here is a pH 6.8. You see, none of the

products would be similar. They all dissolve at a

different rate, and that is a surprise to

development scientists, and these are different

products. I don\'t know if they were approved as

bioequivalent or not actually, but I do not think

they would be bioequivalent in the gastrointestinal

tract even if they were bioequivalent in vivo.

There are some other profiles again

showing that they are quite different. If you

increase the pH to 7.8, more of them become similar

because they all dissolve rapidly above the pH of

the enteric coating. So, if you do a dissolution

at a high enough pH, you can make things look

mostly similar, but at the critical pH where

dissolution is occurring, they would be different.

So, I think that the pH dissolution

profile requiring similar dissolution at, let\'s

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say, in this case we are looking at I think like a

pH of 6.57, 7.0, 7.5, that pH range. We can debate

whether you should do pH 6.0 would be critical.

I am going to skip these because these

questions are already up.

So, what I want to propose that the

committee consider and perhaps recommend to the

FDA, I am not sure, I guess we are going to go

through a list of questions that Rob is going to

discuss, but that we do require in vitro

dissolution as part of our bioequivalence testing

for drugs that are locally acting, and that then

the in vivo test, do we need an in vivo test for

safety purposes, for safety assurance purposes, and

do we need a confidence interval test for in vivo.

I think that may be on a drug-by-drug

basis. You may not want to try and make a decision

for all locally GI drugs. I think depends on the

pharmacology and metabolism of the drug.

But I can say that if had a rigorous

enough in vitro dissolution test, in vivo testing

would not be required.

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That\'s it. Thank you.

Do you want to have questions now?

DR. KIBBE: Shall we do that, because I

think Marvin has a question and so do I. Go ahead.

DR. MEYER: Real quick, Gordie.

Do you think that F2 is an adequate

parameter to use in making a bioequivalence

decision?

DR. AMIDON: The answer is I don\'t know,

Marvin. I have suggested this to a couple of

people, that we need to evaluate that, and whether

F2 or 50, where did that come from, and is it

enough, and the answer is I don\'t know.

I think that the statistics of dissolution

and the dissolution variability that you could

allow, that would keep you within the

bioequivalence 80 to 125. Now, that is not so easy

to answer, and it is going to depend on drug

properties, but I agree, that the F2 or 50 needs

more investigation.

DR. KIBBE: Anybody else? Go ahead, Judy.

DR. BOEHLERT: I finally have a question.

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By making this suggestion that the in

vitro dissolution is a factor, does that presuppose

that the clinical efficacy of this drug only occurs

in a very narrow pH range, so that this pH

difference you see on dissolution is meaningful,

because they could be clinically equivalent or have

the same action, and have different profiles at

different ph\'s because where the drug acts is

across the GI tract, and not just one location.

DR. AMIDON: They could be clinically

equivalent with a different dissolution profile,

but you would have to prove it to me. No one is

going to do that.

DR. BOEHLERT: And how would you do that?

DR. AMIDON: But my answer, I think more

to the point, I think, Judy, is the pH profile

changes through the GI tract, stomach, duodenum,

jejunum, goes 5.5, 6.0, 6.5, and it varies from

subject to subject, and in a fasted/fed state,

during the different Phase I, II, III, of the

fasted/ state.

So, what you want to do is ensure the two

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products will dissolve under any of the pH

conditions that we would see. So, if they dissolve

the same, let\'s say at pH 6.5, 7.0, 7.5, you could

say, well, maybe we should 6.0, maybe 5.5, maybe we

should pretreat for 15 minutes in 10th normal HCL

for a while, pretreat for 2 hours, maybe we should

pretreat at pH 4.0, because that is more like the

average pH in the stomach with food.

So, I think that is more of an issue of

the specific test, and that is going to be a more

elaborate test than our typical so-called

dissolution test.

DR. BOEHLERT: Actually, I guess my only

concern was if, indeed, the drugs were equivalent

at pH 7.8 where it all dissolved at the same rate,

is it really meaningful that it was different at

lower pH\'s.

DR. AMIDON: I would argue that it is,

because the pH in the intestine in humans is more

like around 6.5 to 7.0, and it goes down to 5.0 or

5.5 in the duodenum where you have got the mixing

of gastric acid and pancreatic and bile, so that I

293

would say 7.8 is actually not relevant.

I wouldn\'t do that. The highest I would

go would be about 7.5.

DR. KIBBE: Paul.

DR. FACKLER: If I can just make a couple

of points. First, I agree about the dissolution

and how inappropriate the dissolution we do today

is to certainly the way orally absorbed drugs are

taken. I can\'t remember the last time I saw

somebody drink 900 milliliters of water with their

tablets.

DR. AMIDON: Or even 250 ml.

DR. FACKLER: Or even the 240 or 250 that

we use in the clinics. But let me ask a question.

For systemic drugs, we look at the plasma

concentrations of the compartment just prior to the

site of effect, and for these drugs, we might look

at the plasma compartment as adjacent to the site

of effect just after it, and so in either case, it

might be a good surrogate measurement for the

amount of drug at the site of action in our

traditional case where we have been doing it for 20

294

years, it is just prior to, but for these drugs, we

might consider it just post, and maybe as a

surrogate marker for the amount of drug that was at

the site of action.

DR. AMIDON: I would say the following. I

think that is a good question, Paul, and I thought

some about that. Two things I would say. One is

the drug as it spread along the gastrointestinal

tract, depending on how it is released may be

absorbed in different segments, so the drug might

actually be presented to different sites from

different formulations, and still meet a Cmax and

AUC criteria.

Now, if you were to add in Tmax and/or

some absorption rate measurement in comparison,

then, I would agree with you, it would be

equivalent, but that is complicated. I mean the

FDA has looked into measures of absorption rate

other than Cmax and concluded that there isn\'t

really any good measurement.

So, the answer is if you measured rate and

Tmax and had criteria on that, I would say then

295

plasma would be just the same basically, but if the

drug is very highly metabolized, so the systemic

availability is low, and you are measuring parent,

and assuming there is no problems with metabolite,

which you can\'t assume, then, you have got the

variability issues on the plasma site, so the

plasma site could be a much harder test.

DR. KIBBE: Jurgen.

DR. VENITZ: I think in general I buy the

idea that in vitro dissolution could predict in

vivo dissolution of those products, but you

mentioned kind of in passing excipient effects on

permeability or metabolism. What about food

effects? In other words, food constituents would

considerably at least have the same effects on

either permeability and/or metabolism, which may

affect locally what is going on.

DR. AMIDON: For bioavailability, I would

agree, Jurgen, it would have a big effect

obviously, but for bioequivalence, I would say the

effects would tend to be washed out by the dilution

of the food of any excipient effect.

296

So, I think when we are comparing two

products, the same drug, I would say it is a less

important issue.

DR. KIBBE: Anybody have something because

I have got a whole bunch?

