1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE

Tuesday, May 7, 2002

8:30 a.m.

5630 Fishers Lane

Rockville, Maryland

P A R T I C I P A N T S

Vincent H.L. Lee, Ph.D. , Acting Chair

Kathleen Reedy, R.D.H., M.S., Executive

Secretary

MEMBERS:

Gloria L. Anderson, Ph.D., Consumer

Representative

Mary J. Berg, Pharm.D.

John Doull, M.D., Ph.D.

Judy P. Boehlert, Ph.D.

William J. Jusko, Ph.D.

Joseph Bloom, Ph.D.

Nair Rodriguez-Hornedo, Ph.D.

Lemuel A. Moye, M.D., Ph.D.

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

Marvin C. Meyer, Ph.D.

Arthur H. Kibbe, Ph.D.

Patrick P. DeLuca, Ph.D.

GUEST PARTICIPANT:

Ian Wilding, Ph.D.

INDUSTRY REPRESENTATIVES:

Leon Shargel, Ph.D. R.Ph.

Efriam Shek, Ph.D.

INDUSTRY GUEST PARTICIPANTS:

Aziz Karim, Ph.D.

Dr. Jack Cook

SGE PARTICIPANT:

Gordon Amidon, Ph.D.

FDA PARTICIPANTS:

Steven Galson, M.D., M.P.H.

Helen N. Winkle

Ajaz Hussain, M.D.

Larry Lesko, Ph.D.

Ameeta Parekh, Ph.D.

Dale Conner, Pharm.D.

Lawrence Yu, Ph.D.

C O N T E N T S

Introductions 4

Conflict of Interest 6

Introduction to Meeting, Dr. Helen Winkle 8

Comments, Steven Galson, M.D., M.P.H. 17

Future Subcommittees:

Introduction and Overview, Ajaz Hussain, Ph.D. 20

Clinical Pharmacology Subcommittee,

Lawrence J. Lesko, Ph.D. 25

Committee Discussion 33

Draft Guidance: Food Effect BE Studies:

Introduction and Overview, Dale Conner, Pharm.D. 49

Science Background and Issues, Ameeta Parekh,

Ph.D. 62

Open Public Hearing:

Brian P. Kearney, Pharm.D. (read by Ms. Reedy) 137

David M. Fox (read by Ms. Reedy) 138

Russell J. Rackley, Generic Pharmaceutical

Association 143

Biopharmaceutics Classification System - Next

Steps:

Introduction and Overview, Lawrence Yu, Ph.D. 160

Presentations:

Gordon Amidon, Ph.D. 161

Jack Cook, Ph.D. 185

Lawrence Yu, Ph.D. 197

Committee Discussion 211

1 P R O C E E D I N G S

2 DR. LEE: Good morning. I am calling this

3 meeting to order. I am Vincent Lee, the acting

4 chair of this committee. It is the Advisory

5 Committee for Pharmaceutical Science. I would like

6 to begin by going around the table and letting the

7 members introduce himself or herself, and we will

8 start with my colleague on my left.

9 Introductions

10 DR. ANDERSON: I am Gloria Anderson,

11 Fuller E. Callaway Professor of Chemistry at Morris

12 Brown College in Atlanta.

13 DR. BLOOM: Joseph Bloom, University of

14 Puerto Rico.

15 DR. VENITZ: Jurgen Venitz, Virginia

16 Commonwealth University.

17 DR. MOYE: Lem Moye, University of Texas.

18 DR. BOEHLERT: Judy Boehlert, consultant

19 to the pharmaceutical industry.

20 DR. RODRIGUEZ-HORNEDO: Nair Rodriguez,

21 professor of pharmaceutical sciences, University of

22 Michigan.

23 DR. SHEK: Efriam Shek, Abbott

24 Laboratories.

25 DR. SHARGEL: Leon Shargel, Eon Labs

1 Manufacturing.

2 DR. WILDING: Ian Wilding, Pharmaceutical

3 Profiles.

4 DR. KARIM: Aziz Karim, Takeda

5 Pharmaceuticals, in Chicago.

6 DR. CONNER: Dale Conner, FDA.

7 DR. GALSON: Steve Galson, FDA.

8 DR. WINKLE: Helen Winkle, FDA.

9 DR. HUSSAIN: Ajaz Hussain, FDA.

10 DR. LESKO: Larry Lesko, clinical

11 pharmacology at FDA.

12 DR. BERG: Mary Berg, College of Pharmacy,

13 University of Iowa.

14 DR. DOULL: John Doull, KU Medical Center.

15 DR. JUSKO: William Jusko, State

16 University of New York at Buffalo.

17 DR. DELUCA: Pat DeLuca, University of

18 Kentucky.

19 DR. MEYER: Marvin Meyer, emeritus

20 professor, University of Tennessee, College of

21 Pharmacy.

22 DR. KIBBE: Art Kibbe, Wilkes University

23 School of Pharmacy.

24 MS. REEDY: Kathleen Reedy, FDA.

25 DR. LEE: Once again, Vincent Lee,

1 University of Southern California. Let me ask the

2 committee members to raise their hand so everybody

3 knows who is on the committee. Thank you very

4 much. I think the committee is wide awake and

5 ready to go. Kathleen, would you please read the

6 conflict of interest?

7 Conflict of Interest

8 MS. REEDY: This is the acknowledgement

9 related to general matters waivers for the Advisory

10 Committee for Pharmaceutical Science for May 7,

11 2002.

12 The Food and Drug Administration has

13 prepared general matters waivers for the following

14 special government employees, Drs. Marvin Meyer,

15 Mary Berg, Judy Boehlert, Vincent Lee, Lemuel Moye,

16 Gordon Amidon and Patrick DeLuca which permit their

17 participation in today's meeting of the Advisory

18 Committee for Pharmaceutical Science.

19 The committee will discuss, one, the

20 current status of, and future plans for the draft

21 FDA guidance entitled guidance for industry,

22 food-effect bioavailability and fed bioequivalence

23 studies: study design, data analysis, and labeling;

24 two, discuss and provide comments on the

25 biopharmaceutics classification system, BCS; and,

1 three, discuss and provide direction for future

2 subcommittees.

3 Unlike issues before a committee in which

4 a particular product is discussed, issues of

5 broader applicability, such as the topic of today's

6 meeting, involve many industrial sponsors and

7 academic institutions.

8 The committee members have been screened

9 for their financial interests as they apply to the

10 general topic at hand. Because general topics

11 impact on so many institutions, it is not prudent

12 to recite all potential conflicts of interest as

13 they apply to each member. FDA acknowledges that

14 there may be potential conflicts of interest, but

15 because of the general nature of the discussion

16 before the committee these potential conflicts are

17 mitigated.

18 We would also like to note for the record

19 that Drs. Leon Shargel of Eon Labs Manufacturing,

20 Efriam Shek of Abbott Laboratories, Thomas Garcia

21 of Pfizer, Tobias Massa of Eli Lilly & Company,

22 Aziz Karim of Takeda Pharmaceuticals North America

23 and Jack Cook of Pfizer Global Research and

24 Development are participating in this meeting as

25 industry representatives, acting on behalf of

1 regulated industry. As such, they have not been

2 screened for any conflicts of interest.

3 In the event that the discussions involve

4 any other products or firms not already on the

5 agenda for which FDA participants have a financial

6 interest, the participants are aware of the need to

7 exclude themselves from such involvement and their

8 exclusion will be noted for the record.

9 With respect to all other participants, we

10 ask in the interest of fairness that they address

11 any current or previous financial involvement with

12 any firm whose product they may wish to comment

13 upon.

14 DR. LEE: Thank you, Kathy. Now I would

15 like to call Helen Winkle, Acting Director of OPS,

16 to introduce the meeting.

17 Introduction to Meeting

18 DR. WINKLE: Good morning, everyone. It

19 is really nice to see everybody here. I think this

20 is one of the few times everyone has actually been

21 in the room and present because normally we have a

22 lot of people on the telephone. So, it is good to

23 have all our members here.

24 I want to welcome everyone to the meeting

25 today, and I think this is really going to be a

1 great opportunity for us to meet with the committee

2 and to discuss what I consider to be a number of

3 really important scientific topics. My job this

4 morning is just basically to give everyone a

5 rundown on the agenda for the next two days, and it

6 is a pretty full agenda but I think there will be a

7 lot of things we can discuss and I think it will be

8 very worthwhile.

9 Today, Dr. Hussain will introduce the

10 Center's proposal for future subcommittees to this

11 advisory committee. As you all know, Dr. Hussain

12 has oversight for the advisory committee, and has

13 been looking at a variety of ways that we might

14 help in making the committee as effective as

15 possible. I think it is very difficult with

16 running this type of committee that is focused on a

17 variety of issues because you have to have a number

18 of different disciplines in the room to discuss the

19 issues, and sometimes it is not as easy to flesh

20 those issues out for presentation to the main

21 committee. So, I think we have been sort of

22 bouncing around ideas internally in OPS for ways in

23 which we can help the committee members in being

24 able to be better prepared to make recommendations.

25 So, Dr. Hussain will talk about our proposal for

1 that.

2 Next, following that discussion, we will

3 discuss two biopharm topics, and Dr. Larry Lesko,

4 who has already introduced himself, from the Office

5 of Clinical Pharmacology and Biopharmaceutics, will

6 lead those discussions. The Office of Clinical

7 Pharmacology and Biopharmaceutics, along with the

8 Office of Generic Drugs, has been sort of grappling

9 with these issues in order to finalize several

10 guidances or to actually, in one case, expand on a

11 guidance. So, we will present those issues today

12 and talk about ways that we can move forward in

13 these two really important areas.

14 The first issue that we will talk about in

15 the biopharm area is regulatory recommendations on

16 bioequivalence studies under fed conditions. In

17 order to facilitate getting the guidance out we

18 have basically two questions which need to be

19 addressed today. One is regarding the waivers of

20 in vivo fed studies for ANDAs for BCS Class I drugs

21 and drug products, and the second is the confidence

22 intervals and criteria to claim between fasted and

23 fed states of new drugs and between fed states for

24 generic drugs. This is an issue that I think will

25 have a lot of discussion with it, and I look

1 forward to hearing that. We want to listen

2 basically to what can be added to this

3 scientifically, to get your feel on this and then

4 we will go back and regroup internally, and decide

5 where we need to go with this guidance.

6 The second topic we want to discuss under

7 the biopharm area is next steps for the

8 biopharmaceutics classification system. The BCS

9 has been discussed here I think on several

10 occasions. Basically, we have a guidance out which

11 is what I would call conservative in those

12 particular products that we allow to come in with

13 waivers under BCS.

14 So, what we want to do today is talk about

15 expanding the BCS; get your thoughts on the

16 expansion of it, and to get some ideas as far as

17 the next steps for justifying the expansion or

18 extension of BCS. We have already come up against

19 some challenges, and I think we would like to talk

20 about how we can handle these challenges as far as

21 BCS in the future.

22 There is already some work going on in

23 PQRI, the Product Quality Research Institute, on

24 expanding BCS and we will share a little of that

25 information and discuss whether that research is

1 actually all that we need to sort of capture where

2 we need to go in our efforts with BCS.

3 As I said, obviously this is a pretty full

4 day. I mean, I think there will be a lot of

5 discussion around these topics. Then, tomorrow we

6 will have several items on the agenda as well. The

7 first thing we are going to talk about is to give

8 you an update on the process analytical

9 technologies, PAT. You all know that we have a

10 subcommittee that was formed. The subcommittee met

11 for the first time in February. I think it was an

12 extremely good meeting and I think a lot came out

13 of that meeting as far as helping us focus on the

14 whole initiative of PAT. Dr. Tom Layloff, who is

15 chairing the subcommittee, will report on that

16 meeting that was held in February. Then, Dr.

17 Hussain will provide a progress report and describe

18 what the next steps are for PAT. Then, we will

19 appreciate your input into those steps and what

20 your thoughts are as far as where we need to go.

21 Of course, this is an extremely exciting

22 subcommittee and the issues I think are really good

23 in helping us focus on what we need to do, and the

24 underlying science for the whole initiative.

25 Also along the same line, at an earlier

1 meeting last year we discussed some of the general

2 issues related to rapid microbial testing.

3 Tomorrow we will update you on those issues. Then

4 we will discuss whether the PAT program can

5 adequately address the issues relating to the

6 introduction of rapid microbial testing.

7 After that we will introduce the topic of

8 blend uniformity again. At the last meeting we

9 talked about the PQRI proposal that was coming out

10 on the PQRI research that is being done, and PQRI

11 has now formally submitted that proposal to the

12 agency, and we are finalizing our decision on

13 whether to incorporate their recommendations into

14 our regulatory scheme. So, we will talk a little

15 bit about that final proposal. We still have some

16 questions we need to address as far as that

17 proposal or recommendations and we will discuss

18 that tomorrow as well.

19 Just to mention one thing along this line,

20 as everyone on the committee knows, we did have a

21 draft guidance that was out on blend uniformity for

22 ANDAs and, because of the fact that we felt that

23 guidance really didn't fit into our current

24 regulatory scheme and with the idea that at least

25 the recommendation from PQRI would stimulate our

1 thoughts and expand what we believe to be our

2 regulatory position, we have withdrawn the

3 guidance, the draft guidance on blend uniformity.

4 So, that makes it sort of necessary for us to move

5 on getting the new guidance out. So, we would

6 really like to get to our final conclusions with

7 your recommendations today and move forward on that

8 because we have a lot of people who, you know, are

9 sort of waiting to hear what the results of our

10 decision is in this area.

11 The last item on the agenda tomorrow will

12 be a discussion of regulatory issues related to

13 polymorphism. Basically, I consider this to be an

14 awareness topic, just to seek your input on maybe

15 the direction we need to go in, and then we will

16 plan a more in-depth discussion at a subsequent

17 meeting on polymorphism.

18 Again, a very full agenda and I look

19 forward to hearing the discussion. I think these

20 are all very, very stimulating scientific topics

21 and it will be very helpful to us as we move ahead

22 in these areas.

23 There are a number of other topics that

24 will be coming up in future meetings, including a

25 follow-up on DPK. I know you all have been dying

1 to hear where we are with DPK. I think what we

2 will talk about the next time we discuss this is

3 basically not only DPK, but to look at other

4 possible methods for determining bioequivalence of

5 topical products. I think at the last advisory

6 committee meeting we talked a lot about DPK and

7 felt that it wasn't completely fleshed out, and

8 that probably we did need to expand our focus as we

9 looked at possibilities for determining

10 bioequivalence. So, I don't think DPK is

11 completely off our agenda for the future, but I

12 think that what we want to focus on is other

13 methodology and discuss that with you. I sort of

14 call it a toolbox of methods that you could use for

15 bioequivalence in this area, and I think it will be

16 important for us to discuss these various methods

17 with the committee in the future. We have put out

18 a Federal Register notice--it should come out any

19 day--which will withdraw the draft guidance on DPK.

20 This is just to touch on future topics,

21 but I would also like to encourage members of the

22 advisory committee to bring possible topics to our

23 attention. I think, obviously, you all are out in

24 the working world every day, dealing with a lot of

25 these scientific issues, and we would be glad to

1 hear your recommendations for possible things we

2 can discuss before the committee. So, if you do

3 have any suggestions, please feel free to share

4 those with Dr. Hussain and myself or with Dr. Lee.

5 Last, before I hand over the meeting to

6 Dr. Hussain, I would like to introduce Dr. Steven

7 Galson. Dr. Galson, who is sitting here, on the

8 end, joined the Center last year as the Deputy

9 Director to Dr. Woodcock. We sort of asked him

10 here this morning because we thought it would be

11 helpful to him to meet the committee and get a feel

12 for the types of issues that we do discuss at this

13 meeting. You know, Dr. Galson is already playing a

14 very important role, despite the short time he has

15 been here, in a number of things that are going on

16 in the Center. Mainly he has been what I consider

17 one of the main forces behind risk management

18 implementation. I have asked Steven to say a few

19 words today to sort of introduce himself and some

20 of the things he has focused on, but what I would

21 like to do is bring him back in the future to talk

22 more about risk management. So, before I give it

23 back to Ajaz, I would like to hear from Dr. Galson

24 for a minute.

25 Comments

1 DR. GALSON: Good morning, everybody. I

2 am really happy to be here. As you have heard, I

3 have just been with CDER about a year, and I want

4 to start out by really just apologizing that it has

5 taken me a whole year to come and say hello to you

6 as a group. The work of our advisory committees is

7 incredibly important and in the Office of

8 Pharmaceutical Sciences, headed by Helen and Ajaz,

9 we really are on the cutting edge science in how it

10 is applied to drug regulation. Without your advice

11 frequently in the year, telling us what you think

12 about changes that we may be making or other policy

13 issues, we really can't stay on top of cutting edge

14 science nationally and internationally. So, the

15 work that you do is really extremely important and

16 we are very, very grateful for the commitment of

17 your time. We know that you all have lots of other

18 things you could be doing. Also, your commitment

19 to public service. It is really important for the

20 agency and really important for the country to have

21 people like you who are willing to commit to us.

22 The state of the Center for Drugs is very

23 good. We have an excellent working relationship

24 with the new administration. We have a new Deputy

25 Commissioner, as I think you know, Dr. Lester

1 Crawford, and we have already been working

2 extremely closely with him and he is very involved

3 in some of our issues, and we have a great

4 relationship.

5 Also, the state of the Center is very good

6 with regards to Congress and our overall funding.

7 I think many of you heard about the Prescription

8 Drug User Fee Act. We have been working hard to

9 negotiate a proposal to extend our user fees with

10 the drug industry over the last few months, the

11 last year really, and this has concluded very

12 successfully. We have sent a proposal to Capitol

13 Hill which we are hoping they are going to act on

14 expeditiously. What this is really going to do is

15 re-authorize and re-fund the user fee program in a

16 way that will help us use our resources in a way to

17 continue to apply the best science in a rapid way

18 to get drugs on the market and to the American

19 people, having a positive impact on public health.

20 So, we are very positive about that. It is a very

21 important thing going on. It will happen in the

22 next year.

23 As Helen said, I would really like to come

24 back at a further meeting and talk to you about

25 many of our initiatives in risk management. This

1 is going to be very important to us, as it is now.

2 Congress and outside groups are very, very

3 interested, some of them quite critical, of how we

4 make decisions about approving drugs and how we

5 make decisions about the degree of risk that we

6 allow in our products and in the way our products

7 are used out there in the real world. So, this is

8 an important initiative and I would like to come

9 back and talk to you about it in general when I can

10 and when there is time on the schedule.

11 I have been generally assisting Dr.

12 Woodcock in running the Center for about six

13 months. After September 11 Dr. Woodcock stepped

14 down and worked on a detail on emergency

15 preparedness in the Commissioner's office so I was

16 actually running the Center on an active basis for

17 about six months, and I got an incredibly intense

18 introduction to what everybody was doing and I

19 think I have a good understanding of the Center

20 now, and am going back now, focusing on initiatives

21 and helping in the general management.

22 So, again, I would like to come back later

23 and meet with you more. I will spend a little time

24 here this morning listening to the beginning of

25 your meeting. Again, thank you for all your time

1 and commitment to being here with us.

2 DR. LEE: Thank you very much. Dr.

3 Hussain?

4 Future Subcommittees

5 Introduction and Overview

6 DR. HUSSAIN: Good morning. At a previous

7 meeting of the Advisory Committee for

8 Pharmaceutical Science we had sort of briefly

9 discussed the need for creating discipline-specific

10 subcommittees under this committee itself. We

11 perceived the need because of the broad scientific

12 disciplines that are under the oversight of OPS. I

13 think we are all familiar with chemistry and

14 biopharmaceutics as the key area but clinical

15 pharmacology is one of the major areas, and I think

16 its importance is increasing tremendously. Also,

17 microbiology. We have a subcommittee on PAT but I

18 think I want to talk to you about other committees

19 that we want to bring under this advisory

20 committee.

21 The thoughts are to keep the Advisory

22 Committee for Pharmaceutical Science broadly

23 focused and have expertise from various disciplines

24 that we need to address issues in OPS. The

25 subcommittees will then essentially focus on more

1 detailed discipline-specific topics for discussion.

2 If I use the example of the PAT

3 subcommittee and what we have learned from that

4 subcommittee, bringing experts with hands-on

5 experience in the areas I think really helps us to

6 identify issues and find solutions quickly and more

7 effectively. In that regard, how do we use the PAT

8 subcommittee? Do we keep the PAT subcommittee or

9 do we do something different?

10 The proposal that I will just discuss

11 briefly, before I call on Dr. Lesko to talk about

12 the clinical pharmacology subcommittee as an

13 example of the new subcommittee structure that we

14 want to present, is to look at PAT as a new

15 technology area but in a sense it addresses issues

16 in manufacturing. Chemistry manufacturing controls

17 is a major part of review activities within the

18 Center for Drugs. But, at the same time, issues

19 related to GMPs, which are equally important, also

20 need to be addressed.

21 Currently, for example, the gaps that

22 exist between review and inspection--there is no

23 mechanism to address some of those gaps. Blend

24 uniformity, that you will talk about tomorrow, is

25 one such example. Was blend uniformity a review

1 issue or was it an inspection issue? I think we

2 will discuss that tomorrow.

3 But the frustration that we sometimes feel

4 because of the organization structures and

5 different roles and responsibilities, it is not

6 often feasible, or we don't have a mechanism to

7 bring issues which are on the boundaries of these

8 organization structures or disciplines to address

9 them more effectively.

10 So, the PAT subcommittee right now is

11 focusing on a very specific charter to address

12 process analytical technologies. That committee

13 essentially could sort of be sunset after its

14 initial assignment is over, and be replaced by a

15 manufacturing subcommittee because manufacturing is

16 a general long-term issue and we need a mechanism

17 for addressing issues with respect to GMPs and

18 review in the area of CMC.

19 We currently don't have any mechanism to

20 have discussion or even analysis of issues that are

21 technical in nature, which are in the area of

22 manufacturing, and how do we do that? So, we are

23 thinking probably that as the PAT subcommittee

24 completes its charter of the assigned task, to

25 sunset that committee and put in the place of that

1 subcommittee on manufacturing. That will bring the

2 Office of Compliance, Office of Pharmaceutical

3 Science and Office of Regulatory Affairs together.

4 So, essentially it would sort of be a team approach

5 from the FDA to bring issues to the subcommittee

6 related to GMPs, manufacturing and so forth. Most

7 of the time, we hope there will be focus on general

8 technical issues that need to be addressed. This

9 committee could then possibly provide a means for

10 addressing technical issues that are not being

11 addressed today.

12 One way of looking at the current

13 situation is that the Center for Drugs is

14 responsible for developing policies, especially in

15 the area of chemistry, manufacturing and controls,

16 but the field has to enforce that. We have

17 internal mechanisms to address that but, from the

18 industry perspective, we don't have a way to

19 address technical issues or disputes which are

20 technical in nature. The only solution right now

21 is to issue a 483 or a warning letter. We want to

22 see whether we can have a subcommittee that can be

23 a mechanism to address some of those issues. So,

24 that is sort of an example of what we could do with

25 respect to manufacturing.

1 Microbiology is a very important

2 discipline. Helen has essentially brought the

3 microbiology review staff to the Office of

4 Pharmaceutical Science level to give them

5 visibility; to give them more recognition in terms

6 of importance; and we are starting to discuss

7 microbiology issues. Would we need a subcommittee

8 on microbiology? I think that is a question that I

9 will leave for now but I think we will have to come

10 back to discuss it.

11 Clinical pharmacology will be the next

12 committee, which probably will be the first

13 subcommittee we will form under this new umbrella.

14 I will ask Larry Lesko to walk you through his

15 proposal of what he thinks the clinical

16 pharmacology subcommittee would do, and how he

17 feels we can constitute that.

18 Following that presentation, I request you

19 to sort of have a general discussion on the concept

20 of this, the subcommittee structure which will be

21 focused on disciplines and what subcommittees do

22 you think would be necessary and what we should

23 move forward with. Our current thought is that the

24 next subcommittee we will form will be the clinical

25 pharmacology, followed by manufacturing by

1 sunsetting PAT and moving that into the

2 manufacturing subcommittee.

3 Pharmacology/toxicology is another idea we have;

4 non-clinical studies subsection. I think how we

5 manage that transition to a more general

6 subcommittee on pharmacology/toxicology will be a

7 subject for discussion later on, and so forth.

8 So, with that introduction, I will ask

9 Larry to present his talk on clinical pharmacology

10 and then we can have a general discussion on this

11 concept. Larry?

12 Clinical Pharmacology Subcommittee

13 DR. LESKO: Thanks, Ajaz. Good morning,

14 everybody.

15 [Slide]

16 You should have in front of you two things

17 that are relevant to my remarks this morning. The

18 first is a one-page proposal for a clinical

19 pharmacology subcommittee and the second is a set

20 of slides that I am going to show to walk you

21 through the steps of the formation of this

22 subcommittee.

23 I like what Dr. Galson said in his

24 introductory remarks. He said that OPS is on the

25 verge of cutting edge science. I think this is

1 really no more true than in clinical pharmacology

2 where we are seeing many rapid developments that

3 can impact drug development to the regulatory

4 processes, and it is because of this that we feel

5 that there is a need to develop this clinical

6 pharmacology subcommittee.

7 [Slide]

8 What we have in mind is a membership that

9 would consist of external recognized and respected

10 experts in the general field of clinical

11 pharmacology. However, we would like to emphasize

12 three specific areas. The first is

13 pharmacometrics, which has certainly been growing

14 rapidly over the last five years; the field of

15 pharmacogenetics and pharmacogenomics, which is an

16 emerging field; and the field of pediatrics.

17 I want to point out that none of these

18 areas are the sole domain of clinical pharmacology,

19 so we anticipate that any issues that come before

20 the clinical pharmacology subcommittee would be

21 issues that we would work on collaboratively with

22 our medical staff and with our biostatisticians

23 within the Center.

24 [Slide]

25 What would be the responsibilities of the

1 subcommittee? Well, we see this as a committee

2 that would advise and counsel us on a broad range

3 of issues and questions from new and emerging areas

4 of clinical pharmacology, specifically to talk

5 about the science and how we might use it or apply

6 it in specific areas relative to regulatory review

7 of INDs or ANDAs and then, further downstream, how

8 we might integrate this new information into

9 research or into regulatory policies that might

10 take the form of, for example, guidances.

11 [Slide]

12 Let's talk about those three areas and

13 explain a little bit more specifically what I mean

14 by those. The first is pharmacometrics.

15 Pharmacometrics encompasses, in our mind, three

16 broad areas. The first is the area of population

17 PK/PD analyses, using samples from clinical trials.

18 The second is modeling of

19 exposure-response relationships, whether they be

20 broadly speaking dose response or more specifically

21 PK/PD. The third is clinical trial simulation.

22 What we see as potential applications of

23 this technology and where we would like to go in

24 working with the subcommittee is to develop

25 standardized approaches using each of these

1 technologies in regulatory decision-making. That

2 is to say, what are the best practices given the

3 current state of knowledge?

4 Secondly, in particular we are interested

5 in developing a standardized approach to adjusting

6 doses in special populations when we see an

7 increase or decrease in exposure as defined by area

8 under the curve or Cmax.

9 Third, we would like to apply this

10 knowledge in a more integrated way in the selection

11 of optimal doses for drug approval and, last, to

12 use clinical trial simulation in the design of

13 Phase III trials to try to focus a little bit more

14 on optimized doses.

15 [Slide]

16 The second area is very exciting. It is

17 the area of pharmacogenetics and pharmacogenomics.

18 We are quite interested in this area because of the

19 rapid increase in the number of NDAs and INDs that

20 contain this type of information. In our Office we

21 recently conducted an informal survey and found

22 that over fifty applications have this type of

23 information in them. Two-thirds of those

24 applications utilize genetic information from the

25 polymorphic aspects of drug metabolism. Many of

1 these applications have come about in the last two

2 years, even though our informal survey covered five

3 years.

4 But some of the things we would like to

5 bring before the committee for discussion include

6 the role of genotyping in the management of risk of

7 previously approved products. We have some very

8 good examples where prospective trials of TPNT

9 polymorphism, for example, has been shown to

10 influence the toxicity of the purine drugs such as

11 6-mercaptopurine. If you look at the label for

12 those products, there is no indication in the

13 dosage or administration section of the label that

14 a physician should utilize these genotypes, which

15 are now becoming widely available, before

16 prescribing the drug.

17 Secondly, we are beginning to sense a

18 development of drug-device combinations where

19 approvals are based on the measurement of genetic

20 markers, oftentimes linked to clinical outcome,

21 utilizing pharmacodynamic measures of one sort or

22 another. An example might be the

23 haplotype-dependent receptor polymorphism that has

24 been reported publicly in the literature and on the

25 web page of certain companies.

1 The third thing we would like to think

2 about in the subcommittee is the study design and

3 analysis of early phase clinical trials. These

4 could be Phase I trials or Phase II trials but

5 basically with the ability to genotype patients as

6 potential entry criteria. It would be worthwhile

7 to talk about enrichment strategies for Phase I and

8 Phase II trials.

9 [Slide]

10 This is a slide of a pediatric study

11 decision tree that we developed in the Center with

12 our other disciplines. I am putting it on here to

13 illustrate a framework which we have used in

14 approving drugs for pediatrics under the

15 exclusivity arrangements that we have.

16 If you look down that tree very carefully

17 you see that many elements of it have to do with

18 clinical pharmacology, whether it is PK studies,

19 whether it is concentration response relationships

20 or PD measurements.

21 [Slide]

22 We have been using this as a general

23 framework but it brings us to the next issue, which

24 is the fact that over the past couple of years we

25 have had a huge number of written requests from

1 sponsors to conduct pediatric trials. As of March

2 1 of this year, we have had 241 written requests

3 which embodied 568 studies and over 33,000

4 pediatric patients. That is not to say that all of

5 these studies have been or will be conducted but

6 they represent the intention of sponsors to gain

7 pediatric drug approval.

8 Where we have seen these types of written

9 requests and, in fact, where we have seen studies

10 conducted, the breakdown of those studies is

11 illustrated on this slide. Notice that efficacy

12 studies represent 34 percent of the studies; safety

13 and PK, 30 percent; safety, 17 percent; and PK/PD,

14 10 percent. The point is that many of these

15 studies rely upon clinical pharmacology to provide

16 the evidence of efficacy or safety in the pediatric

17 population. We see this across all medical

18 divisions, the exception being imaging where we

19 have had not much activity, and that slide gives

20 you a range from 0-45 in cardiorenal.

21 Following that, we have had 56 approved

22 active moieties that have been given exclusivity.

23 We have changed about 30 or 40 drug labels with

24 regard to pediatric dosing. But it brings us to

25 the question that we would like to interact with

1 the subcommittee on, and that is to say what have

2 we learned from all of this?

3 [Slide]

4 What we would like to do in the upcoming

5 months is to do a retrospective characterization of

6 this database on pediatrics, and look at the

7 magnitude of age and body size dependence of PK and

8 PD of the studied drugs, compare those to the adult

9 population and check whether our assumptions going

10 into these studies were accurate or whether they

11 need to be refined. We have a tremendous database

12 here that needs to be looked at very critically,

13 and I think we would like to do that and bring the

14 information to the clinical pharmacology

15 subcommittee.

16 Why would we like to do that? We want to

17 do that because with this experience in hand we

18 could then discuss the general principles that

19 underpin the types of studies that the agency

20 requests for pediatrics, and begin to look at the

21 role of clinical pharmacology studies and whether

22 we should continue with that role or refine it

23 based on the evidence that these studies have

24 provided.

25 [Slide]

1 That is the initial charge of the

2 subcommittee. What we would like to do going

3 forward is to nominate a chair and at least one

4 other member from the current advisory committee,

5 the ACPS; constitute this clinical pharmacology

6 subcommittee with no more than nine members. These

7 would be renewable terms of three years. We hope

8 to meet at least once a year for general briefing

9 on these and other issues. However, we would like

10 to also have the ability to consult on more

11 occasions on specific issues that might relate to

12 the areas I just mentioned. Thank you.