DR. MORRIS: I have just one quick one.

Gordon, were you assuming that this would be done

in the normal dissolution apparatus or is that an

open question?

DR. AMIDON: That is an open question in

my mind, yes.

DR. MORRIS: Because I think there is a

fair amount of concern, hydrodynamic at the very

least, with the current apparati. I just wondered

if you are not restricting it to that.

DR. AMIDON: I guess my position is

changing dissolution apparatus should be done with

great care and with good justification.

DR. MORRIS: Oh, absolutely.

DR. AMIDON: But I believe that a

bioequivalence methodology needs to look at

reflecting in vivo processes, and we should start

297

with that.

DR. MORRIS: I agree with your premise.

DR. KIBBE: I follow up on Ken and go down

a road with a lot of variables in it. I love in

vitro tests if I have control of all the variables,

and when I start losing control of the variables,

then, I start to get worried about the test.

I can imagine two products that have

slightly different excipient compositions who

appear, in a dissolution apparatus, to dissolve

equivalently, but that they aren\'t presenting the

same amount of drug to the surface of the membrane

for one reason or another.

There might be an excipient in there that

forms cells that trap some of the drug, there might

be an excipient that binds the drug, but in a

dissolution apparatus, the excipient is small

enough so that it goes into solution, but then it

doesn\'t allow it to release.

I can imagine interactions between food

substances that are different for this dosage form

versus that dosage form. I mean I really would

298

like to go back to the if you could show me that

both formulations have the same inert or inactive

or excipient ingredients and in the same basic

dosage form, then, I am really happy with

dissolution studies as a mimicker because we are

really looking at the levels of drug in that lumen,

that then gets presented to the surface where it is

supposed to have its effect.

The other thing that I wonder about is if

some of these excipients are permeation enhancers,

than one drug, they both would dissolve the same in

the in vitro dissolution apparatus, but the one

with the permeation enhancer would start to leave

the site where you want it and end up in the blood

supply where you don\'t want it, and you really have

to link that to some marker at the back end to see

how fast it is leaving where I want it to be.

If one gets into the body in this case

better, that\'s worse.

DR. AMIDON: It could be, at least in the

systemic circulation.

DR. KIBBE: So, the questions that I come

299

back to is what is the dissolution apparatus, what

are the criteria that we have to put on the product

to narrow it down, so that we know that the

dissolution apparatus can tell us if the two are

behaving the same before we put it in a person, and

then when we do that, aren\'t we better off still

getting minimalist levels in the plasma just to

look for the odd chance that one of them is

permeating better than the other, so that we can

either prevent levels going up, so that we might

have toxicity in one or the other, or prevent

levels being too low, so that we have some

secondary measure.

Now, if we are going to do that, which one

does a better job of actually measuring the drug at

what I would call the biophase where the drug is

having its real action, and I really think they

both measure it incompletely.

DR. AMIDON: One side and the other. We

have got it sandwiched in between, right?

DR. KIBBE: Right. So, I would argue that

you have to do both somehow.

300

DR. AMIDON: Maybe we need an intermediate

step here to get more experience. So, I could see

where we might require some type of pharmacokinetic

measure, plasma levels, as well as dissolution,

both. That is, I am recommending both.

Now, I believe that when we know enough,

and maybe for some, maybe most, but probably not

all drug products, dissolution would be enough, but

we are not there yet.

DR. KIBBE: I could support that once I

start narrowing down my variables.

DR. AMIDON: So, we get into the

discussions of dissolution, but I mean and I could

throw things out, but it is going to take more than

me to kind of evaluate what might be a good

criteria here and dissolution methodology. I think

what is important at this stage for the committee

is to say, yes, we think this is the right path to

go down and tell the FDA to figure it out, like

Congress does, you know, you go figure out what to

do with bioavailability.

DR. KIBBE: Ken wants to say something

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else.

DR. MORRIS: I have two caveats I guess,

the first of which is that in that dissolution is a

manifestation of the product itself, as we have

discussed, I like that because it is looking at

changes in the product.

But aside from the apparatus issues and

the tactical issues, there is the statistical

sampling issue that we still face with our normal

dissolution testing that I think is probably only

addressed by the consistency that we had hope to

achieve.

DR. AMIDON: Statistics will be here, too.

DR. MORRIS: Yes, sir. I was going to

insult Nozer, but he has left already.

DR. KIBBE: Marvin.

DR. MEYER: Gordie, what do you with the

situation where your in vitro is too

discriminating? You have three different products

and clinically they all work, maybe to different

degrees, but close enough, and yet your dissolution

says there is a 20, 30 percent difference.

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DR. AMIDON: Good question, Marvin. I

have tried when I talk about dissolution and talk

to the dissolution people at the FDA, say do not

use the word discriminating, because that is not

what your job is. Your job is to ensure in vivo

bioavailability.

If the manufacturer wants to be

discriminating because of his quality standards,

that is fine, the manufacturer can do what he wants

as long as he meets the standards that ensure

bioequivalence.

So, I don\'t think the FDA should be

regulating on the basis of discriminating

dissolution tests. I think they should be

regulating on the basis of a test that will ensure

in vivo bioequivalence. I don\'t know if anyone

agrees with me, maybe you do, but I don\'t like the

term discriminating because you can always get

discrimination.

DR. KIBBE: Ajaz wants to say something.

DR. HUSSAIN: Gordon, I think you put

something right on, and that is a challenge. The

303

last several months we have been struggling with

this in a sense. I did share with you my

presentation to the USP meeting, and so forth.

Since we do not have a good handle on variability

because of the calibration issues, and so forth, I

think the tendency has been at the Agency to say,

all right, how do you minimize that.

I want a big difference, so I feel

confidence, and I think the time has changed to say

what is the intended use, and so forth, so I think

the point you made, I don\'t think we have consensus

throughout right now, but it is a very important

point, and I think we have to move in that

direction and sort of discuss and debate that.

DR. KOCH: I just had a quick question

that goes back to some involvement I had maybe over

20 years ago where there was a dog model set up,

and I imagine it could be most animals where they

actually had a trapdoor on his stomach, where you

were able to, in this case, primarily watch

disintegration and subsequent effects by monitoring

plasma levels on dissolution.

304

But is there any development that could be

called pseudo in vivo to check for absorption, not

to do what we are talking about here, but sometimes

there is a question somewhere between the in vitro

and the in vivo?

DR. AMIDON: I think my answer to that

question is no, there is no way to make a step

forward dosage forms. I would say we regularly

test in dogs, recognizing, though, that the average

pH in the upper small intestine of dogs is about 1

pH unit higher than humans, so therefore,

enteric-coated products are not going to be

reflected by the dog.

We do controlled release in the dog, but

we only look at the first 6, 8 hours at most,

because of the shorter transit time, and you have

got to just discard any data after that.

The dog, as I understand, is not

basogastric acid secreter, so the pH in the stomach

is much more variable. So, the answer is I don\'t

think it will do the job for this, and any smaller

animal you can\'t do because you can\'t scale the

305

dosage form down very well, or can\'t at all maybe,

I guess. I mean make an enteric-coated tablet for

the rat and scale it up to humans, you have got

bioequivalence issues again.

DR. KIBBE: The pig is really good.

Meryl?

DR. KAROL: Am I assuming correctly that

the question really is are we going to test for

bioequivalence locally, that includes the pulmonary

tract, as well as the GI tract?

DR. AMIDON: Me, no, I am not ready to go

that step in terms of topical or inhalation

although I could make some case that the principles

apply. The difficulty with topical, for example,

is that you are putting your formulation in direct

contact with the absorbing surface, so the

formulation will affect, let\'s say, the

permeability of the skin.

The big saving grace about the

gastrointestinal tract is there is this big

dilution in the stomach, and that is why I think

the excipient effects are small. I mean we have

306

got this big dilution in the stomach, so all the

excipient effects are diluted out.

DR. KIBBE: We can talk about that.

DR. AMIDON: Inhalation, also, there is

the physics of the dosage form particle size and

deposition along the GI tract, so I am not an

expert at that, so I am not very knowledgeable

about that. This is focused on GI.

DR. KIBBE: Ajaz.

DR. HUSSAIN: I think the other aspect is

if you recall the discussion Rob Lionberger had

presented on topical skin products, there is a

fundamental principle that is evolving, it is

quality by design.

What that means is in a sense, comparing

formulations at anything worth critical and then

trying to relate that to that, and I think the

aspects of excipient similarity, and so forth, a

lot of this formulation information can be

supportive information that can give you all this,

and so forth.

So, I don\'t want to discount that in the

307

sense I think Rob Lionberger\'s presentation on the

topical decision tree had those elements, so in

many ways, I think the proposal for looking at an

in vivo relevant bioequivalence test using in vitro

method is a confirmation of all that similarity or

all the design that sort of comes through.

So, keep that in mind as you think about

it.

DR. KIBBE: Ajaz, that was clearly the

point we get to. Once we get an understanding of

the formulation itself, and can look critically at

what is in there besides the active, then, we are

much more confident in what Gordon is proposing as

a way of measuring what is happening because if we

know there is nothing in there that has a habit of

doing the things that might disrupt it, then, we

are done.

I still think that we are going to find

early on it is going to be very comforting, if you

will, to get some blood levels just to make sure

that there is something that we haven\'t expected

that is happening, but I think we need to go in the

308

direction of dissolution testing. I think that is

a wonderful way to go in a situation.

Anybody else?

We have another presentation, right?

DR. AMIDON: Right. Thank you.

DR. KIBBE: Thank you.

Dr. Lionberger.

Regulatory Implications and Case Studies

DR. LIONBERGER: What I am going to talk

about is just give some examples that are

illustrates of how we apply some of these

scientific principles to several different products

with the intention of sort of spurring discussion

although we have already had some very good

discussion.

The first scientific issue is dissolution,

we are not really going to talk about because you

have had a very good discussion about dissolution.

The second scientific issue that I want

you to keep in mind through my presentation is the

issue of sort of how we should interpret

pharmacokinetic measurements that we make on the GI

309

acting drugs.

Certainly, they are related to safety, but

I also want to just indicate that, you know, you

often hear that the peak pharmacokinetics of

locally acting drugs aren\'t correlated with

therapeutic effect, so I want to sort of focus your

attention on the sort of last point here, on how

the pharmacokinetics of the GI acting drug is

related to formulation performance, and that will

sort of lead into some of the discussion that we

would like to have on how we should use

pharmacokinetic data in evaluating bioequivalence.

So, the first example that I want to talk

about today is for the drug mesalamine. This is an

anti-inflammatory drug mainly targeting the colon.

It turns out that it is actually pretty rapidly

absorbed from the intestine and this drug can be

measured in the plasma. There is also some

extensive metabolism pre-systemic circulation, as

well.

The one thing that is sort of interesting

about this drug is sort of a case study, is that

310

there is a wide variety of formulations of this

drug that are currently on the market, so you can

do a lot of sort of comparisons to see which

different types of tests can actually distinguish

between these different formulations.

The sort of key scientific issue that is

driving these formulations is you want the drug to

target basically the colon, but it is rapidly

absorbed, so the formulation technology is either

pro-drugs or some sort of delayed release enteric

coating are designed to sort of keep the drug from

being absorbed until it reaches the target.

So, this sort of raises the issue of

targeting different areas of the gastrointestinal

tract and some of the issues that that might raise.

The first product is sulfasalazine. This

is the oldest mesalamine product. It is the third

molecule down in the chemical structures, and it is

a pro-drug that consists of mesalamine moiety and

then the other moiety, sulfapyridine.

For this case, the mesalamine acts

locally. The other moiety of the product is

311

actually rapidly and quickly absorbed. So, this

drug is old enough that OGD has actually approved

ANDAs for this product, and the basis for the

bioequivalence determination in this case was

pharmacokinetics, but it was the pharmacokinetics

of the inactive part of the pro-drug, primarily

because it\'s rapidly absorbed and it has much lower

variability than the active moiety itself.

Also, for this drug, the sulfapyridine

itself has pharmacological activity, and there are

also its systemic exposures is highly related to

some of the safety issues with this product.

So, for this product, this moiety was used

primarily because, as we will see later, there is a

high variability associated with the

pharmacokinetics of the active ingredient itself.

So, that is sort of just one example, and

Lawrence sort of pointed these out, that sort of in

the past, FDA, for these GI acting drugs, has used

sort of a wide variety of different ways to

evaluate bioequivalence, and we would like to sort

of put together a sort of more fundamental

312

scientific framework on sort of when we should use

which aspect.

So, a second mesalamine is the Pentasa

product, and this is a slow release, microgranular

formulation, sort of releases continuously through

the intestine. It is not really pH dependent on

how it releases.

During some of the development of the

evaluation of the NDA for this product, there are

PK studies attempted for bioequivalence between

pilot and production scale products. Again, here

the issue was we weren\'t really able to conclude

bioequivalence because of the high variability of

the active ingredient, but they were able to

establish in vitro/in vivo correlation between

dissolution and the pharmacokinetic studies, and

that was used to demonstrate equivalence between

different pilot and production scale formulations

for that particular product.

So, a third mesalamine formulation is the

Asacol product. This is a delayed release, coated

formulation, and here, there is pH sensitive

313

dissolution that allows it to target the colon.

So, when you have all of these different

products, we can look at sort of the different

possible ways of testing these products. The

discussion points that were presented to the

committee were what is the role of dissolution,

pharmacokinetics, clinical studies, so that we can

look at these types of comparative studies between

these different formulations to sort of get at

least some sort of solid basis for discussion.