13 Committee Discussion

14 DR. LEE: Thank you, Larry. Ajaz, shall

15 we take questions now or do you have other

16 subcommittees?

17 DR. HUSSAIN: Well, I think the

18 discussion, if you could focus specifically on

19 clinical pharmacology but also broadly on the

20 concept of specific subcommittees.

21 DR. LEE: So, you have no other

22 subcommittees to introduce?

23 DR. HUSSAIN: No.

24 DR. LEE: Any questions for Larry? I

25 think Larry has introduced a very important topic.

1 In fact, maybe I can begin and ask you a question.

2 You identified three topics and those three are

3 pretty diverse, and it would seem unreasonable to

4 have one subcommittee to cover the entire

5 waterfront.

6 DR. LESKO: We thought about that and, you

7 know, at the core each of these topics we have

8 basic principles of clinical pharmacology relating

9 exposure to response. You know, response can be a

10 genetic marker; it could be a pharmacodynamic

11 measure in a pediatric population; and, of course,

12 pharmacometrics is the tool that we would use to

13 analyze that data. So it is a lot like three

14 overlapping circles and I think they have some

15 commonality to them that will allow us to nominate

16 a strong subcommittee group.

17 The other aspect of this is that we would

18 like to take, as I mentioned, nine members of the

19 group and try to identify three or four experts in

20 each one of these areas as lead individuals on the

21 subcommittee so that they can take the discussion

22 based on their specific expertise. So, we kind of

23 think the specific expertise of three or more

24 members in a given area, plus the general

25 background of clinical pharmacology would provide

1 an excellent committee for input.

2 DR. LEE: Thank you. Dr. Doull, you have

3 comments to make?

4 DR. DOULL: Yes, I am delighted to see

5 that you are going to deal with the pediatrics

6 problem. What you are really dealing with is the

7 issue of sensitive populations. As I am sure you

8 know, EPA in regard to pesticides, has well as

9 Congress, has simply established a dose factor of

10 ten in the Food Quality Protection Act for

11 pesticides. It would be a disaster, I think, if we

12 were to do that in the drug area. So, this makes

13 much more sense. You are going to use science to

14 decide in which cases you do need, in fact, a

15 protective factor.

16 But my question is there are lots of other

17 sensitive populations, and how would you deal with

18 those? Add those on? Old folks, diabetics and

19 what-have-you?

20 DR. LESKO: That is a good point. I think

21 the pediatric population is particularly

22 interesting now because we have so much data

23 in-house that we have gained from the pediatric

24 exclusivity situation. That is not to say our

25 other special populations may not be of interest.

1 In fact, we are looking at gender, ethnic origin

2 and other intrinsic factors that define special

3 populations in other settings. But that is not to

4 say this committee's purvey wouldn't include a

5 discussion on, for example, exposure response and

6 dose adjustments in those special populations.

7 I think that is kind of the beauty of the

8 subcommittee. The principles that underlie all

9 these are pretty much the same. How do you bridge

10 data acquired in one setting, for example in an

11 efficacy/safety trial, to a special population

12 whether it be pediatrics, or a population defined

13 by genetics, or a population defined by age or

14 gender. So, I think that is something that we

15 would certainly be open to in the subcommittee. It

16 would depend on the priority and what is going on

17 in other working groups and other committees.

18 DR. LEE: Dr. Berg?

19 DR. BERG: Yes, in regards to gender and

20 the special populations, just so I understand, you

21 would be looking at products already on the market

22 as well as new applications? In other words, what

23 we have on the market and then also new ones in the

24 hopper?

25 DR. LESKO: I think we need to look at

1 both. We certainly have a database of products

2 that are on the market for which information, for

3 example in pediatrics, has been obtained. Ideally,

4 I think we want to look at this information in a

5 more prospective fashion to learn as we are moving

6 forward and I think treat it as a continual

7 refinement of the paradigm for assessing pediatric

8 information and drug dosing.

9 DR. BERG: I know just recently FDA

10 received some appropriations for a database for

11 gender--for the globalization through the Office of

12 Women's Health--

13 DR. LESKO: Right.

14 DR. BERG: I think that is very good for

15 the new products.

16 DR. LESKO: Right.

17 DR. BERG: But looking at the products

18 already out on the market, I know we have been

19 looking at this back in Iowa for about three to

20 four years actually with my students, and literally

21 there still is question with regards to looking at

22 gender analysis and then getting into the question

23 of ethnicity analysis for a database. So, those

24 populations are as sensitive as the pediatric group

25 as well.

1 DR. LESKO: Yes, a lot of the analyses of

2 databases are focused on the numbers, how many have

3 been in clinical trials, as opposed to the results

4 and what has the result signal in terms of need to

5 look at something differently or reassess the way

6 we interpret the data. So, I would see this

7 initiative as really getting into the data in the

8 population and really analyzing it in a systematic

9 way. We have begun to do this in the Office with

10 some projects that the Center has funded. It is

11 not starting out from scratch but it is starting

12 out with a preliminary assessment of the database

13 that I think will be much more quantitative as we

14 move forward, and then use it in a real-time

15 fashion to provide us feedback on how we are

16 approaching these special populations.

17 DR. BERG: Yes, this is really good

18 because it gets back to the push for the GO reports

19 in regards to gender analysis that came out last

20 year. In other words, industry has been recruiting

21 women into studies but there hasn't been a separate

22 analysis. I know there was quite a big to-do last

23 summer in regards to the report. So, this really

24 helps to really push that issue for that subgroup

25 analysis.

1 DR. LESKO: And I think we can go from the

2 specific to the general. I mean, if we look at a

3 class of drugs for which we have had some, say,

4 pediatric approvals or other special populations,

5 what can we say about the class in general so that

6 one might take the next member of that class and

7 perhaps treat it a little bit differently based on

8 what has been learned so far.

9 DR. BERG: Yes, this is a really great

10 start.

11 DR. LEE: Any questions from the other

12 side of the table? Jurgen, any comments?

13 DR. VENITZ: I only want to support that

14 wholeheartedly. I think it is an excellent idea.

15 One of the things I guess I am still unsure about

16 is what is the reporting mechanism in terms of

17 reporting information back from the subcommittee to

18 this committee.

19 DR. LESKO: I don't know if we have a

20 precedent for this or not but, in my mind, what

21 would happen would be that the chair of the

22 clinical pharmacology subcommittee would report

23 back to this committee at least once a year and if

24 this committee met more often and there was a need,

25 more than once a year. But I think the chair of

1 this committee will be very important and that

2 would be the connection between the ACPS and the

3 subcommittee.

4 DR. HUSSAIN: I think that the process

5 would be similar to any other subcommittee. Two

6 members of this committee would be members of the

7 subcommittee and essentially the chair reports

8 back, like, tomorrow Tom Layloff reports back to

9 you for the PAT subcommittee. The subcommittee

10 essentially is advisory to this and decisions

11 essentially are made in this committee.

12 DR. LEE: It seems to me that this

13 committee is rather proactive. Is that what you

14 have in mind? A rather proactive committee

15 identifying new issues?

16 DR. LESKO: You know, knowing the members

17 of this community in clinical pharmacology, I

18 expect it will be very proactive and we will be

19 too. We have some issues in mind that we want to

20 start with so I think that is important.

21 DR. LEE: What about the issue of life

22 style?

23 DR. LESKO: Well, that is an interesting

24 issue. I haven't thought of it in the context of

25 this particular subcommittee but I am sure you are

1 leading up to another comment.

2 DR. LEE: If you have a global community

3 and all this kind of stuff, I think it is very

4 exciting and I will be very interested to see how

5 this subcommittee will evolve because in my

6 estimation it will probably work rather closely

7 with your Office as well. Isn't that true?

8 DR. LESKO: That is what I expect will

9 happen but, again, there will be other disciplines

10 involved with this as well like, for example, if we

11 start out with the drug safety group there will be

12 multiple disciplines involved.

13 DR. LEE: Dr. Doull?

14 DR. DOULL: I think the only thing that

15 still concerns me is that it seems to me that you

16 are going to be right in the middle of the area of

17 risk management in a sense when you deal with

18 sensitive populations, and somehow the decisions

19 that we make in clinical pharmacology are going to

20 have some really broad implications in terms of

21 risk management. I guess somehow one needs to

22 coordinate so that you don't get crosswise in this

23 subcommittee with, say, a policy that affects risk

24 management for the agency as a whole, food and

25 devices and all that.

1 DR. LESKO: That is a good point. I mean,

2 risk management in the Center, as we think about

3 it, is really not one-dimensional by any means.

4 Any risk management strategy has had multiple

5 dimensions and sometimes is pretty complex.

6 I think working with Dr. Galson and others

7 at the Center level on various risk management

8 approaches, this is going to be a piece of the

9 puzzle but I think it is an important piece that we

10 need to look at and integrate with other pieces of

11 information. I can see the information being

12 learned from this exercise going on to become part

13 of other risk management plans that are being put

14 in place. Maybe it will lead to a more systematic

15 approach to risk management that I think the Center

16 would like to get to.

17 DR. GALSON: Just one comment on that, I

18 think that is an excellent point but it shouldn't

19 be a cause of worry really because there isn't any

20 other advisory committee that is working on this

21 particular angle. We do need to put it all

22 together. There aren't any other advisory

23 committees with the expertise of this one that is

24 being discussed that will be dealing with this

25 specific issue. So, we will really count on what

1 is coming out of this group in figuring out what

2 direction to go in for the whole Center. But

3 coordination is very important.

4 DR. LEE: Any other comments? Efriam?

5 DR. SHEK: I have more general comments

6 with regard to the characteristics of the

7 subcommittees. If you take the PAT example, it

8 looks like it was a specific task, an assignment to

9 look at that. Now this committee, it looks like it

10 is a more standing committee which will be a

11 permanent, let's say, subcommittee. The same thing

12 may be for toxicology and safety.

13 When we bring up the manufacturing the

14 issue is should we consider broadly if that is

15 going to be permanent for the whole area of CMC? I

16 believe we, in industry, realize that CMC is an

17 umbrella. We cannot just look at drug product

18 manufacturing; we have to look at the drug

19 substance; we have to look at the QC. Everything

20 is tied together, and whether we should consider

21 broadening it to CMC type of a subcommittee.

22 DR. HUSSAIN: That is a good point. What

23 we will plan to do is bring a proposal, like Larry

24 did, on the manufacturing committee and its makeup

25 at the next meeting. The thought process is to not

1 only discuss CMC from the review side, but bring

2 and invite Office of Compliance and our Office of

3 Regulatory Affairs to be partners with us on that.

4 So, it will be a whole umbrella of all CMC and

5 manufacturing issues in sort of one direction. So,

6 we will flesh out the proposal and bring that to

7 you next time.

8 DR. LEE: Other comments? Larry, I think

9 you have touched on a topic that is quite

10 interesting so I have another question. What about

11 geriatrics? People like me?

12 DR. LESKO: You have about ten more years

13 before you worry about that! That was probably the

14 first ever "special population" that the agency

15 looked at back in 1983 or '84, '85, and we do have

16 things in place that direct a sponsor to look at

17 age on the high side, specifically within a

18 clinical trial, along with race and gender.

19 Again, I am not excluding that from the

20 domain of this subcommittee but I would say at the

21 moment it is not a high priority, based on where we

22 are with other policies in place with respect to

23 the elderly. We usually have a pretty nice

24 assessment of that within the clinical pharmacology

25 database and look at it quite routinely for any

1 need of dose adjustment.

2 DR. LEE: Thank you.

3 DR. MEYER: Would you be more politically

4 correct if you said pediatrics and other special

5 populations?

6 DR. LESKO: I think that would be a good

7 idea. It would really encompass a lot of the

8 comments that the committee members made and

9 signalled that other things can be brought before

10 the committee. So, I would be in favor of that

11 change, sure.

12 DR. LEE: Bill?

13 DR. JUSKO: I have a very strong

14 endorsement of this plan and commend you for doing

15 it. I imagine the committee membership will be

16 somewhat like this one with independent consultants

17 of sorts, as opposed to having representatives of

18 scientific organizations?

19 DR. LESKO: That is correct. I envision

20 the committee as being one of expertise based on

21 the science and the clinical experience as opposed

22 to organizational dependence, for the reasons that

23 we have indicated the reasons for the subcommittee

24 are.

25 DR. LEE: Ajaz?

1 DR. HUSSAIN: The plan is to move forward

2 and actually hold the first meeting of the

3 subcommittee to coincide with the next meeting of

4 this committee. I think Larry has already looked

5 at individuals he wants to be on this committee,

6 and I think after this meeting we will be moving

7 forward, contacting them and actually putting the

8 subcommittee together.

9 DR. LEE: I am delighted to see this topic

10 on the agenda. I think it is good to have a

11 somewhat formalized system of subcommittees working

12 with this full committee and also with the Office

13 so that there will be tighter integration and

14 continuity and a sense of progressiveness.

15 Are there other questions before we let

16 Dr. Lesko off the podium? If not, we are doing

17 very well. Thank you, Larry.

18 DR. LESKO: Thank you.

19 DR. LEE: Yes?

20 DR. HUSSAIN: One question would be since

21 the thought process is clinical pharmacology,

22 followed by manufacturing, pharm tox and

23 microbiology are on the tabl, does the committee

24 have any thoughts on what the priority should be

25 with respect to the next few committees? Clinical

1 pharmacology, we thought, was the highest priority

2 committee to move forward. What do you thing the

3 other priority should be for the rest of the

4 disciplines?

5 DR. LEE: Shall we turn to the industry

6 representatives?

7 DR. SHARGEL: I would think manufacturing,

8 from my perspective. I don't know if Efriam would

9 agree.

10 DR. SHEK: Yes, I think as you raised the

11 thing with regard to compliance and GMP issues,

12 there are a lot of activities going on there.

13 DR. BOEHLERT: I would agree with the

14 manufacturing, and I also would suggest that you

15 broaden the area to include things like product

16 development because they are all tied together. It

17 is not just manufacturing of a finished product, an

18 active ingredient or the control but product

19 development is definitely tied in, as we found with

20 PAT. That is a very important part of the process.

21 DR. LEE: Well, it looks like the

22 committee is fairly quiet this morning. We are

23 ahead of schedule. Shall we take a break?

24 DR. HUSSAIN: Yes, we could and then we

25 can get started with the next part.

1 DR. LEE: All right. Let's come back at

2 about, shall we say, 9:35? Thank you.

3 [Brief recess]

4 DR. LEE: I have been asked about why I

5 didn't get a conversation going before the break

6 because I do know that we have some substantive

7 issues we need to talk about for the rest of the

8 day. Kathy whispered in my ear that she new

9 something about the difference between a

10 subcommittee and a committee, and I thought it

11 would be very useful for us to hear what the

12 regulation has to say.

13 MS. REEDY: The structure is codified in

14 FACA, the Federal Advisory Committee Act, for

15 subcommittees and their relationship to parent

16 committees and 21 CFR Part 14 delineates the report

17 system, and it is as was described. So, it is

18 codified.

19 DR. LEE: In other words, we cannot do

20 whatever we want.

21 [Laughter]

22 Now we are going to the next agenda item,

23 which is on draft guidance, food effect BE studies.

24 You all have the agenda, and i would like to invite

25 Dale Conner to introduce the topic.

1 Draft Guidances: Food Effect BE Studies

2 DR. CONNER: Good morning. First off,

3 before I start I would like to thank Drs. Ian

4 Wilding and Aziz Karim who have graciously come

5 here to help us and the committee out. They are

6 both experts who have worked in this area before,

7 and the committee can call on them for opinions in

8 this particular area and I am sure they will have

9 some interesting things to say, perhaps not all

10 agreeing with me but that is what makes it

11 interesting.

12 [Slide]

13 It is my job today to introduce this

14 topic, and then Dr. Ameeta Parekh will do the bulk

15 of the work by actually showing the data and some

16 of the thinking in that regard. I am going to try

17 and give some background on this because one of the

18 issues I found, even among the experts, is when you

19 talk about--most of this topic is about

20 bioequivalence and people often get confused and

21 they sometimes mix up issues that are pertinent to

22 bioavailability to those of bioequivalence.

23 Sometimes the issues and the endpoints in what you

24 are trying to accomplish are quite different. So

25 in the next couple of slides you are going to see

1 quite a bit of information comparing BA and BE,

2 bioavailability and bioequivalence, and that is

3 mainly to try and introduce those topics to make

4 sure that we keep each one straight and separate.

5 As my slide says, this is based on

6 discussions of a portion of the new FDA proposed

7 draft guidance. You will note from the slide that

8 this replaces another draft guidance that was out

9 for quite a few years, and has some substantial

10 changes over that original. Larry keeps correcting

11 me but I would say that we have been working on

12 this draft guidance anywhere from about 7 years to

13 12 years, depending on how you count it. When you

14 look at the guidance you are amazed that it took us

15 so long. However, it has proven to be a very

16 difficult enterprise and has gone to a lot of

17 iterations, but I think that we, at least the

18 authors, are content that this is something that

19 was worthy to go out and be discussed in the

20 public.

21 That is, indeed, what we did. The draft

22 guidance was issued in October, 2001 and went

23 through a comment period. We received comments

24 back and basically some of the issues we have

25 before you today are based on those comments. We

1 will talk about what those issues are.

2 [Slide]

3 Basically, I have started off by saying

4 why do we do these studies? Why do we do

5 bioavailability studies and why do we do

6 bioequivalence studies, and what is the nature of

7 the studies? Basically, the bioavailability

8 studies are mostly done in NDA type of efforts, IND

9 or NDA. They attempt to be descriptive and to

10 understand how the drug substance and also the drug

11 product, the formulation, behaves; how it is

12 absorbed, over what time course; what factors

13 affect that absorption; and also the interaction of

14 the drug substance with whatever proposed

15 formulation is made. So, the BA part is very much

16 new drugs or an NDA type of question of how does

17 this work. How does the drug behave? And, how do

18 formulations effects affect that knowledge?

19 When we get to bioequivalence it is

20 somewhat different in that, at least if you look at

21 the way we do generic drugs or pharmaceutically

22 equivalent products, the drug substance is the

23 same. So, the BA part is merely a comparison of

24 two formulations. If it is a generic drug type of

25 situation, an NDA type of situation, the

1 formulations are pharmaceutically equivalent. So,

2 if you have an immediate release tablet you are

3 comparing it against an immediate release tablet.

4 If it is a solution, it is against a solution. If

5 it is a suppository, it is against a suppository

6 and they contain the exact same amount of drug

7 substance. So, the comparison is entirely on how

8 that formulation performs. That is basically what

9 I have said here.

10 What we are interested in is, is there a

11 differential effect in this particular case, when

12 we talk about food studies, of food on the

13 formulation compared. That is not the same

14 question you would ask early on in the BA, is there

15 a food effect? It is a question of is the food

16 effect different between the two formulations. So,

17 we are looking either for a differential food

18 effect of a lack of a differential food effect. In

19 other words, are they equivalent in the fed state?

20 This can be a direct effect of food on the

21 formulations or it can be based on physiologic

22 effects because, as we all know, food has very

23 significant physiologic effects on the GI tract and

24 a number of other systems as well.

25 So just to keep it in perspective, when we

1 are talking about BE, and a lot of these issues and

2 discussions that we are going to talk about are

3 more about bioequivalence issues than

4 bioavailability, keep in mind that it is strictly a

5 formulation question or a comparison of two

6 formulations containing the exact same drug

7 substance.

8 [Slide]

9 I have expanded the first part into a

10 series of questions, and these might be termed

11 questions either the FDA asked, or a sponsor, or

12 someone who is trying to develop a drug or drug

13 product to answer the questions or points that I

14 brought up originally.

15 First I am going to go over the BA or the

16 bioavailability. The first one is does the food

17 affect the drug substance? It is really a question

18 of is there some property of that drug substance

19 whose bioavailability or pharmacokinetics is

20 affected by food? That almost says that that

21 effect is going to occur within reason, no matter

22 what formulation I put it in. It is just simply a

23 property of the drug substance.

24 Furthermore, does food affect the

25 formulation performance? When I use the term

1 formulation performance, I mean how that

2 formulation--that tablet, that capsule, that

3 suppository, whatever--releases the drug substance

4 into an available state, usually into solution.

5 So, does the food actually affect, in effect, the

6 tablet or the formulation as a delivery system in a

7 way that delivery system works or functions?

8 Sponsors always ask, well, what food effect

9 bioavailability studies should be done in an NDA?

10 How should they be analyzed? Is it simply a

11 descriptive effect with little statistics, or is it

12 actually a rigorous statistical method that should

13 be applied to make, for an NDA, eventual labeling

14 statements? Are the effects statistically

15 significant if I am doing statistics and,

16 furthermore, beyond the statistical part of it, are

17 those effects clinically relevant? So, I may get a

18 statistically significant effect but, you know,

19 does it really mean anything in a clinical sense?

20 [Slide]

21 For BE the considerations are somewhat

22 different and in some cases significantly different

23 if you read carefully. Does the food affect the

24 formulation to different extents? Again, we get

25 back to what I said originally. This is looking at

1 differential effects of two formulations. what we

2 are interested in is perhaps two formulations that

3 are pharmaceutically equivalent and in a fasting

4 state perform exactly the same way but when I give

5 them in the fed state I see a big difference in the

6 way they perform. One is what is dramatically

7 affected by food and the other one perhaps stays

8 the same or goes in the opposite direction.

9 That is what I am interested in

10 discovering with these studies, are these products

11 equivalent and, therefore, interchangeable when I

12 give them with food? Of course, the sponsors and

13 even FDA reviewers often ask what fed BE studies

14 need to be done to determine this. What strengths

15 need to be studied? Do I need to do every single

16 strength in the product line, or is one strength

17 enough? And, we have ways in our regulations that

18 instruct us on how to do that. How should these

19 studies be analyzed, which is part of the questions

20 we are getting into today, and what are the BE

21 acceptance criteria is another part of the issue

22 that you are going to be talking about today.

23 [Slide]

24 Just to briefly discuss, and Ameeta will

25 go into a little bit more detail on what the actual

1 comments were from the industry, as I said, we put

2 out the draft guidance for public comment. There

3 was a comment period. We received comments from

4 about 13 sources. Currently only 11 of them were

5 submitted in the official accepted way, which is to

6 the docket where all the public can look at them.

7 Two more were sent in e-mails and we are trying to

8 get those people to also submit to the docket as

9 well, which is the proper method. Just as an

10 aside, if any of you do submit comments to any

11 draft guidance, whether this one or any other,

12 please submit them to the docket because that is

13 the proper way, and instructions are usually

14 included with the draft guidance about how to

15 properly submit those.

16 So, the total number of sources, including

17 two that were not submitted to the docket, are 13.

18 The approximate number of comments was about 130.

19 I say approximately because some of them were text

20 comments and it was very difficult to determine

21 where one comment stopped and the next one began.

22 So, I am saying approximately 130 by our count. It

23 is not 130 different and unique comments. A lot of

24 them were duplicates, either commenting on the same

25 thing or actual identical duplicates of the other.

1 So, people obviously collaborated and sent in the

2 same comments under different covers. So, there

3 are really not even 130 unique comments.

4 When we distilled all those down--we

5 actually took a couple of months and read them over

6 very carefully and complied them and what we have

7 come to you today with, based on those comments, is

8 two issues that we felt were very significant to

9 the commentors and very significant to the FDA as

10 far as how the comments came in and the amount of

11 controversy that those particular points raised.

12 [Slide]

13 The first of two issues in the draft

14 guidance provide for a waiver of BE studies under

15 fed conditions based on biopharmaceutics

16 classification system. I think you have all

17 probably heard talks in this committee before about

18 what the BCS, the biopharmaceutics classification

19 system, is but I will give a very brief review, and

20 you will hear plenty about that this afternoon,

21 probably as much as you can handle.

22 Specifically, the guidance tried to allow

23 for the waiver of fed bioequivalence studies for

24 Class I drugs. If you recall, under BCS the Class

25 I status is achieved when a drug substance is

1 highly soluble, highly permeable and the drug

2 product is rapidly dissolving. So, one has to have

3 all of those three to be granted a waiver of

4 fasting studies under the current final BCS

5 guidance. As I say down below, when these

6 characteristics are proven about a product or a

7 drug substance through scientific studies, then

8 that is suitable for waiver under Class I status.

9 I think the question comes down to should

10 we also waive fed bioequivalence studies under this

11 same rationale? I mean, if we put the science

12 together that says that we can not only waive the

13 fasting studies but we can also waive for many

14 products the fed studies. My interpretation of

15 this is that a deeper scientific question is when

16 you have a Class I drug that is classified as such,

17 does something that the food does change it into a

18 different category? I think that is the heart of

19 the question really. Do you believe or have any

20 evidence that you would have a Class I drug clearly

21 categorized that you would waive in the fasted

22 state, yet, something about giving it with food

23 changes its characteristics? And, I am talking

24 about the characteristics that I have listed. For

25 example, giving food with a drug substance might

1 change its permeability or might change its

2 solubility. Or, giving it with that product may

3 slow down the dissolution of the dosage form to

4 such a degree that it could no longer be considered

5 rapidly dissolving. Therefore, effectively it

6 would essentially transfer that into another class

7 which we wouldn't normally waive. I think that is

8 the basic question.

9 [Slide]

10 This is a study that I have adapted from a

11 talk that Ajaz gave. I think the question is,

12 well, why is it BCS at all? Why is it so

13 important? I think the justifications are that we

14 have a need to decrease or reduce our reliance on

15 in vivo studies as much as possible. A part of the

16 regulations actually instruct us that no

17 unnecessary human research should be done. So,

18 when we get to the point where the science advances

19 to such a state that we consider those studies

20 unnecessary, then the regulations actually instruct

21 us that we shouldn't be doing them anymore, or that

22 we should find some method of decreasing those in

23 vivo studies.

24 The additional factor is that, the more in

25 vivo studies you do, the more the time of drug

1 development is extended and the more time on our

2 part to review those studies as well. So, if good

3 science dictates that those studies are unnecessary

4 and that we can make the same decisions effectively

5 with, say, only in vitro information, then the

6 regulations, common sense and good practice force

7 us to go and actually decrease the number of in

8 vivo studies.

9 [Slide]

10 The second issue that came out of the

11 comments, and probably the second significant part

12 of this guidance is a proposed change in how we are

13 going to be analyzing the fed bioequivalence

14 studies. As you may recall, for studies currently

15 that are done in the fed state for bioequivalence

16 the criteria are that the geometric mean of the

17 ratios has to be within 80 to 125. So, there is no

18 real analysis of the variability of the comparison

19 or variability of the products as we do with fasted

20 studies.

21 So, the second issue of the proposal is to

22 change the criteria for those fed bioequivalence

23 studies to true equivalence criteria, identical to

24 what we do with the fasted studies as well. This

25 approach would also be used for NDAs to say that if

1 a BA study which is fed against fasted was shown to

2 be not equivalent under this criterion, then it

3 would be labeled as having a food effect.

4 For the fed BE studies it would say that

5 two formulations are truly interchangeable. It is

6 a scientifically and statistically rigorous

7 approach that we already use in other types of

8 studies, especially the fasting studies, to say

9 that two products are interchangeable or

10 switchable.

11 So, the questions that I pose under this

12 issue or the questions that I think this distills

13 down to are in two parts. These reflect what the

14 concerns of the commentors were. A good deal of

15 the comments were from industry. The first is, is

16 an equivalence approach desirable? You know, I am

17 guessing, purely guessing that if you went out to

18 physicians or the public patients and said when you

19 switched from, say, a brand name to a generic, do

20 you want to be assured that when you take this with

21 food that it is truly interchangeable? You know,

22 perhaps the naive answer would be yes, of course, I

23 want that. The second question is how much does

24 this cost?

25 Number one, is it worth it and the second

1 one is in doing this are we going to be increasing

2 dramatically the number of subjects that are

3 studied and, therefore, not only the number of

4 people exposed in these trials but also the dollar

5 cost of drug development and eventual dollar cost

6 of the product? Again, it is a benefit versus cost

7 type of equation.

8 I think Ameeta will show you we did a

9 survey of some of the studies, food studies done

10 under ANDAs under current practices and what type

11 of a change we would predict based on the data of

12 studies that were done in the current way.

13 Approximately how many studies would pass under the

14 current power and how many wouldn't need to have an

15 increased power and, therefore, increased subjects?

16 Basically, that is the introduction to the two

17 issues and now I will turn it over to Dr. Ameeta

18 Parekh who will go into a lot more depth and show

19 you some of the data that we have put together to

20 support these issues.

21 Science Background and Issues

22 DR. PAREKH: Thanks, Dale. That was a

23 nice comprehensive overview of the different

24 components of the food effect bioavailability and

25 bioequivalence studies guidance.

1 Since Dale started out with a comment on

2 how long we have worked on this guidance, I would

3 like to add a little bit to it because I have been

4 with this guidance throughout. Just to clarify the

5 history, I think we, as the agency, started looking

6 into these since mid-'80's when theophylline issues

7 surfaced and one of our visitors here, Dr. Aziz

8 Karim, was directly involved in that. Since then,

9 we started looking at the science of food effect

10 studies. I would say that for the last ten, twelve

11 years that Dale mentioned we were discussing the

12 science of food effect bioavailability studies.

13 Specific to the guidance though, we have been

14 looking at the guidance for the last five years.

15 That is a reasonable amount of time but, given the

16 complexities, we are trying to make sure that

17 everything is ironed out.

18 I would like to take this opportunity to

19 acknowledge the food effect working group who

20 contributed to the development of the guidance, and

21 also several other people who helped in this

22 effort.

23 [Slide]

24 I will just start with some background.

25 As Dale mentioned, the draft food effect

1 bioavailability-bioequivalence studies guidance was

2 published in November of last year and there were

3 public comments that we received. We got comments

4 from 11 sources to the docket but there were two

5 others, as Dale mentioned, that we are trying to

6 get to the docket as well. There was a total of

7 about 130 comments and, as Dale mentioned, several

8 were repetitious. A lot of them were editorial,

9 format type of comments, but there were several

10 that were very good scientific comments and we are

11 looking through these. We have gone through all

12 the comments and we have identified two primary

13 issues that represent a change from our current

14 position. We have taken these two comments for

15 discussion with the advisory committee meeting

16 today.

17 The advisory committee was presented with

18 a background package that contains these two

19 issues. These two issues were identified in the

20 package, and related to these two issues, we also

21 have a list of questions that we will try to focus

22 on today.

23 [Slide]

24 Again, I am going to reiterate something

25 that Dale mentioned already but I think it is

1 important to make a distinction between the food

2 effect bioavailability and the fed bioequivalence

3 studies here. The reason I think it is very

4 critical is that the rest of the discussion really

5 hinges on this discussion. Just to emphasize, we

6 are not going to discuss the food effect

7 bioavailability part of the guidance today. We are

8 going to stay focused on the two issues that Dale

9 mentioned that are related to the fed

10 bioequivalence studies.

11 But just to reiterate what the

12 distinctions are, the food effect bioavailability

13 studies, the ones listed on the top, are typically

14 sent with new drug applications, NDAs, and the

15 question here is for companies developing a new

16 product there is one product which is the test

17 product and how does this test product perform

18 under fed conditions as compared to the fasted

19 conditions? When we say "perform" we are really

20 looking for measures of exposure. How is the

21 exposure, the rate and extent, different under fed

22 conditions as compared to the fasted conditions?

23 If there is a difference, how clinically relevant

24 is this difference and how should it be labeled?

25 Basically, as you can sense, the question is that

1 of prescribability. Typically, we ask this

2 question of all new chemical entities, of all new

3 products, new formulations.