Gordie in detail showed this data on the

dissolution studies of mesalamine products,

basically different a pH-independent product.

These are mainly European formulations, they are

not the formulations that are marketed in the U.S.

You can definitely see that at the low pH,

you see only the sort of slow release product

dissolving. As you raise the pH, the different

enterically-coated products start to dissolve

depending on what pH they are particularly

targeting.

So, by choosing appropriate dissolution

314

conditions that are relevant to the in vivo

conditions where the product started, and you can

distinguish between the different products and what

region of the intestine they may be targeting.

There is also some studies that have done

comparative pharmacokinetic studies. Again, here

is sort of a pellet and tablet type formulation,

not the sort of currently marketed formulations,

but sort of similar ones.

You see in this case, you look at the Cmax

and AUC. Definitely, in this case, the

pharmacokinetic studies actually show a large

difference between the products, but again, here,

this is just scientific publications for these. It

is small sample sizes, so they didn\'t evaluate

confidence intervals, but the variability of the

measures for these drugs are very high.

So, that sort of complicates the

determination of bioequivalence using

pharmacokinetic measures.

So, with all these different products on

the market, there has been some interest in trying

315

to say which one clinically is more effective. So,

there have been, not complete head-to-head trials

between all products, but there have been a large

number of clinical studies, and sort of a recent

review, came to the conclusion that clinical

studies haven\'t been able to demonstrate

significant differences in the efficacy between

existing mesalamine formulations and stuff, two

examples here, but there are sort of many studies

available in the literature.

So, if you were trying to sort of

determine equivalence between two formulations, you

might have a very hard time using the clinical

study to have a sensitive discrimination of

formulation performance, because these existing

formulations, which use very different

technologies, aren\'t very well distinguished by

sort of clinical studies using the usual efficacy

endpoints.

So, if we just summarize the mesalamine

example, if we want to sort of distinguish the

current products, we would probably yes, if we

316

chose the right dissolution criteria, we could

clearly see the difference between the products.

Pharmacokinetics, it looks like again we

could see the difference especially because if the

products release early, they are rapidly absorbed.

If they are delayed into the colon, then, the

absorption is much slower, so differences in local

release actually do show up in the pharmacokinetics

through especially Cmax for this case.

But again, with this particular product,

there is the issue of pharmacokinetics of highly

variables. If you want to do clinical comparisons

in terms of the bioequivalence study, again, that

would be very challenging in terms of getting a

sensitive test of the formulation differences.

So, just to bring in a slightly different

example, another example of a locally acting

product is Acarbose. This is an intestinal enzyme

inhibitor that acts to reduce glucose absorption.

For this product, there is no measurable

absorption, so you can\'t use pharmacokinetic

studies, however, there are pharmacodynamic

317

endpoints available.

Again, you can look at changes in glucose

or insulin level in response to a meal with the use

of this drug or a comparator product.

Here, one sort of interesting thing to

think about is when we think about the

pharmacokinetic studies, like the pharmacodynamic

endpoints, are usually downstream measures of the

formulation performance, in the same way that the

pharmacokinetic measurements are here. So, there

is some sort of mathematical similarity between how

we might interpret pharmacodynamic endpoints and

pharmacokinetic measurements for GI acting

products.

Another example of a product where there

is not much detectable absorption is

cholestyramine. This is a bile acid sequestrant,

essentially binds to cholesterol in the intestine.

This is sort of an older product. In

1993, FDA guidance recommended using an in vitro

binding assay to demonstrate equivalence of these

products, so there is no dissolution of

318

pharmacokinetics. These assays measured affinity

and capacity.

One of the issues, here, we talked a

little about the role of excipients. For these

types of products that are involved in binding

there, then, you sort of worry that if there is

differences in the excipients in the formulation,

that that might make a difference in how they bind

to other products, and these types of in vitro

binding assays can be valuable and interesting,

those types of concerns if they are relevant to a

particular product.

So, before I lead into our discussion, I

just want to sort of return again to some of the

scientific issues that were raised by the GI acting

drugs.

The first is the BCS classifications and

biowaivers again for systemic drugs. If we have

high permeability and high solubility drugs in

rapidly dissolving dosage forms, we often consider

waiving in vivo bioequivalence studies.

So, the question is how should we extend

319

this to GI acting drugs. I think one more question

is what should the permeability play. If

permeability doesn\'t play any role in the

absorption process, should we extend the biowaivers

to sort of all highly soluble drugs in rapidly

dissolving forms irrespective of what their

permeability is, or is there something about the

classification of drugs in terms of high

permeability, low permeability that may make that

more risky, perhaps interactions with excipients or

the role of absorption in the intestinal tract.

So, that is one of the issues that we

might like to have some discussion on.

Again, I just want to come back to the

issue of the role of pharmacokinetic studies in the

absorption from the GI tract. Again, for a

systemic drug, what you see is that the formulation

performance is what we are really trying to make a

determination about. Again, this essentially is

controlled by the dissolution.

The drug goes through the absorption

process, reaches the plasma concentration, and that

320

is the place where you take a pharmacokinetic

sample, and that is also the place where the effect

of the drug takes place.

So, the difference for a GI acting drug is

essentially the relationship between sort of the

formulation performance, pharmacokinetic sample,

that is still the same, but the only thing that

sort of moved is where the effect is taking place.

If you think about how we conduct

bioequivalence studies, we usually conduct them in

healthy people. We don\'t really concern ourselves

with the effect, so that whatever connection we are

making for systemic drugs between PK sampling and

formulation performance, the connection is still

there for the GI acting drugs.

So, I think the big concern with looking

at the pharmacokinetic studies in the GI acting

drugs is essentially when, for the systemic drugs,

since we know the effect is taking place where we

are taking the sampling, we have some sort of

intrinsic way to know what a significant difference

is.

321

We sort of say 80 to 125 percent

difference in the plasma concentration is sort of a

general definition of clinical significance, so we

know that if we meet that, that sort of gives us an

idea of what equivalent formulation performance is.

When we go to the GI acting case, where

the effect is now separate, we don\'t have that

connection as to what the calibration is between

difference in pharmacokinetic sampling and a

significance clinical effect in the same way that

we do for the systemic drugs, so that I think is

the issue for interpreting the pharmacokinetic

studies is we don\'t have the sort of intrinsic

calibration of how significant the effect on

formulation performance is.

But still the relationship between

formulation performance and pharmacokinetics is

still there in both cases in a way that maybe it is

not for other locally acting drugs, say, inhalation

products where you have the case where if the

product reaches the lungs, it also can be absorbed

by different pathways, and you are not sure that it

322

is passing through the exact same pathway.

For the GI acting drugs, you know that in

both cases, it is being absorbed through the same

site.