4 The fed bioequivalence studies, on the

5 other hand, are typically submitted to ANDAs. Here

6 the question is I have two formulations; one is

7 already on the market. Here is an ANDA product

8 that is likely to be switched with this other

9 product. How similar are they under these

10 conditions of use? So, the question here is, is

11 the test product, which is the ANDA product, close

12 enough to the reference product under fed

13 conditions that they could be switched in the

14 patient population? The question here is that of

15 switchability and approval. All modified release

16 formulations for ANDAs typically are expected to do

17 these studies. For immediate release dosage forms,

18 however, whether or not a fed BE study is done, it

19 really is label driven.

20 The current criteria, as Dale mentioned,

21 for approval of these fed BE studies is hinged on

22 acceptance of ratio within a certain range

23 typically or commonly known as point estimates.

24 So, it is basically the geometric mean ratio of the

25 test and the reference product, called point

1 estimate, to fall within a certain boundary. In

2 other words, is the test product given under fed

3 conditions within a reasonable distance on average

4 from the reference product given under fed

5 conditions? Note that the acceptance is based on

6 point estimates. The distribution around this is

7 not taken into consideration based on the current

8 criteria.

9 [Slide]

10 The two items that I have listed with an

11 asterisk are the two issues that we are going to

12 discuss today. Issue number relates to immediate

13 release dosage forms, are there some types of

14 products that could be classified as BCS Class I

15 drugs and BCS Class I drug products, rapidly

16 dissolving? Could we comfortably say that we could

17 waive those fed BE studies in vivo provided there

18 is in vitro data to support our comfort level on

19 the equivalence of those products? So, basically

20 using similar dissolution profiles as a surrogate

21 for the measure of in vivo fed bioequivalence, and

22 this is not the first time we are approaching this

23 premise. We have done this in the recent past with

24 the fasted BE studies as well. So, here we are

25 trying to extrapolate this to the fed BE studies.

1 The second issue for discussion, again as

2 Dale mentioned, is implementation of true a

3 statistical equivalence approach and the criteria

4 for the fed bioequivalence studies. As I mentioned

5 earlier, right now we use point estimates and we

6 are considering maybe moving to a more statistical

7 approach of confidence intervals within a certain

8 range, and that is what we currently use for the

9 fasted BE studies.

10 [Slide]

11 I will discuss these two issues

12 sequentially. Where possible, I will give a

13 scientific rationale and, where available, I will

14 provide some confirmatory and supportive data.

15 Some justification for waiver of BCS Class I, and

16 Dale has already touched upon that, but the primary

17 supportive data that I am going to provide is from

18 our University of Tennessee studies that were

19 funded by the FDA.

20 [Slide]

21 Just to go into the scientific basis for

22 this, and again we are revisiting this; this is

23 nothing new, we use these for the fasted BE studies

24 waiver and we are really extrapolating that to the

25 fed BE situation now. Just to emphasize, the BCS

1 Class I drugs and drug products are defined as

2 those that are rapidly dissolving across a range of

3 pH's, therefore, the formulation effect is

4 minimized. So, we have kind of negated any

5 formulation effect if there is any. Once

6 dissolved, the belief is that once you take this

7 product it is practically in solution very rapidly.

8 So, in solution the drug substance, with it comes

9 from formulation A or B it is the dug substance,

10 and the drug substance is highly soluble and highly

11 permeable and, therefore, well absorbed.

12 So, given that there is minimal

13 formulation effect, given that the drug substance,

14 whether it comes from formulation A or B is well

15 absorbed, there are several examples, and Dr. Aziz

16 Karim has published on this, several BCS Class I

17 drugs have no food effect. They are well absorbed.

18 They are pH independent or, I should say, they are

19 similar between the two formulations and generally

20 there are no food effects unless they are high

21 first-pass drugs or if there is some complexation

22 but both of these are drug substance effects rather

23 than the formulation effect. Therefore, the bottom

24 line is if there are two formulations of the same

25 drug that have minimal formulation effect, BCS

1 Class I drugs, rapidly dissolving drug products,

2 they should be bioequivalent and if, in fact, there

3 is some effect it is probably because of the drug

4 substance and, therefore, we could probably waive

5 fed BE studies for the two products.

6 [Slide]

7 To provide some supportive data that we

8 collected from FDA-funded studies at the University

9 of Tennessee, the objective of these studies--there

10 were two studies and the objectives were to

11 investigate the relative bioavailability of two

12 FDA-approved generic products administered under

13 fed conditions. So, the two model drugs that we

14 picked were metoprolol and propranolol. They are

15 BCS Class I and, in fact, metoprolol happens to

16 have high solubility, high permeability boundary

17 but they are, in fact, BCS Class I drugs. The two

18 generic products that we chose for each of these

19 drugs were based on the furthest possible in vitro

20 dissolution. So, we chose the worst possible

21 scenarios that we had for these two formulations

22 for metoprolol and propranolol independently.

23 [Slide]

24 I will share some results with you for

25 these bioequivalence studies that we performed

1 under fed conditions. Metoprolol, 18 subjects. As

2 you can see in the last column, it met the

3 confidence interval. The point estimates were

4 reasonably close, three percent for AUC and seven

5 percent for Cmax. Again, note that metoprolol is

6 highly soluble, highly permeable boundary

7 conditions, and note that both these drugs have an

8 increase in bioavailability with food and that is

9 theorized to be partly due to the high first-pass.

10 So, in spite of this big food effect that we see

11 for propranolol and metoprolol, we used those as

12 the challenge drugs for testing this hypothesis of

13 BCS Class I potential waivers and metoprolol shows

14 that, yes, it could meet bioequivalence.

15 [Slide]

16 The same thing was shown for propranolol.

17 Again, propranolol is a high solubility, high

18 permeability drug; much more increase in

19 bioavailability with food. When I say increase in

20 bioavailability wit food, I am talking about

21 fed-fasted comparison and also again for point

22 estimated differences, two percent on average; five

23 percent on average for EC and Cmax.

24 [Slide]

25 Just for completeness, I will show the

1 hydrochloric acid. I forgot to mention that. The

2 propranolol that was used was from a combination

3 product, propranolol hydrochlorothiazide. The

4 consideration here is that there was no

5 interaction; there is no pharmacokinetic

6 interaction of propranolol with

7 hydrochlorothiazide. We thought this would be a

8 challenge to propranolol using a drug that doesn't

9 have high solubility, high permeability in

10 combination with propranolol. So, we used a

11 combination product for the test of propranolol as

12 the model for BCS Class I. So just for completion

13 I am showing you the hydrochlorothiazide data as

14 well. You can see that met bioequivalence as well.

15 [Slide]

16 Conclusion: Formulation factors are

17 likely to play a minor role in the bioavailability

18 determination of BCS Class I rapidly dissolving

19 drug products. Studies with metoprolol and

20 propranolol, which are BCS Class I rapidly

21 dissolving drug products, demonstrated

22 bioequivalence under fed conditions and, therefore,

23 the data supports the BCS-based recommendation for

24 the waiver of fed BE studies.

25 [Slide]

1 I will move on to the next issue, issue

2 number two, again reiterating what Dale had

3 mentioned, that this is basically saying we are

4 going to try and see if a different approach,

5 implementation of a true statistical equivalence

6 approach for fed BE studies would be a better

7 approach to go with the fed BE assessment. Right

8 now, as I mentioned, we go with the point estimates

9 for the ratio of the test and the reference,

10 geometric mean ratios of the test and the

11 reference. Here we are proposing the same criteria

12 that we used for the fasted BE studies, namely, 90

13 percent confidence intervals for the test and the

14 reference, log transformed ratio to fall within a

15 range which is 80 to 125. This is both for AUC as

16 well as Cmax. With this approach, the question I

17 think we need to ask ourselves--

18 DR. MOYE: Excuse me. I am sorry to

19 interrupt. I have to ask a question just to make

20 sure I understand what this is about. Can you go

21 back for a second, please? When you talk about the

22 criteria for the 90 percent confidence interval,

23 are you saying that the entire confidence interval

24 has to fall within the 80-125? Overlapping is not

25 sufficient? It must lie completely within?

1 DR. PAREKH: Right. So, it is a

2 bioequivalence approach and we use the same for the

3 fasted BE studies.

4 DR. MOYE: Thank you. Sorry to interrupt.

5 DR. PAREKH: Does that mean I can start

6 talking?

7 [Laughter]

8 [Slide]

9 All right, the question is what is the

10 purpose of these fed BE studies, and it depends on

11 what your answer is. If your answer is to assure

12 interchangeability of two formulations, and I snuck

13 in another question, how certain do you need to be?

14 then the answer is right there. This is nothing

15 new. We have used these for fasted BE studies. If

16 your answer is, yes, we want to be sure that they

17 are interchangeable products under fed conditions,

18 then we already have these criteria in place. So,

19 the regulated criteria for the BE studies right now

20 for interchangeability assessment is 90 percent

21 confidence intervals for the ratio of population

22 geometric means for the test and the reference

23 treatments to fall within 80 to 125.

24 [Slide]

25 But every good thing I guess comes with a

1 price. So the next question relates to what is the

2 price for this, and are these criteria likely to

3 increase the regulatory burden? We are concerned

4 about that too. So, what we did was, rather than

5 just putting it in place, we thought let's go and

6 see what it means if people will consider these

7 criteria for fed BE studies.

8 So we went back and did a retrospective

9 analysis for the ANDA database that we had. It is

10 a partial analysis. We took a subset of 40 ANDAs.

11 I just counted and I think there were about five

12 that were repetition drugs; 35 were independent

13 drugs. We looked at the fed-fed BE aspect of these

14 ANDAs that were turned in and reviewed in the

15 Office of Generic Drugs.

16 So, we looked at the fed BE studies.

17 Remember, these studies right now are not powered

18 for meeting the confidence interval criteria. That

19 is an important thing to keep in mind. Right now

20 the criteria, as I mentioned earlier, is point

21 estimates to fall within a range. With that, we

22 did consider are we looking at a biased piece of

23 data and we thought not really because these

24 studies are not powered for confidence intervals.

25 These are really just assessment of point estimates

1 being close enough. So we thought let's go back

2 and recalculate the 90 percent confidence intervals

3 on these fed-fed BE studies. So, we did that with

4 40 ANDAs.

5 [Slide]

6 This slide summarizes the results of this

7 small pilot retrospective analysis that we

8 conducted. Of the 40 ANDAs, as shown in this pie

9 chart, 35 passed the confidence interval. So you

10 could say 87.5 percent of this small subset made it

11 in spite of the fact that these were not powered

12 for confidence intervals. There is a small subset

13 that didn't make it and, again, keep in mind that

14 these studies were not prospectively powered for

15 confidence intervals.

16 For those five ANDAs that failed to meet

17 the 90 percent confidence interval, it doesn't

18 necessarily mean that they were not bioequivalent

19 if they were powered right. If you look at the

20 numbers on the top, that represents the confidence

21 intervals for all of those five that didn't make

22 it. But a small subset did not make the confidence

23 interval criteria. However, it was a small subset

24 and, keep in mind, these studies were not powered.

25 Of the five, there were two that failed on AUC and

1 there were three that failed to meet the confidence

2 intervals on Cmax.

3 [Slide]

4 In conclusion, if the current criteria for

5 fed bioequivalence studies, which is point

6 estimate, were to be changed to confidence

7 intervals a retrospective analysis of the existing

8 data suggests that for most studies no increase in

9 number of subjects would be necessary, however,

10 there will be a small subset that may need a larger

11 sample size.

12 With that, I want to summarize and say

13 that there are situations where in vitro

14 dissolution comparisons could suffice or could

15 serve as an acceptable surrogate for in vivo

16 bioequivalence studies, the case being BCS Class I

17 rapidly dissolving drug products. A waiver for in

18 vivo bioequivalence studies, in this case fed

19 conditions, could be considered. However, when the

20 studies are conducted, depending on what the

21 question is, if the question is what is the purpose

22 of these studies, the fed BE studies--is the

23 purpose to address a switchability question, then

24 if so, we need to address the appropriate

25 statistical criteria in that situation. Thanks.

1 DR. LEE: Thank you very much, Ameeta.

2 There are two questions put before us, and I have

3 asked Marvin Meyer to digest this information and

4 provide us with some perspective. Before we start,

5 since we have plenty of time, what is the

6 definition of food? This is a half-serious

7 question.

8 DR. PAREKH: That definition of food took

9 us the first twelve years.

10 DR. LEE: I see.

11 [Laughter]

12 DR. PAREKH: We went through a lot of

13 scientific discussion trying to debate what is

14 food. There were papers that said there is no such

15 thing as the right meal. You could be eating

16 something; I could be eating something totally

17 different. Rather than addressing it as a social

18 question, we thought we could address it as what is

19 the regulatory question here. The regulatory

20 question is what happens when I take a drug with

21 meals. Given all the physiology of food

22 effects--gastric emptying time, cholecystokinin,

23 all those things, bile acids, pH changes--we went

24 through a lot of literature. We went through the

25 examples that were tested for theophylline which

1 were bench-marking the meals that could be

2 discriminating. We thought let's take a meal that

3 would represent the worst case scenario for maximum

4 perturbation of the gut, and let's use that as the

5 meal. The meal that was chosen was similar to the

6 meal that was shown to be discriminatory in those

7 early theophylline studies.

8 DR. LEE: So, we are asked to think about

9 food that way. Also, I suppose we should think

10 about the subject not as pediatrics or geriatrics

11 but the average population in age. Right?

12 DR. PAREKH: That is right.

13 DR. LEE: And also think about Class I

14 drugs as the average of that range. Right? So,

15 these are the boundary conditions. I am beginning

16 to complicate matters.

17 DR. HUSSAIN: Yes, I am not sure. With

18 respect to bioequivalence, we have always tried to

19 have sort of a general population to study that.

20 The issue essentially is making sure in vivo that

21 the release of the drug from the product is

22 essentially similar. So, that is the question we

23 are asking. With respect to special populations, I

24 think that is more a bioavailability question, not

25 a bioequivalence question. So, if we can keep

1 those two separate.

2 DR. LEE: Thank you.

3 DR. CONNER: Just an aside, the meal was

4 very high in fat, the meal that Ameeta was talking

5 about. After a lot of discussion and a lot of

6 research, they came up with a very high fat meal.

7 Now, if you go to different places in the world or

8 even in the United States, that is not necessarily

9 a representative breakfast, hopefully, that most

10 people eat. If they do, their arteries are going

11 to be in very bad shape after a few years. So, in

12 another country, that country may have chosen to do

13 a much more representative meal. For instance, I

14 have reviewed some ANDA food studies for Japan

15 where they took a typical Japanese breakfast which

16 was much, much different than what we are talking

17 about here. It is interesting to look at those

18 side by side. However, we chose something that

19 would have the highest likelihood of being a

20 challenge to the dosage form and the drug

21 substance.

22 DR. LEE: Okay, I wanted to make sure we

23 understand it because now we are looking at version

24 two and pretty soon we will be working on version

25 three.

1 DR. HUSSAIN: I think in terms of

2 standardization, the question you raised also goes

3 to the standardization of the meal because this is

4 a quality assurance type of a test. We went to the

5 commercial sources that provide this reproducibly.

6 DR. PAREKH: Yes, we went and picked up

7 things from little fast food places. I remember a

8 few years back Hank Malinowski took a group and we

9 tried out the meal. It is a big meal. I could

10 handle it!

11 [Laughter]

12 Just to get to specifics, Dr. Lee, the

13 meal that is defined in the draft guidance is about

14 800-1000 calories, and we specify the meal as an

15 example meal but 150, 250 and about 500 calories

16 from protein, carbohydrate and fat. You don't have

17 to stick to a certain meal in terms of the

18 components as long as the fat, carbohydrate and

19 protein are similar or close to this, because this

20 is what has been tested in the literature to cause

21 the maximum perturbation. So, we want to know what

22 is the worst case scenario and so go with the meal

23 that represents the worst case scenario.

24 DR. LEE: Very well. Thank you very much.

25 I want to remind the committee that we have two

1 consultants, at the other end of the table, to

2 collaborate with. Yes?

3 DR. ANDERSON: On page two of the handout

4 you have something about similar dissolution

5 profiles. Would you comment on how close the

6 dissolution profiles have to be in order to qualify

7 for this?