Just to lead into sort of the specific

questions that we wanted you to discuss, just sort

of outline, a sort of potential framework for

thinking about bioequivalence of locally acting

drugs, sort of the first point would be again the

sort of critical importance of dissolution testing

in conditions based on understanding of the

formulation and how it interacts with the in vivo

environment, so choosing the right conditions for

in vivo and in vitro dissolution testing.

The second part of that is pharmacokinetic

and pharmacodynamic studies. Again, the sort of

potential we always see for those is really, they

sort of confirm the dissolution testing. They

confirm the relationship between the in vitro

dissolution testing and the in vivo dissolution,

which determines product behavior.

They are also important for assessing

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systemic exposure in terms of any type of safety

concern.

The third element of the framework is

concern about excipient interactions, and if, say,

the product\'s mechanism of action is binding to

like the cholestyramine mean example, binding to

something in the GI tract where an excipient could

be competitive or inhibitory for that binding

process, it might be useful to require some sort of

in vitro assay for that type of process for

particular products if there is a mechanistic

reason why the excipient interaction may be

important.

So, here, I just want to remind you of the

discussion questions that we suggested to you.

We wanted your input on the role of

pharmacokinetic studies, the role of the in vitro

dissolution tests, and the role of clinical studies

in these particular products.

I have sort of listed out sort of slightly

more detailed versions of these questions, you

know, how should we use the pharmacokinetics data,

324

if it\'s measurable, to evaluate formulation

performance? What drug specific information would

be valuable in sort of calibrating our

interpretation of pharmacokinetic studies, when it

would be valuable, when it would not be valuable?

When is it possible to use dissolution

testing alone to demonstrate bioequivalence, and

when do we actually need the confirmatory data from

pharmacokinetic or pharmacodynamic studies, as

well?

When should comparative clinical trials be

conducted, what types of issues there?

The final question on who we should look

at extending the BSC-based biowaivers for GI acting

drugs.

With that, hopefully, we will be able to

have some more discussion on some of these issues.

Committee Discussion and Recommendations

DR. KIBBE: Marvin is ready.

DR. MEYER: Kind of relating to your in

vitro question, are there any drug products that

are known to act locally in an undissolved state,

325

particles, fine particles?

DR. KIBBE: What about Sucralfate?

DR. MEYER: Yes, Sucralfate. Dissolution,

PK, would that work?

DR. LIONBERGER: I think you have to

consider the mechanism of action. I am thinking

primarily here of drugs, you know, where the sort

of mechanism of action is distinct from the

formulation. I think when you have products where

the sort of mechanism of action is very connected

to how the drug is formulated, then, you have to

have some measure of the formulation performance in

vivo.

So, if you were thinking mainly of drugs

where the drug is released from a formulation

before it reaches the site of action, and I think

there are sort of other issues where the

formulation acts, just the formulation or, you

know, manufacturing acts directly.

I think that issue probably will come up a

lot when we look at nanotechnology.

DR. MEYER: I sort of subscribe to

326

Gordie\'s point of view. There is probably a

dissolution test that will work, and I think we

know enough about dissolution testing if we want to

use paddle and basket and three different RPMs and

five different pH\'s, and surfactants, and

everything that anyone has ever done, and two

products are equivalent under a myriad of

conditions, they are probably going to be

bioequivalent. \"Probably\" is not a good regulatory

word.

DR. AMIDON: It would be very low risk of

bioINequivalence.

DR. MEYER: Somebody would argue, well,

that\'s overkill, you shouldn\'t have to do 89.

Well, that is a lot cheaper than doing a clinical

trial with these products, so that might be one

approach.

DR. KIBBE: I think Paul would agree that

it is cheaper than doing a clinical trial.

DR. FACKLER: Could I make a couple

comments?

DR. KIBBE: Oh, please.

327

DR. FACKLER: Just to answer your

question, there are some rectal suspensions that

might fall into the category of drugs that are

effective without dissolving.

My understanding of the lower part of the

colon is that it is relatively water-free, and

these undissolved\-- mesalamine being one of them,

by the way\--products, hydrocortisone is another

one, both of which, by the way, OGD has approved on

the basis of pharmacokinetic comparability.

The other way that mesalamine, for what it

is worth, is delivered to the colon is by

suppository in the United States, I think. So,

there is an oral tablet, there is an oral capsule,

there is a rectal suspension, and a suppository,

all of which are equally efficacious and making you

wonder about the utility of clinical studies. I

will just leave it at that.

DR. KIBBE: That is a valid point. Once

you have lots of different routes of

administration, and for a local effect, and the

formulation effects clearly go away when you look

328

at the clinical impact, but remember that clinical

endpoints are very wide goalposts, and we tend to,

I guess being slightly anal-retentive, want

narrower ones for regulatory purposes.

Just a small point. Most drugs don\'t act

in the central blood supply, they act someplace

else, and even though we measure, we measure

central because we assume, having never actually

verified this, assume that they are in relative

strict proportionality to the amount of molecules

of drug at the actual biophase, and that is the

whole basis for kinetics and what Marvin and I have

done for all our lives, so we are reticent to give

that up, but you can\'t say that that is where the

drug works, because that is not where it is working

either.

DR. KIBBE: Ken.

DR. MORRIS: I just had a question because

I think, Art, actually, you mentioned Sucralfate.

What is the criteria for bioequivalence? That is

not absorbed at all, right?

DR. KIBBE: Right.

329

DR. MORRIS: So, what is the criteria for

bioequivalence for that?

DR. AMIDON: I know originally, they were

doing clinical studies. There were clinical

comparison studies.

DR. MORRIS: It just seemed to me I mean

it would make no sense to do pharmacokinetic

studies on cholestyramine, which never dissolves

even when it is active.

DR. KOCH: Just to add to that, the

cholestyramine is an interesting one, because from

an in vitro type, you can\'t really duplicate the

sequestering. I mean bile acid is just one of the

things that it sequesters it. Basically, it\'s a

handful of ion exchange resin, and ion exchange

resins are trained to go after a lot of things

where it can pick up that ion.

So, that would be a difficult one I think

to just run one simple in vitro test.

Another point that I thought of when we

talked about the suppository, Ajaz, when you go to

Europe, do you do a check in terms of dosage forms,

330

as well, because it was very interesting on a

European assignment, it turns out that more of our

drug deliveries were suppositories than they were

tablets, and someday we will start to see that as

another way of administration, particularly as

dosages get smaller and smaller.

DR. KIBBE: I think suppositories are much

better accepted among the populace in France and

Germany than they are here.

You had a comment.

DR. AMIDON: I worked with the FDA

extensively and did a lot of in vitro testing on

the bile acid resins, with different bile acids

under differing conditions, and so it is a fairly

rigorous test in terms of the capacity of the ion

exchange resins to bind relevant bile salts.

I think if you look at the guidance, you

would look at it and say if two resins appear the

same under all of these conditions, they are

likely, likely, the risk of bioINequivalence is

low.

Of course, the questions in plasma, what

331

are you going to measure? You wanted to do

cholesterol lowering. That is a long, extensive

study, so clinical studies, at least I interpret

here, clinical studies meaning efficacy studies are

much more complicated, much more variable, and I

think quite insensitive to formulation differences.

So, I think we can make an adequate case,

and if you come up with something that you think

might affect the in vivo performance, we can

enumerate what happens in all of the components in

the GI tract, and they can be tested, so we can do

an in vitro test to see if it has an effect and

decide whether it is relevant or not.

DR. YU: I just wanted to comment on

Paul\'s comments for rectal suspensions, especially

for the mesalamines, when we look at the

pharmacokinetics, we also look at a dissolution

very closely. Thank you.

DR. KIBBE: So, you have a whole body of

data then on pre-existing products of varying

formulation, so the Agency actually has a real good

handle on whether or not there are a diversity of

332

excipients and could actually do dissolution

testing on samples of all the products already on

the market in various environments to come up with

a criteria.

DR. YU: That\'s correct.

DR. KIBBE: Anybody else got anything?

Ajaz has a comment. Good.

DR. HUSSAIN: As I think about these

questions, I think Dr. Amidon and Ken Morris both

have pointed out in a sense I think what is in

vitro test conditions and how appropriate they are.

That is a significant challenge.

I don\'t want to sort of jump in and say

all right, BCS Class I was highly soluble, highly

permeable, 900 ml, and so forth, because the volume

and the hydrodynamics, and so forth, I think we

have to give some thought to how we would approach

that, so it is not a trivial matter.

DR. KIBBE: Go ahead, Ken.

DR. MORRIS: I guess I would just echo

that. The principle I think is sound, you know,

which is no surprise coming from Gordon, but the

333

tactical aspects of that really are quite a

challenge. There is still a lot of work to do in

terms of dissolution testing. As Gordon said,

redesigning the dissolution test is no seed for the

faint hearted, I mean that is something that is

going to really take some serious scientific and

engineering work.

DR. MEYER: Is it correct, Gordon, that a

Class I BCS is likely to appear, at least to some

extent, systemically, and a Class III similarly,

maybe not so much so, but still, because of high

solubility, you are likely to have something you

can measure, and therefore, you could do a PK

study?

DR. VENITZ: If it has high first pass

effect, it might not be systemic.

DR. MEYER: That\'s true.

DR. KIBBE: Detectable levels are going to

be a problem.

DR. AMIDON: Class III drugs tend to be

not very highly metabolized, so it would probably

work there, and that is where I think it is the

334

most important, because for a low permeability

drug, there is obviously permeability dependence

along the GI tract, because there is some

absorption, and then it stops. It has to because

it is not fully absorbed. So, I think Class III

drugs is where it is more critical.

DR. MEYER: Therefore, you wouldn\'t need

to give a waiver, you could do PK.

DR. AMIDON: You could. I am not saying

you can\'t do PK. In fact, PK plasma levels in

general, even for GI drugs, I mean if you can

measure something, you know, it would give you the

highest assurance. The question is what is the

best test, and broadly, for bioequivalence, Cmax,

AUC is our gold standard. I think our focus on

Cmax, AUC has kind of preempted us from thinking

about what is the real issues here, which are for

oral absorption and/or, for GI, the GI locally

acting drugs, the dissolution process is where the

action is at, and when we want to set standards,

some drugs are going to be simple and some drugs

are going to be complicated, so let\'s try and

335

decide where we can simplify the standard and make

it maker, and then where it is complicated, well,

that is where science is today.

DR. KIBBE: I agree with Gordon. I think

if you have a lot of background data, we can safely

go to a dissolution test with something like this.

In the absence of it, it is always nice to have a

little bit of PK data, blood level data, maybe a

simplified study just to get a sense for the

levels, because we want to be careful of toxicity

and equivalence, and it is going to be case by

case.

Anybody else? Jurgen.

DR. VENITZ: I was just going to speak and

for being a former clinician, in favor of clinical

studies. I mean everybody here is mentioning a

true statement. They are not very sensitive to

formulation effects, but on the other hand, they

are the ultimate relevant test. I mean they make

what we are doing clinically relevant.

So, as much as I am personally in favor

and moving along with looking at dissolution

336

testing as the base of your surrogate of in vivo

bioequivalence, there is a price to be paid, and

that is, we are going to find differences in those

dissolution tests between formulations that

clinically are irrelevant.

So, we are looking for discriminating

tests\--excuse the term\--that discriminates between

formulation differences that are clinically

probably meaningless.

DR. KIBBE: And the question I guess boils

down to an economic one, do I want to spend the

money to do a clinical test to show obviously that

the differences are meaningless, or can I do a

fairly well designed dissolution test which doesn\'t

cost me much and is very discriminating, and if I

pass that, I am guaranteed that I will be okay on

the clinic, and that is really what these tests

are. These are surrogates for the ultimate use of

the drug in 400,000 people.

DR. VENITZ: We had a similar discussion a

couple of years ago when we talked about intranasal

products, and I guess this committee voted in

337

favor, and the FDA ultimately accepted the fact

that the only way to assess bioequivalence of

intranasal products is the walk in the park, in

other words, a clinical test.

Given the fact from my perspective that I

think we understand much more about GI dissolution,

GI absorption, all of which you presented, Gordon,

I am personally comfortable in moving along with

that, and not making the clinical gold standard a

requirement, but I am just cautioning that in the

process, you are going to throw out formulations

that are clinically probably equivalent.

DR. KIBBE: To ahead, Ajaz.

DR. HUSSAIN: That is one of the reasons,

I think, why we pushed the concept of quality by

design, and so forth, because all the relevant

formulation information and all that has never been

brought into that discussion.

It was simply a test to test comparison

discussion, so over the last several years, we

have brought that discussion up, and then as you go

towards understanding your formulation,

338

understanding what pharmaceutical equivalence could

mean from that perspective, we actually can open

that debate again because of that.

DR. KIBBE: Ken.

DR. MORRIS: Just a quick question,

Jurgen. You are still doing dose-ranging studies

when you are doing the initial development, I

guess, so if you are going to use the prior

knowledge, use the dose-ranging studies, doesn\'t

that help you when it comes time to determine

whether or not the tests are over-discriminating or

not?

DR. VENITZ: But I mean most of the time,

even a two-fold dose range, you may not be able to

distinguish clinically, so you are talking about

100 percent difference in formulation performance,

and clinically, you may not be able to tell the

difference.

DR. KIBBE: Paul has another one.

DR. FACKLER: I just want to correct

something. On the nasal products, the clinical

study is required, but in addition to that, the

339

only way to get a generic product approved is to

also pass a PK study and also pass in vitro plume

geometry and spray pattern.

So, one of those three isn\'t good enough,

two of those three aren\'t good enough, all three

need to pass in order for the nasal products,

which, in my personal opinion, is overkill for

demonstrating that the two products are equivalent.