8 DR. HUSSAIN: In terms of the fasting

9 study where the BCS guidance was first used, the

10 rapid dissolution is defined in terms of a time

11 limit in terms of the rate of dissolution. It has

12 to essentially dissolve within 30 minutes, and it

13 has to dissolve in a pH range of, say, 1 to 6.8 and

14 three different pH conditions. The similarity is

15 that it has to be within about 10 percent. The two

16 profiles should be within plus/minus 10 percent; it

17 is an approximate similarity.

18 DR. ANDERSON: Plus or minus, yes.

19 DR. LEE: Thank you. We do have two

20 questions in front of us. We need to answer these

21 questions and if there is time we can go into other

22 questions. Marv?

23 DR. MEYER: I have a question of your

24 presentation before I get to that, and then I want

25 to make a comment before I get to that. You have

1 40 ANDAs that you sampled. Out of how many

2 possible does the 40 represent, and were they a mix

3 of IR and modified release? Thirdly, do you have a

4 recollection of what the point estimates were for

5 the five drugs that failed?

6 DR. PAREKH: I am glad I got up early this

7 morning and checked that. Yes, it was a mix of IR

8 and MR. We didn't select ANDAs based on a certain

9 thing; we just took 40 and there were IR and there

10 were MR. The ones that represent not making the

11 confidence intervals are a mix of IR and MR. So,

12 it is not just all MR or IR. For AUC, there was

13 one that was as high as 151. The point estimate

14 was about 20 off, so 1.2, 120. The other one was

15 also close. It was 118 or somewhere in that range.

16 You can see from the width that that is where it

17 would be.

18 DR. MEYER: So, one could argue that of

19 the five failures, the Cmax failures all could have

20 been taken care of by a few more subjects, and

21 maybe the AUC failures, the 120 and the 118 really

22 shouldn't be approved anyway.

23 DR. CONNER: You know, in looking at that,

24 and obviously I have the ability to know which

25 applies to which product, but I actually just

1 looked at the overall and I had the same reaction.

2 You know, when Ameeta and I were going over the

3 results I looked at those five and I said, well,

4 the Cmax, some more subjects, we didn't go through

5 the exercise of calculating how many more subjects

6 would have been required although it is perfectly

7 reasonable to be able to do that. But when I

8 looked at the AUCs I said, oh, these don't look so

9 very good to me because the point estimates,

10 although we don't have them on the slide, are

11 obviously pretty far out. I mean, they are within

12 the 80 to 125 but they are like about 120 or in

13 that range. I don't have the exact numbers. So, I

14 think that simply adding power to that, although

15 theoretically if you added enough power it might

16 squeak by, it is pretty unlikely that adding a

17 reasonable number of subjects to that study would

18 get those to pass the confidence intervals.

19 The open question still is do we really

20 feel comfortable approving those? Now, it is

21 important to say for the record that we are not in

22 any way saying that what we have done in the past

23 or what we are currently doing with the point

24 estimates, that there is anything wrong with that.

25 I don't want anyone to conclude that there is a

1 real hazard here. I think we have had some good

2 experience with that. Doing it this way hasn't

3 really created any clinical problems that we are

4 aware of. Our attempt here is, I would say, just

5 to tighten things up and to make a more rigorous

6 equivalence evaluation rather than, you know, what

7 is kind of a "feel good" type of approach but a

8 more rigorous type of approach in what we are doing

9 with point estimates. So, I don't think that what

10 we have been doing in the past is wrong; I think

11 this is just better.

12 DR. MEYER: One point of order, Vince. We

13 have two invited guests and I think a couple of

14 other speakers on this topic. I always wonder why

15 we don't hear from those people before we

16 deliberate.

17 DR. LEE: Because once they start

18 talking--

19 [Laughter]

20 --but I am sure that they will interject

21 at the appropriate time.

22 DR. MOYE: One advantage of moving away

23 from just using the point estimate is that you

24 really don't know what the operational

25 characteristics of it are. You have historical

1 information. Sometimes historical information can

2 be very leading and sometimes it can be misleading.

3 If I understand this process correctly,

4 the way it currently is now, and please tell me if

5 I am wrong and I apologize for interrupting you

6 earlier but I was in imminent danger of being badly

7 and irreversibly confused so I really needed to

8 stop and ask you--the way it currently is now, a

9 sponsor will carry out a research effort and come

10 up with an effect size, a point estimate. Even

11 though there is a standard error associated with

12 that and even though the standard error is

13 available, that standard error is set aside and the

14 question is simply asked whether that point

15 estimate is greater than 0.8 or less than 1.25.

16 The suggestion is to replace that with the

17 confidence interval of 90 percent and ask whether

18 the 0.8 to 1.25 range completely encompasses and

19 encloses the 90 percent confidence interval. That

20 is correct?

21 I am not really sure why we need to go

22 through this two-step process, the first step to

23 compute the confidence interval and then, the

24 second step, decide whether the confidence interval

25 falls completely within 0.8 to 1.25. It seems to

1 me in order to determine how well that is going to

2 work, again holding historical information aside,

3 it is kind of a complex computation to ask about

4 where the range of a confidence interval is going

5 to fall. So why not, as an alternative, just ask

6 the question how likely is it that the population

7 ratio will fall between 0.8 and 1.25 given the

8 point estimate and given the standard error? That

9 is a fairly easy computation to do, and you can set

10 a value for that probability. That probability

11 must be above some value, and for that the

12 computation is much more direct and, hopefully,

13 much more interpretable.

14 DR. CONNER: It is important to point out

15 that this is not a new method, which is what we are

16 talking about, which is the two one-sided test

17 procedure to determine equivalence. That is

18 something that we have been doing for quite a few

19 years for fasted studies. If you are saying that

20 this, when applied to food studies, may not be

21 totally understood I don't agree with you but I

22 take that criticism. But as far as the properties

23 of this calculation, the properties of the

24 statistics, we understand those very well. We have

25 been doing them for perhaps ten or twelve years

1 now, I think, on fasting studies.

2 DR. MOYE: There are two statistics here I

3 think. Are you talking about the one that just

4 uses the point estimate and asks whether that is

5 between 0.8 and 1.25? Is that the one you are

6 talking about?

7 DR. CONNER: No, no--

8 DR. MOYE: Or are you talking about the 90

9 percent CI?

10 DR. CONNER: The fasting studies are done

11 in exactly the way we are proposing to now do fed

12 studies. It was developed by Dr. Sherman and

13 others, the two one-sided test procedure. In other

14 words, what the test essentially does is run two

15 one-sided tests, one in one direction and the other

16 in the other, you know, one test one bound and the

17 other test the other bound. They are run at the

18 alpha equals 0.05 level. So, we have 0.05 on one

19 side--

20 DR. MOYE: Right.

21 DR. CONNER: --and 0.05 on the other. So,

22 the way of actually doing all this in one test, one

23 calculation, is to calculate the 90 percent

24 confidence interval so you get the 5 on one side

25 and 5 on the other, and each one of those has to be

1 what we have determined to be a clinically

2 significant difference. The actual operation of

3 this, for the most part the point estimates of

4 fasting studies, when we have done similar types of

5 surveys, for the vast majority of the products we

6 approve based on the fasting results the point

7 estimates don't vary by more than about 4 percent

8 either way from a ratio of 1. We have a few

9 isolated cases where we have as much as 10 or 12

10 percent, but most of them cluster right around the

11 ratio of 1, plus/minus 4 percent for both Cmax and

12 AUC. So, the operational characteristics of

13 controlling that point estimate, the experimental

14 point estimate are actually quite good.

15 DR. MOYE: It sounds like the answer to my

16 question is that this is a procedure that has been

17 well established--

18 DR. CONNER: Yes.

19 DR. MOYE: --and has been used in other

20 analyses looking at bioavailability for fed and

21 fasting. Is that right?

22 DR. CONNER: It is used somewhat in the

23 NDA world but primarily this is used to determine

24 the equivalence or switchability of two

25 pharmaceutically equivalent products. So, the drug

1 substance, the amount of drug substance, the type

2 of dosage, all that is held constant and most of

3 the studies we do are crossover so, you know, each

4 individual gets both products. And, we want to

5 make sure that in the end the judgment we make and

6 the generic product we approve, if someone goes

7 into their pharmacy and they are currently taking,

8 say, the brand name, if the doctor switches them to

9 this other pharmaceutically equivalent dosage form

10 they will be getting essentially the same results

11 without any distinguishable difference.

12 DR. LEE: So, you are answering question

13 2.3, what alternative approaches?

14 DR. MOYE: If you say so.

15 DR. CONNER: As an aside, I am not sure we

16 should get much into it today, but if you have

17 suggestions on how we might do this whole thing

18 better--I mean, what we are doing now is simply

19 expanding what we have done for many years to this.

20 If you have some other, you know, just general

21 comments that you might have a better method,

22 perhaps another forum might be the time.

23 DR. MOYE: Well, I wouldn't say it is

24 better at this point; I just say it is an

25 alternative and it may be simpler.

1 DR. LEE: Do you have slides?

2 DR. MOYE: Not right now but I can prepare

3 them.

4 DR. LEE: All right. Since the two

5 consultants were mentioned, maybe I will just take

6 the opportunity to see if they have anything to

7 say.

8 DR. KARIM: You mentioned about food

9 effect. I have been talking about food effect for

10 the last thirty years, and one of the most usual

11 and common questions asked is we never have this

12 type of meal so why does FDA do a food effect

13 study? The question here is it is not really the

14 sort of food you would be taking every day. It is

15 really performance of a dosage form under

16 conditions which would produce maximal perturbation

17 of the formulation. So, it is really a quality

18 control test of your formulation, and that is the

19 food which would produce the maximum effect. So,

20 it is not the usual food you take but it is quality

21 control type of food.

22 The second point I want to make is that,

23 in fact, it is correct that I have found that drugs

24 which belong to Class I do not show food effect

25 response in terms of AUC, and in drug development

1 the very first study in humans that we do is a food

2 effect study because if there is no food effect

3 response, then we are able to categorize our drug

4 as a Class I drug which, I think, is a new approach

5 of food effect response. We use it a great deal in

6 drug research.

7 One thing which I still feel hasn't been

8 covered is that food will produce, even for Class I

9 drugs, delay in absorption because 50 g of fat will

10 result in stomach emptying time, and if you have a

11 drug which is specifically used for very fast onset

12 of action--an analgesic, antiarrhythmic--you will

13 miss the point because the Tmax is not used in

14 bioequivalency assessment. So, I think the agency

15 needs to look at that before saying that the Class

16 I drugs would not require food effect response

17 because the question of Tmax has not been

18 addressed, what is the effect of a given meal or of

19 food on Tmax.

20 The third point I want to make is that if

21 a drug or formulation is labeled to be taken with

22 food, and if that is how patients take the drug,

23 then it is obvious that the bioequivalency must be

24 shown under fed conditions. I have said that again

25 and again. We should use all the statistical

1 criteria used under fasting state to apply to the

2 fed state.

3 I am surprised that the bioequivalency was

4 shown in even 17 to 18 subjects with food because

5 when you give the drug with food you are adding

6 another variable, and that is gastric emptying

7 time. I would be very interested to see whether in

8 a crossover situation the gastric emptying time

9 under fed condition is similar or not. I know

10 under fasting state they are very similar, but I

11 would have expected under fed conditions the

12 gastric emptying time to vary more, and I would

13 have expected that we would need quite a few more

14 subjects to do bioequivalency testing. Thanks.

15 DR. LEE: Thank you.

16 DR. MEYER: Can I ask Aziz a question?

17 DR. WILDING: Can I pick up first because

18 we do a lot of work actually visualizing what fat

19 does to gastric emptying properties in formulation

20 performance. It is certainly true that the current

21 high fat meal as put into regulatory guidance has a

22 maximum effect on the GI tract. That is, it

23 effectively stops the stomach for a couple of hours

24 in most individuals. The reality is that if you

25 put that amount of fat into the stomach, it takes a

1 while to realize that it has that large amount of

2 material to deal with and actually sits still for a

3 period of time.

4 What you have to recognize also is that

5 today's population eats less fat than the previous

6 populations. Therefore, what was maximal for them

7 is probably now super-maximal for today's

8 individuals. That is an issue that is worth

9 contemplating. So, I think what we see often is an

10 effect on Tmax associated with significant delays

11 in gastric emptying.

12 Now, the question is, is the CV percent

13 greater in terms of intra-variability fed compared

14 to fasted? Certainly, in our experience there will

15 be no difference between those two that will be

16 noticeable from statistical comparison purposes.

17 Now, unlike Aziz, I don't think that Tmax is an

18 issue because it is a bioequivalence issue or

19 switchability, not prescribability. Therefore, I

20 don't think in this context I could imagine where

21 there will be a Tmax difference associated with a

22 Class I drug that would lead to issues in that

23 particular regard.

24 My final comment, food effects are a

25 generic phrase and we do run risks with the phrase

1 food effects because it is, in many respects, an

2 active pharmaceutical ingredient issue, a

3 formulation issue, and there is the combination of

4 the API, the formulation and the food. That is

5 where I think, as Ameeta indicated, it is

6 bioavailability in terms of API alone, formulation

7 alone, but there is also a

8 bioequivalence/bioavailability issue that kicks in

9 when you are contemplating active forms of

10 ingredients of the formulation and drug together,

11 and that is the hardest one to tease out.

12 DR. LEE: Thank you.

13 DR. MEYER: Aziz, you were talking about

14 Class I and saying you have not personally seen any

15 differences in bioequivalence under fed conditions.

16 You said AUC. How about Cmax?

17 DR. KARIM: Yes, what I do is we take AUC

18 ratio fed/fasting and if they fall within 10 or 20

19 percent we categorize it as Class I drug. Now,

20 Cmax I haven't looked at in that detail, but I

21 would say probably it won't be as rigid as AUC.

22 DR. HUSSAIN: Let me sort of go to the

23 issue of Tmax that Aziz raised, and so forth, and

24 let me go through the thought process of the BCS in

25 the fasting state. One of the reasons we designed

1 or devised rapid dissolution criteria for the

2 fasting state was because of unpredictability of

3 the gastric residence time and the rapid emptying

4 that occurs under the fasting state, and there were

5 concerns with volume and you will see that in the

6 afternoon discussion also.

7 In fact, the 30 minutes that we have as

8 rapid dissolution criteria was for fasting state.

9 That is overly conservative for a fed state.

10 Although we are not suggesting we change that, we

11 don't believe there will be Tmax differences

12 because of formulation effects. There will

13 definitely be a shift in Tmax because of the

14 gastric emptying time. But if you are going to

15 retain the dosage form in the stomach, which is

16 essentially a reservoir, for a long period of time,

17 then you are giving far more time for dissolution

18 to become peak before it gets emptied out. So, it

19 is less of a concern under the fed condition. We

20 were more sensitive and more conservative in the

21 fasting state.

22 So, that is the reason dissolution-release

23 in vivo under fed conditions, because of the large

24 volume and because of the long gastric residence

25 time, is less of a concern. So, I think our

1 proposal will be far more conservative for the fed

2 state.

3 DR. MEYER: Ready?

4 DR. LEE: Yes.

5 DR. MEYER: The questions at hand then are

6 posted there, as well as in the handout we received

7 from Kathleen Reedy on April 22. The questions are

8 really broken into two sections. To what extent

9 can we waive fed bioequivalence studies for Class I

10 drug? Then, secondly, should confidence intervals

11 be applied to fed studies?

12 The first question then, can we waive fed

13 bioequivalence studies for Class I drugs which, of

14 course, are highly soluble, very rapidly dissolving

15 and highly permeable?

16 One question I have, that will come up

17 again this afternoon, is the definition of high

18 permeability. Is propranolol really highly

19 permeable? It is fine to do an intestinal

20 intubation but then what other kinds of

21 measurements can be made? My recollection is that

22 propranolol is not 90 percent systemically

23 available; large first-pass effect. How do we

24 measure high permeability if all we have is bio

25 data? I have no problem with the definition of

1 high permeability if it is 90 percent excreted

2 unchanged in the urine or the AUC relative to IV

3 doses is 90 percent. Beyond that, it becomes a

4 little more arbitrary. I see Ajaz is shaking his

5 head.