The clinical study alone should have been enough.

If the patients are being benefited equally, the

products to some extent are bioequivalent.

The other thing I wanted to correct was

just that the variability of mesalamine is

admittedly high, but not so high that it can\'t be

dealt with in a pharmacokinetic sense.

DR. YU: At the last Advisory Committee

meeting, we had a topic on how to deal with highly

variable.

DR. FACKLER: Only that I know there are

some relatively new data on some mesalamine

products available to the Agency, so that the

variability, at least from rectal suspensions, is

340

defined and was manageable in an BE sense.

DR. VENITZ: Just to follow up on that,

you are correct. I mean for the intranasally

administered drugs, they have to pass all three.

What I would like to see for this in terms of the

future progress, would be not to get to that level.

If we accept in vitro dissolution as a surrogate of

in vivo dissolution, as a surrogate of in vivo

bioequivalence, let\'s stick with it.

If you decide that we don\'t

mechanistically understand enough what is going on

and we require clinical study, let\'s stick with the

clinical study.

DR. KIBBE: Thank you, Jurgen.

Anybody else? I see by the clock on the

wall that we are running out of time. Have we

given you enough guidance on this one to move

forward without taking any formal votes? Lawrence

wants some more information.

DR. YU: That\'s correct. Thank you.

DR. KIBBE: He wants to thank me. That\'s

good.

341

I have on my calendar of events that there

is a summary and conclusion, summary remarks, and I

have two names, and they are looking at each other

like which one of you is going to say anything. I

would be happy to just rule you of order and close,

if you don\'t have anything to say.

Go ahead.

Conclusion and Summary Remarks

DR. HUSSAIN: I think again as the

previous meeting, I think the discussions were very

valuable and I think help us think more. The one I

think you probably for the first time got an

opportunity to see the range of laboratory and

other such activities that we have ongoing, and I

think the Critical Path Initiative clearly is not

just lab based, it is much broader than that, but

that discussion allowed us to think more carefully

about how to approach the Critical Path Initiative.

It also helped us to start thinking about

how do you align such programs, especially the

laboratory programs, to be targeted and the key

questions. The challenge is great and I think we

342

want to maintain as many best practices as we have,

and you did see a number of best practices sort of

come out in the discussion, and maintain that, and

bring all the offices in OPS to be aligned

together.

The immediate office project that we

articulated, the three projects, all interrelated,

I think will be a means to not only identify the

best practices, but also to bring a system approach

to address uncertainty and complexity, and I think

that would be the key aspect and in many ways, that

allows us to approach bioequivalence, follow-on

proteins, generic drugs, all of those challenges

next year in a systematic manner.

So, I think in a number of cases, I think

irrespective of what that pathway for these

products might be, the follow-on proteins, the

scientific framework for the decisionmaking process

should be common irrespective of that, and it

should be related to the uncertainty and complexity

of the dosage form set of products that we have.

At the same time, I think you saw an

343

impressive array of laboratory research from

biology to quality, and how do we align that, I

think is a significant challenge. We have sort of

summarized that discussion early this morning, and

the key questions, the metrics, I think will be the

key part for sort of making sure whatever approach

we use is measurable and then quantifiable in terms

of its benefit to the critical path, and so forth.

But I do want to emphasize in the sense

that FDA is only one part of that critical path.

Industry, academia, and other agencies play an

equally important role. Our role will be more also

of coordination, but the need for research,

especially fundamental research in this area and

need for public funding is acute.

I do want to go back and say the

formulation development, manufacturing has been a

neglected area, especially in the U.S., and if you

don\'t bring the focus on that, I think we are

already 10 years behind Europe and Japan in many of

these areas, so we will lost that part of the

industry, so that is important, so seek your help

344

to make that case also.

I think in terms of the gaps going to the

desired state, Helen outlined some of the key

fundamental organizational gaps. Some

reorganization is already occurring. White Oak

provides an opportunity to really bring a team

approach and peer review process to the CMC

function in Office of New Drug Chemistry, but at

the same time, I think one key aspect is a

question-based CMC review process which focuses on

risk.

That is already in the works, but also

support that with tools that we have not often

utilized in this arena, and that is chemometrics

modeling and other aspects of that.

I have a virtual team for chemometrics

right now, but I think we are adding people with

computational fluid dynamics, and others, to really

make a core team that will support the review

function in many aspects.

For example, computational fluid dynamics

is the issue of hydrodynamics, issue of inhalation

345

products, and so forth. So, hopefully, we will

have that team up and running soon.

I think the science gaps are significant

from a training perspective, but those are not, in

my opinion, unsurmountable. I think we have seen,

we have the expertise within the Office of New Drug

Chemistry, Generic Drugs, and so forth. It is

simply identifying and aligning that expertise bear

on some of those challenges, but also provide a

training program for all of our reviewers.

In fact, I really think the PAT training

program opened up a lot of opportunities for our

staff to excel in areas and become leaders

worldwide, and although we cannot do the entire

period, training for all of our staff immediately,

especially the practicum part of it, but as we go

to the next PAT training program, we intend to open

the didactic sessions that we have locally to all

of CMC reviewers to be part of it. So, we will

bring that onboard.

I think Jon outlined for you some of the

directions we will make more in policy. Jon is

346

aggressively moving in that direction and I think

his leadership will help us align. A number of

people have joined his group. He has a group that

is focused on that now.

So, policy alignment and the OPS

Coordinating Committee with Gary Buehler and Keith

Webber co-chairing that, sort of brings all in one

place now to sort of make sure that the policies

that evolve are aligned with where we want to go.

The issue I think I do want to mention,

the issue of two-tiered approach, I think there is

a risk of that, clearly, there is a risk of that,

but I think we will try at least at the draft 3.1

for Q8, at least I felt that the language was

written not to invoke a two-tiered approach. It\'s a

continuum, it will be a challenge to manage, but I

think we will get there.

I am hoping in Yokohama, Japan, starting

November 12th, we will bring Q8 to Step 2. I am

keeping my fingers crossed. As soon as that

happens, I think things will start moving rather

quickly.

347

Pharmaceutical development information is

already coming in. Many companies were willing to

take the first step, and have done so, and the

initial experience is positive, but we will have a

quality system, along with peer review process, to

make sure consistency and proper utilization of

that comes in.

I thin, the other two topics are probably

fresh in our minds. I think bioINequivalence is a

significant challenge, but it is a challenge right

now we are facing to minimize our resources being

spent in things which we think are not value added,

and I think as we move forward, the discussion here

will be helpful.

We will probably not bring that topic back

and we will probably come with an approach, and

then solve that in a way which is consistent with

the way we do it, so I think the discussion will be

helpful, but I still feel, I think Jurgan and

Professor Nozer Singpurwalla, I think we have to

start using prior information, prior knowledge more

effectively, and especially with biostudies that we

348

will have access to, I think it allows us to be

more proactive and make decisions more quickly, so

that Gary and his staff really don\'t have to spend

so much time in answering these questions in a

legal perspective, and so forth.