6 DR. HUSSAIN: No. The BCS guidance that

7 was issued in September of 2000 actually went

8 through and described several methodologies to

9 assess permeability. It also includes a method

10 based on in vitro and HeLa cell culture methods, PK

11 studies, extent of absorption. So, you have a

12 whole host or toolkit for assessing permeability.

13 You are absolutely right, metoprolol and

14 propranolol are both high first-pass effect drugs.

15 If I am not mistaken, the absolute bioavailability

16 of propranolol is 35 percent but its extent of

17 absorption is actually complete and that is the

18 basis for the high permeability class membership.

19 That is the reason we selected propranolol for the

20 challenge studies that we did at the University of

21 Tennessee. The reason is it is so sensitive to

22 food effect. In fact, there is a study from an

23 Australian hospital--I am not able to quote the

24 reference of that, but you can actually induce fed

25 effect studies of propranolol by just smelling

1 food; not even eating it. So, that is how

2 sensitive propranolol is to food effects.

3 DR. LESKO: I will address the same

4 question and remind us that the propranolol and

5 metoprolol were two of the drugs that we had in our

6 initial database that defined the BCS. That means

7 the permeability of these drugs was established in

8 human volunteers through intubation of the small

9 intestine. Thus, we have very accurate, gold

10 standard type permeability on those two drugs as

11 opposed to circumstantial data which might have

12 come from CACO 2 or bioavailability studies.

13 As Ajaz said, the reason we picked those

14 two recent studies in Tennessee on fed effects is

15 because we had established previously their

16 membership in the class. Propranolol is highly

17 permeable in terms of passing through the gut wall.

18 Metoprolol was picked because it was more of a

19 borderline between Class I and some other classes

20 based on its permeability characteristics. But

21 they both succeeded in those two studies.

22 DR. LEE: Larry, are you saying that it

23 has taken the metabolism into account, the

24 permeability?

25 DR. LESKO: Well, we have to separate two

100

1 things, absorption from the lumen of the intestinal

2 tract and the bioavailability. The permeability

3 refers to the passage of the drug from the lumen of

4 the intestinal tract into the blood stream. So, it

5 is talking about transversing that border. After

6 it transverses that border there may be some

7 first-pass effects in the liver that will reduce

8 the bioavailability. So, when we talk about

9 permeability we are thinking about absorption as

10 opposed to bioavailability. So, you could have a

11 drug with good absorption characteristics but

12 relatively low bioavailability if the reduction in

13 bioavailability is related to a first-pass effect,

14 say, in the liver.

15 DR. LEE: I think that maybe what Marv was

16 alluding to is the metabolism during passage across

17 the gut wall.

18 DR. LESKO: Well, if it is a 3A4 substrate

19 that is being metabolized in that passage it still

20 has permeated that segment of the wall, as

21 indicated by its high permeability.

22 DR. HUSSAIN: One other way of looking at

23 permeability is that it is essentially the ability

24 of the drug to leave the aqueous compartment that

25 is in contact with the epithelium and get into the

101

1 cell. Essentially, when we went to the BCS, as

2 Larry said, we distinguished between transport and

3 then subsequent metabolism.

4 DR. MEYER: Personally, I think I would

5 feel if the regulation said a product that is 90

6 percent bioavailable relative to IV or maybe even

7 an oral solution, that is something I can hang my

8 hat on and I don't have to worry about gut wall

9 metabolism or metabolism prior to reaching the gut

10 wall. Short of intestinal intubation, let's say,

11 the generic industry--I doubt very many of them are

12 going to do intubation type studies to establish

13 permeability, and CACO 2 and those other surrogates

14 haven't been totally proven, I don't think.

15 DR. HUSSAIN: I think we have.

16 DR. MEYER: Have you?

17 DR. HUSSAIN: Yes. I think those are

18 established.

19 DR. MEYER: Given that then, to what

20 extent does the committee feel that in-house data,

21 which I take it are partially propranolol and

22 metoprolol--

23 DR. HUSSAIN: I think the challenge

24 studies that we did in Tennessee were two products,

25 one metoprolol alone; one containing propranolol

102

1 and hydrochlorothiazide. Hydrochlorothiazide is

2 not a highly permeable drug. So, that was an

3 additional challenge that we had. So, those were

4 prospective studies designed to challenge the

5 system, and we selected two generic products to

6 have a head-to-head comparison. We didn't have

7 such data before because we have looked at

8 historical data that we have in-house and made that

9 conclusion, and we wanted to truly challenge that.

10 DR. LEE: I think the question is very

11 simple, you know, Class I and Class II and so

12 forth, fed state, fasting. I think we all

13 understood that. But I guess Marv was thinking

14 about exceptions. He was thinking beyond the

15 current definition and is not comfortable with the

16 risk.

17 DR. VENITZ: To follow-up on something,

18 Dale, that you mentioned, is there any evidence to

19 suggest that for the Class I and non-Class I drugs

20 there is a differential food effect between the

21 formulations? Because you alluded to the fact that

22 it is unlikely, and I guess based on my

23 understanding of BCS I would agree with that, but

24 do you have any experimental evidence to the

25 contrary?

103

1 DR. CONNER: I am not sure I was trying to

2 imply that it was unlikely. I think that is a

3 question for you.

4 DR. VENITZ: Right.

5 DR. CONNER: You know, how likely you

6 think it is. I posed the question because it

7 seemed to me that the critical thing is do we have

8 any examples, or do we realistically believe that

9 one exists that when we gave a product that was

10 rated as Class I that it would behave differently,

11 that it would behave like it was another class

12 which we wouldn't ordinarily waive? So, I will

13 give you some theoretical examples, and I can't

14 come up with any examples to say the food got in

15 there and this would affect both the formulations

16 equally, but if something in the food complexed

17 with the drug substance and actually formed, say, a

18 permanent or semi-permanent complexation which

19 didn't have the solubility or, more likely, didn't

20 have the permeability that the original drug

21 substance had, I mean, then your resultant effect

22 would be that it wouldn't be permeable anymore; it

23 wouldn't have the bioavailability that it started

24 out with if something in the food complexed with

25 it.

104

1 DR. VENITZ: But it would be a

2 bioavailability not a bioequivalence issue. Right?

3 DR. CONNER: Yes, but it would then mean

4 though that this BCS system that we designed would

5 technically no longer apply to it. It would not

6 necessarily then result in bioinequivalence. It

7 would take it out of the realm of the BCS system

8 into another class and, therefore, even though we

9 would think the likelihood that there would be

10 bioequivalence would not necessarily increase, we

11 would then, based on our BCS system, have to do an

12 in vivo test to confirm that. But the likelihood

13 of a differential effect on the drug substance is

14 small, very small but it would still take it out of

15 the realm of BCS.

16 DR. HUSSAIN: Let me sort of add to that.

17 I think when we were going through this development

18 we had extensive discussion on this. I said I want

19 to have a formulation that would behave differently

20 than the other one. For immediate release

21 formulations it is very difficult to come up with

22 an example, but since Dale raised the issue of

23 complexation, how can I formulate two products, one

24 which will have food effect and one which may not

25 have food effect? If I use complexation as a

105

1 mechanism, then I could include in one of the

2 formulations a chelating agent, sodium EDTA for

3 example, and that could be a trigger for saying, if

4 its a metal complex, you are essentially binding

5 the available metal, and so forth.

6 But those are sort of theoretical

7 assessments and we haven't seen any real examples

8 that actually could be achieved. When we look at a

9 waiver, we also look at the excipients and so

10 forth. So, actually in a BCS waiver we go through

11 an analysis of excipients, and so forth. So, that

12 would sort of come up and be covered under that.

13 So.

14 DR. VENITZ: So, it is correct for me to

15 assume that you haven't seen any evidence either

16 in-house or in the public literature that a Class I

17 drug shows a differential food effect?

18 DR. HUSSAIN: We couldn't find any

19 evidence of that.

20 DR. LESKO: I think I want to qualify that

21 a bit though because in trying to find those kind

22 of differences you described there are two

23 obstacles. One is that frequently you can't

24 identify the BCS class, say, in a new drug

25 application based on the data submitted. So, the

106

1 best we can work on is a suspicion of what the

2 class would be because the company had no reason

3 necessarily to define the solubility at all pH's to

4 measure permeability. So, when we looked at that

5 question to look for the exceptions, we were flying

6 a little bit blind by not knowing for sure whether

7 these were Class I drugs. So, there is that

8 aspect.

9 On the ANDA side, we are sort of a captive

10 audience to what is being submitted to the Office

11 so there are things that may be out there that we

12 don't see or aren't aware of. That may address

13 your question. But recognizing those two

14 limitations, I guess the answer would be no, we

15 don't have any direct knowledge of exceptions.

16 DR. LEE: There is another question about

17 the issue about the mechanism of absorption as

18 well. What if a drug falls in Class I because of

19 an affinity for whatever transport might be in

20 place in the gut?

21 DR. HUSSAIN: With respect to the fasting

22 study, the mechanism of absorption I think came

23 into consideration with respect to the methods of

24 permeability. For example, there is no restriction

25 that a carrier-mediated transport of an active

107

1 transport mechanism would preclude a drug from

2 being a Class I or a highly permeable drug. But

3 the methodology used to assess permeability then

4 has to be looked at more carefully. For example,

5 in the BCS guidance use of CACO 2 or in vitro,

6 essentially we don't recommend using those for

7 actively transported drugs, and so forth. So, that

8 is how we managed that process.

9 DR. VENITZ: But don't you also have a

10 restriction on dose proportionality--

11 DR. HUSSAIN: Yes. Dose linearity was one

12 of the mechanisms to address some of that question.

13 DR. LEE: Other comments from the

14 committee? Yes, Judy?

15 DR. BOEHLERT: I have a question coming

16 back to the dissolution profile when you said it

17 could be plus/minus ten percent. If bioequivalence

18 were waived and then the manufacturers were relying

19 on dissolution to show equivalence and if, indeed,

20 they had test and reference products that were at

21 the extremes of that range and one was plus ten and

22 the other was minus ten, are there any data to say

23 there would be clinical relevancy to that

24 difference?

25 DR. HUSSAIN: I think we looked at that

108

1 quite extensively, and for Class I drugs we don't

2 think there is a reason to believe that. If we

3 were looking at only one pH condition, then I would

4 not be confident with that. That is the reason we

5 request multiple pH conditions. The reason for not

6 relying on one pH condition is, for example, a

7 wheat base. If you just do the dissolution in 0.1

8 normal HCL that may not truly be reflective or

9 discriminating under, say, a less acidic condition,

10 and so forth. That is the reason we went with

11 multiple pH conditions.

12 DR. BOEHLERT: Would that imply that the

13 product would be continually tested at those

14 multiple pH conditions, or would you refer it just

15 to the 0.1 normal HCL and would that be enough to

16 show a difference in physical properties?

17 DR. HUSSAIN: The multiple pH conditions

18 come into play when there is a request for a waiver

19 or there is a substantial formulation change under,

20 say, the SUPAC. For routine quality control or

21 quality assurance you will have the traditional

22 classification.

23 DR. LESKO: I just want to clarify that a

24 bit. With the Class I drugs, when you talk about

25 dissolution it is possible to have a single time

109

1 point. In other words, if the products dissolve

2 within 15 minutes, 85 percent, then we will look at

3 that and say they are the same because that is such

4 a trivial difference. On the other hand, if the

5 dissolution goes to 30 minutes, we then would look

6 at a profile and what we are looking at is

7 basically two profiles, a test product and a

8 reference product. The statistics that are used to

9 differentiate those are called the F-2 statistic.

10 The reality is that to have an F-2 of 50 or

11 greater, which is "passing," you need to have very

12 similar profiles and they can differ by no more

13 than ten percent between the test and the

14 reference. So, you really can't have ten on this

15 side or ten on that side. It is really comparing

16 the two profiles. Generally the differences that

17 cause something to not pass an F-2 statistic occur

18 very early on, say, in the first five minutes or

19 first ten minutes where, clinically speaking, I

20 doubt that they are important but we do have that

21 standard in place to look at that.

22 DR. LEE: Bill?

23 DR. JUSKO: I am in strong agreement with

24 the theoretical and practical arguments pertaining

25 to the Class I type of drugs in relation to

110

1 bioequivalence, but I don't have a very good

2 feeling for the extent of literature that confirms

3 these observations. There were early review

4 articles and now I am hearing that it is rather

5 difficult to determine permeability of these

6 compounds so it is uncertain with a new chemical

7 entity exactly what its permeability is so as to be

8 able to preclassify it in this group.

9 Is there any better evidence for numbers

10 of drugs that have been evaluated to find that

11 there is no problem with bioavailability or

12 bioequivalence for Class I compounds?

13 DR. HUSSAIN: I think the hesitation to

14 say a drug is Class I and Class II has sort of

15 regulatory implications, in a sense. Unless we

16 follow the guidelines that we have provided to

17 classify we hesitate to say this is Class I and

18 Class II. But, clearly, we have a sense of what

19 the likelihood is, and based on that, I think

20 Ameeta did an internal survey and I think Aziz has

21 published extensively on that too. So, maybe they

22 can comment on that. So.

23 DR. KARIM: I think I agree with the

24 theoretical background that if you have a Class I

25 drug, in vitro dissolution specially F-2 tests

111

1 would be appropriate, and you don't even have to do

2 the food effect study. But, believe me, I feel

3 that determining permeability has not been

4 established, and that is a big issue. I mean, you

5 talk about absolute bioavailability of 90 percent.

6 For how many drugs do we have absolute

7 bioavailability or 90 percent? Very few. So, to

8 me, the major unknown is permeability. I think to

9 measure solubility is very easy. To measure

10 dissolution is also reasonable. That is why I use

11 the food effect response as a way of classifying

12 whether the drug is Class I or not and it works

13 very well.

14 So, to answer your question, if you have a

15 Class I drug and truly establish that it is a Class

16 I drug, then I think I am all in favor ofthe

17 guidance that you don't need to do a bio study.

18 DR. HUSSAIN: Again, I would respectfully

19 disagree with that in a sense because folks who are

20 familiar with CACO 2 and other methodologies, and

21 so forth, are very confident of their method. So,

22 our position essentially is that in vitro methods

23 are acceptable under certain conditions once you

24 have established method suitability, and so forth.

25 And, just relying on a food effect study to

112

1 classify a drug was not an acceptable method in our

2 guidance. The reason is that permeability is based

3 on extent of absorption and you do see food effect

4 for highly soluble, highly permeable drugs that

5 have a high first-pass effect, and those are the

6 two drugs we selected for the study. So, that is

7 sort of our position.

8 DR. LEE: I think we are caught in a

9 circular argument. My sense is that question 1.1

10 is premature. Yes?

11 DR. SHEK: Just one comment, looking at

12 the way the question is being phrased--

13 DR. LEE: Yes?

14 DR. SHEK: --it talks about bioequivalence

15 about ANDAs. It doesn't say anything about the

16 existing labeling for the reference, whether that

17 indicates it might be a Class I and indicates

18 specifically food effect. Will that be taken into

19 consideration, or how is that going to be handled?

20 I don't know how many of those 40 ANDAs have

21 something in the labeling about food effect. And,

22 if we don't do the study will the labeling be

23 changed?

24 DR. CONNER: Well, I can tell you our

25 current policy for what triggers us to ask an ANDA

113

1 sponsor for a fed bioequivalence study, and you

2 have to differentiate between a food effect study

3 which asks if there is a food effect on the product

4 or the drug substance versus a fed bioequivalence

5 study where the two products are compared under

6 equivalent or the same fed conditions. The trigger

7 that causes us to ask for a fed bioequivalence

8 study is some mention of food in the innovator

9 labeling, the reference listed drug labeling.