Locally acting products clearly are part

of the critical path for the generic drugs. It is

not only GI, inhalation, topical, it is an entire

area of research that Lawrence will have to sort of

spearhead and move forward, and that is a critical

path research for generic drugs.

Approval of generic drugs in a timely

manner hinges upon that. I think that PAT concept,

the cGMP, the Quality by Design are all positioned

right to help generics and help innovators all

together, and so you will see that happen.

With dissolution testing, I do want to

sort of say that I think dissolution testing, we

have to think carefully about the variability

aspects of that and how we calibrate. In many ways,

I think our labs have started putting a document

together. They feel that mechanical calibrators

349

and others are sufficient and relying on an

external calibrator of poor quality actually is

diverting attention away and actually creating

problems, unnecessary problems, so we will issue

something on that soon hopefully.

With that, I will hand it over to Helen.

MS. WINKLE: Ajaz did a wonderful job of

recognizing, I think, the contributions that the

committee made. I think there were some excellent

discussion over the last two days and some

excellent recommendations that have been made to us

on things that we need to focus on more and areas

that we need to do more planning and even more

research.

I did also want to mention I thought that

the presentations made by Dr. Boehlert and Dr.

O\'Neill on the two workings groups, the

subcommittee for Dr. Boehlert and the working group

for Dr. O\'Neill, were very beneficial to those

discussions. I think both groups are working hard

to accomplish a lot and to get answers back to us

that are really necessary.

350

The Manufacturing Subcommittee at the last

meeting I thought did an excellent job, and think

their report back to you yesterday was indicative

of how much effort they are putting in to helping

make some of the recommendations that we need to

move forward.

Also, with the Dose Uniformity Working

Group, they, too, have worked very hard during the

year, and I think that the report Bob made was well

accepted by the committee and is a good indication

of how these working groups, too, can be beneficial

to the committee in making recommendations to us in

the future.

I do have some other little things,

though, I want to talk about, and that is the two

people that are leaving the committee. It is a sad

time for us, I think here at FDA, because we have

appreciated both Marv and Art\'s contributions.

They have been very, very significant in helping

direct us at the Agency in the directions that we

really need to go, and they have also provided a

great deal of scientific expertise and knowledge,

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not only on the committee, but in other aspects,

too, and they have been very valuable to us.

The one thing, too, I would like to add is

they have also added a great deal of humor to this

committee, which I think many of us are going to

miss. Now, how long we will miss it is

questionable, because they are both SGEs and can be

called back at anytime\--just like Gordon is over

there shaking his head\--they can be called back at

anytime to participate in different discussions,

and I think that we are probably going to continue

to take advantage of them.

But today, being their last day on the

committee, I do want to present them with these

plaques in recognition of their service to the

Advisory Committee.

The first one is to Dr. Kibbe. Not only

has he been an excellent, excellent member of the

committee, he has also been a very, very

thought-provoking chair even though a little

schizophrenic, I worried about today, when he

thanked himself. But we certainly appreciate all

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your service and everything.

Thank you.

\[Applause.\]

MS. WINKLE: And the other plaque goes to

Marv, and the one thing I want to say about Marv, I

have enjoyed having dinner with Marv in the

evenings. Last night, for you who weren\'t at

dinner, he had this huge, huge plate of food, and

he said, \"It is actually bigger than it looks.\"

He has contributed a lot at this meeting,

and we are going to miss him.

\[Applause.\]

DR. KIBBE: Marvin, would you like to make

a comment, a last shot across the barrel?

DR. MEYER: It took I guess 30 years to

get on this committee, but I have thoroughly

enjoyed it. Everyone around the table brings a

different perspective, and that is what makes it

good for the FDA and fun to be part of.

We have good chairs, Vince Lee, and then

Art Kibbe, and so I would highly recommend this

position for three years to anyone who wishes or

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gets invited to participate. Beyond three years

may be questionable.

So, thank you.

DR. KIBBE: Thank you, Marvin.

I have a whole series of points to make.

First, is that this has been a real joy and an

opportunity to serve and do what I think are useful

things, and to work with people who are dedicated

to having positive outcomes for the American

public.

Most of that, of course, goes, the blame

for how well it turned out goes to Ajaz and Helen,

who lead a great ship and have become close

friends, as well as good working colleagues.

I think we did quite a bit over the years

and I think there is quite a bit more to do, and

the committee needs to move forward, and I would be

happy to help in whatever manner I can.

One of the things that I think you need to

be careful about is that the speed of change is

ever increasing, and like Alice, you are running as

hard as you can just to stay where you are, and to

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get ahead, you have to jump off of that treadmill

and get on a different path.

One thing that I didn\'t mention this

morning that you need to keep in the back of your

mind is that according to the U.S. law, treaty

trumps law. If the Senate and the President want

to sign a treaty with some country that allows for

something to happen, the Food, Drug, and Cosmetic

Act is trumped by the treaty, and whatever rules

and regulations you have, the treaty wins.

Yes, it is absolutely true. Treaty trumps

law, and the President signs it, and the Senate

agrees to it, and the House of Representatives can

complain all they want, and the regulatory agent

have to readjust.

I would love to see the industry take some

of its money that it spends on direct-to-consumer

advertising and put it into, first, getting the

American public to understand how cost effective

drugs are relative to other therapeutic moieties,

because they don\'t understand that, because they

see the bill in front of them and they don\'t see

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the other bills.

The other thing is to get them to

understand that drugs aren\'t safe, and they

shouldn\'t just use them because somebody says it

might be a good deal. I don\'t know whether we can

get the industry to do that, because I know that

the ads are meant to sell things rather than not

sell things, and taking out ads to tell people not

to do things is hard to get them to do, but I would

love to do that.

We need to change the criteria for how we

evaluate who well the FDA is doing. I think there

is way too much pressure on them to produce new

drugs, to produce new reviews, to produce new

things, and I don\'t know what the right

productivity criteria is.

I know we need to change the productivity

criteria for the U.S. Patent Office, that we have

got to stop them from just issuing patents to make

sure they have issued three patents, and give them

credit for not issuing a patent that shouldn\'t be

issued.

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Then, lastly, the goldpost. When you use

science to establish the goldpost for regulatory

approval, you have moving goalposts because science

moves, science progresses, current best thinking is

always better than it was 10 or 15 years ago, and

both the Agency and the industry have to understand

that that is not a threat, that is an opportunity.

I truly have enjoyed myself and I hope

that what little I have done has contributed to

everybody else having a good time.

I think that it is 4:30 and it is an

appropriate time for us to adjourn. If there are

not other dramatic statements that need to be made

by anyone else, I will see you next time maybe.

\[Whereupon, at 4:30 p.m., the meeting was

adjourned.\]

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