10 People are often confused by saying, well, so it

11 has to be some positive food effect; there is a

12 change. Simply saying, you know, in the labeling

13 we have studied it and there isn't any is enough to

14 cause us to ask an ANDA sponsor for a fed

15 bioequivalence study. So, almost any reasonable

16 mention at the current time of food in the labeling

17 will cause us to ask for a fed bioequivalence

18 determination of an ANDA sponsor. I think that is

19 actually in this guidance. This question simply

20 says, okay, we have gone there; we have determined

21 that we need some kind of decision or determination

22 of fed bioequivalence studies but, further, if it

23 is a Class I drug we could still waive the

24 necessity for that in vivo study based on what we

25 have just described here and discussed. So, that

114

1 is basically our current policy and how we hope or

2 have proposed it to evolve in the this guidance.

3 DR. MEYER: I think we have to remember

4 though that permeability is drug specific. It has

5 nothing to do with the formulation. So, even if we

6 are off a bit in our permeability assessment, the

7 key measurements to me are the solubility that is

8 fairly rigorous, that is fairly reasonably defined,

9 the highest dose in a certain volume; dissolution

10 over a range of pH's, which I think is excellent;

11 and very rapid dissolution for Class I drugs.

12 So, given that scenario, I feel

13 comfortable, I think, with the Class I waiver.

14 Going beyond that I feel much less comfortable.

15 So, I think there is a lot of rationale here. If

16 you don't like what they are presenting, how are

17 they going to fix it is really the 1.2 question.

18 What additional data and what types of experiments,

19 what does the committee need to see next time in

20 order to say, well, they are right?

21 DR. LEE: Yes, Larry?

22 DR. LESKO: I want to get back to the

23 discussion of the permeability issue because it is

24 one that is already established in our guidance.

25 In other words, we can now, today, allow a sponsor

115

1 to identify a drug as a Class I drug based on

2 solubility and permeability in a way that we have

3 indicated in the BCS guidance which came out in

4 2000. So, I think we have established some

5 standards already on how to define permeability,

6 and we can probably better not go back and debate

7 that today but the question is, given that

8 standard, can we then extrapolate it to the fed

9 state?

10 Now, behind that standard, when we put the

11 2000 guidance out on the BCS for fasting studies

12 there was a fairly extensive database of 30 drugs

13 in which we actually measured permeability, extent

14 of absorption, and then correlated the two. That

15 then was built into the guidance in that a company

16 would standardize their CACO 2's using internal

17 controls that represent those drugs in that

18 database. So, there was a continual linkage of

19 human data to CACO 2 and to the other

20 circumstantial evidence such as extent of

21 absorption that gave reliability to characterizing

22 something as permeability.

23 I am not sure how we can do much better

24 with permeability, other than do human studies all

25 the time. But we did get to the point, and we did

116

1 present to the committee here, the ACPS, the

2 fasting BCS guidance and the standards we were

3 going to use for permeability, and that has been in

4 place now for a year and a half. So, I just want

5 to remind people that we are not crossing new

6 ground with this permeability definition.

7 DR. LEE: Art?

8 DR. KIBBE: Just a couple of things, and I

9 love being a devil's advocate so I will probably

10 raise some issues. But to start with, when drugs

11 are marketed, in the labeling they usually have

12 indications as to whether to take them with food or

13 without food. If you have a drug on the market

14 that is clearly indicated to take without food,

15 then the question in my mind is why do we care

16 about a food study if patients are told not to take

17 it with food anyhow? If they follow the

18 instructions, and if their physician and clinician

19 get them to do it correctly, they are not going to

20 even introduce that variable. So, if you have a

21 Class I drug whose labeling from the innovator says

22 take it without food, or take it on an empty

23 stomach, it is almost a moot question to try to

24 look for the other.

25 The second, what we are saying in effect

117

1 by waiving food studies for Class I drugs is that

2 we cannot imagine a formulator formulating

3 something where a formulation would interact with

4 food differently than any other formulation, and I

5 am not prepared to say that. So, I don't know how

6 I respond to that situation because the

7 classification is all about the active ingredient,

8 and the interaction that we care about when we do a

9 bioequivalence study is not about the active

10 ingredient; it is about the formulation. So, at

11 that point I am saying, well, as long as you use

12 spray dry lactose for your direct compressible I

13 don't care if you do a fed study because lactose

14 dissolves so fast that it is out of the way and

15 leaves the drug behind. But if you use a directly

16 compressible product made out of the chick bean

17 grown in Upper Uganda I don't like it. mean, that

18 whole road is kind of difficult for me.

19 DR. HUSSAIN: Just to add to that, that is

20 the reason why a waiver is limited to immediate

21 release dosage forms, not even suggesting it is for

22 modified release. In fact, Ameeta kept mentioning

23 theophylline and the dose dumping situations that

24 we have with theophylline were for modified release

25 only. So, we are talking about immediate release

118

1 dosage forms that dissolve rapidly under different

2 pH conditions. The focus is on formulation

3 similarity from that respective. So, you are

4 talking about pharmaceutical equivalence. You are

5 looking at an excipient database of an acceptable

6 set of excipients and then you are looking at

7 similarity and dissolution as a function of the pH.

8 DR. KIBBE: So, what you are saying is

9 that I could use starch 1500 as a directly

10 compressible excipient, and the agency says it is

11 exactly the same as lactose.

12 DR. HUSSAIN: No, we are not saying that

13 the excipients are the same. The excipients could

14 be different but as long as the product dissolves

15 in a comparatively similar profile under different

16 pH conditions that should be okay. In fact, I will

17 turn that around. I say, all right, now you have a

18 direct compression tablet, say, based on dicalcium

19 phosphate. All right? Then you have a formulation

20 based on starch lactose. So, if you look at it,

21 the dose would still be pharmaceutically equal and

22 they have very different sort of pH behavior.

23 Dicalcium phosphate tends to be fairly highly

24 soluble at pH 1 but the solubility goes down at pH

25 2, and so forth. So, a product containing that

119

1 will not have a similar dissolution profile as that

2 of starch or lactose based formulation. So,

3 actually dissolution is far more discriminating

4 under those conditions for a formulation difference

5 than in vivo. In fact, my concern is that I think

6 the dissolution that we are recommending is far

7 more conservative for the fed state.

8 DR. KIBBE: What you are saying is that

9 the generic which has that is going to have to

10 prove that there is no food effect because a

11 dissolution study isn't going to be similar.

12 DR. HUSSAIN: Unfortunately, yes.

13 DR. WILDING: I would like to echo Ajaz'

14 comments. I mean, that is the key here in the

15 sense that if those two formulations are rapidly

16 dissolving and meet the current requirements under

17 the BCS guidance, then given the fact that they are

18 going to be extended in their residence time in the

19 stomach and they have longer to dissolve in vivo,

20 it is a very conservative approach that we are

21 taking in this particular regard. I think as was

22 indicated by one of your colleagues, if we go

23 outside Class I it is a whole new ball park. In

24 the context of Class I, I think given we have an

25 acceptance of in vitro bioequivalence for Class I

120

1 compounds taking it into the fed domain is actually

2 not a big leap of faith.

3 DR. MEYER: Could I ask just one question?

4 In all the comments that you received, did anyone

5 cite an example that said, well--I like Ajaz'

6 approach of if there are two formulations and I

7 have all the wealth at my command I can make

8 whatever formulations I want, can I make two that

9 will dissolve in 15 minutes; will have similar

10 dissolution profiles but will have a pronounced

11 different food effect? Did anyone comment with an

12 example?

13 DR. PAREKH: No.

14 DR. MEYER: So, we are dealing with a fear

15 of the hypothetical or a fear of the unknown, and

16 the only way to prove the unknown is to do

17 everything which is going to be very expensive.

18 DR. LESKO: But related to that, there is

19 prior information that we can go back to. When we

20 did the original research with the BCS we did make

21 formulations designed specifically to be far apart

22 in their dissolution profile, huge differences in

23 dissolution, probably more so than you would expect

24 to see even with food and fasting. Those

25 dissolution differences for the Class I drugs did

121

1 not translate into bioinequivalence in in vivo

2 studies. They were very close to being

3 superimposable in essence.

4 So, we know that. I mean, that is prior

5 information. We have that document not only for

6 the model drugs, in this case propranolol and

7 metoprolol, but some other drugs as well. I think

8 that is useful information as background to have

9 with regard to differences in dissolution for Class

10 I drugs and what it means in vivo for

11 bioequivalence.

12 I also want to comment on Dr. Kibbe's

13 comment, and maybe Dale can confirm it but I

14 believe if the label says "take on an empty

15 stomach" there is no food effect for an ANDA

16 because, you are right, patients aren't going to

17 take it that way. Is that correct, Dale?

18 DR. CONNER: Yes. I think that is

19 supported by the language in this guidance.

20 However, if you read a lot of labeling, you know,

21 you expect these definitive statements which really

22 aren't there. I mean, a lot of times that type of

23 statement which you mentioned will say, we

24 recommend--you know, I am not literally

25 translating, we recommend that you kind of take

122

1 this with food, leaving the option open to the

2 physician or the patient to say, well, you know, I

3 don't really want to take it with food, or

4 sometimes I want to take it with food and sometimes

5 not. As long as you leave discretion open to the

6 clinician or to the patient you don't have a

7 definite "must take with food." So, I would say

8 that if the labeling is very strong, the

9 instruction saying "do not take this with food," or

10 "take only on an empty stomach," then I agree with

11 you, that should kick into place. But if it is

12 very wishy-washy, giving discretion to the

13 clinician or the patient I would say we have no

14 guarantee that they are not going to instruct the

15 patient, you know, if it will upset your stomach

16 take it with food, or don't.

17 DR. LEE: I think we do need to move on.

18 DR. HUSSAIN: One point that has not been

19 made and I just want to make is that in terms of

20 bioequivalence studies, the fasting studies are far

21 more discriminating than the fed studies. That has

22 been our position. So, if we waive a fasting study

23 it is logical that we would waive a fed study. So,

24 we are actually caught in a logical bind here

25 because when we put the BCS guidance together we

123

1 went for the most difficult part and left the

2 easier part, in my opinion, behind. So, there is

3 an inconsistency in our approach with BCS.

4 DR. LEE: Yes, I think this is the

5 conclusion I want to draw. I am glad that you said

6 it, and I think on that basis we should move on.

7 Sometimes you don't have data in the literature

8 because it can never be published.

9 The question then is what other additional

10 evidence will you need to make yourself feel

11 better? I think that has to be on a case by case

12 basis. It depends on the mechanism, complexation

13 and all that kind of stuff. Isn't that true?

14 DR. DOULL: Wasn't that Marv's suggestion?

15 The question of what additional information would

16 you need, the question is what do you really need

17 to know versus what would be nice to know. The

18 need to know would be additional Class I drugs.

19 You know, we really only have the two just to prove

20 this hypothesis. So, the question is how much more

21 information do you really need in order to be

22 comfortable with accepting that all Class I drugs

23 should not meet that food criteria?

24 DR. LEE: More sponsor studies.

25 DR. DOULL: More drugs, information on

124

1 more drugs.

2 DR. HUSSAIN: I am not sure. Let me sort

3 of summarize. The question is are we willing to

4 agree or make a recommendation that with the

5 guidance, as it is in the draft form right now, we

6 can move ahead and make the recommendation that the

7 waiver for food effect bioequivalence studies for

8 Class I rapidly dissolving drugs is okay. That is

9 the question.

10 DR. KARIM: Just to comment, who puts the

11 rubber stamp that this is a Class I drug?

12 DR. HUSSAIN: It is a review decision.

13 So, FDA.

14 DR. MEYER: Do we need to come to a

15 consensus?

16 DR. LEE: Well, I don't think we need to

17 come to a consensus. I think what is important is

18 for the agency to hear what our individual

19 collective thoughts are. Some issues may not ever

20 come to consensus. It has taken them about seven

21 years to--

22 DR. LESKO: That was the debate about

23 food. But to answer Dr. Karim's question, the

24 specific review division that is looking at the

25 application makes that decision, but a lot of those

125

1 decisions are discussed within the BCS technical

2 committee as well. So, it is really a collective,

3 joint decision between the Office of Generic Drugs

4 and the Office of Clinical Pharmacology.

5 DR. MEYER: In case my individual opinion

6 then wasn't heard, I am in favor of the proposal.

7 DR. LEE: So, what about question number

8 two, the confidence intervals?

9 DR. SHARGEL: I have a question on that,

10 if I may, Vince. My understanding from the agency,

11 as you mentioned, Dr. Conner, is the question of

12 clinical risk. In the past we have only done point

13 estimates. From what I understand, the desire for

14 confidence intervals is to have a more rigorous

15 test. If we use a more rigorous test, the data

16 showed that five studies out of 40 failed. Those

17 would not have been approved on the basis of the

18 new guidance if it were formalized.

19 DR. CONNER: Basically, presumably if you

20 knew the new criteria you would have done those

21 studies all properly powered. You know, I am

22 looking at them again not with a lot of in-depth

23 analysis of those particular studies and probably

24 three of them with somewhat more power would have

25 likely passed. Two of them would have had a great

126

1 deal of difficulty and would probably have failed

2 no matter what the power. But we can't definitely

3 say that. It just looks like to me that the ones

4 that had such extreme AUC values, I am not really

5 sure power would have helped those if the criteria

6 were changed.

7 As you know, when you change the criteria

8 people then adapt to the change and design their

9 studies accordingly with, hopefully, appropriate

10 power calculations. I actually found this even a

11 little surprising, that so many from a randomly

12 selected group like this would have passed using

13 the power that people use to power for point

14 estimates. I was pleasantly surprised. I expected

15 it to be a small difference but the results of the

16 group we picked surprised me. I would have

17 expected a few more to be on the edge but I was

18 pleasantly surprised when we actually looked at the

19 values.

20 DR. SHARGEL: May I just continue on this

21 a little bit because I am just curious in terms of

22 if there is no risk, clinical risk, what the basis

23 is for a more rigorous test. What we are doing is

24 we are using a meal that gives maximal

25 perturbation, as has been mentioned, and this would

127

1 give the largest variability to be observed on Cmax

2 and AUC. Generally in the labeling it would say

3 food effects of the drug but it never really

4 specifically says what kind of food, so that any

5 sort of diet--I prefer a bagel and cream cheese in

6 the morning; that is my preference--we would know

7 if there is a clinical effect of the food. If

8 there is a clinical effect, then you would say take

9 it without food, in the development of the product

10 if there is a big effect in the bioavailability

11 study. Or, if there is reason to take it with

12 food, we already require the 90 percent confidence

13 interval. So, my question here really is, is the

14 requirement here really necessary to have a more

15 rigorous test? And, what does it mean if we fail

16 in terms of safety risk?

17 DR. CONNER: Well, there are a great many

18 products that are labeled out there with simply a

19 descriptive statement of a food effect and, in some

20 cases, how much, the estimate of how much. It

21 doesn't mean that those are unusable products. It

22 doesn't mean that they are automatically restricted

23 from taking with food. A lot of it is in that area

24 of concern where I think the firm and the division

25 that is reviewing it at FDA feel that it is

128

1 important to let clinicians know about that. But,

2 based on the labeling, the physician can still use

3 that drug under those conditions as long as that

4 effect is known.

5 Granted, although there is some variance

6 in the type of meals that people do for NDAs, I

7 think in most modern NDAs we have a very similar

8 meal used. In fact, part of what this guidance

9 does is to bring the ANDA meal and the NDA meal to

10 be the same thing. So, basically what we are

11 saying is, no matter what other food studies are

12 done, the NDA will have a determination of the

13 effect on bioavailability with a virtually

14 identical meal. So, I mean, that will be part of

15 the NDA and part of the labeling.

16 I think from a statistical standpoint,

17 this is really just saying that, you know, we are

18 doing a test here. The meal that we have chosen,

19 as has been said before--you know, we can't really

20 test every conceivable meal. I don't think the

21 generic industry would want to go in for that kind

22 of thing, doing 30 different meals and 30 different

23 studies. So, if we only have one study to do, the

24 meal that we have chosen I think has the most

25 likelihood of being extreme and causing an effect.

129

1 So, if we don't see an effect under those

2 conditions, we are reasonably confident that lesser

3 meals or meals that are less stressful to the

4 dosage form are going to have any effect. I mean,

5 if you only have one chance you use the maximum

6 possibility to obtain an effect.

7 From a statistical standpoint, we would

8 like at the end of the day to say that these are

9 equivalent, that a generic is equivalent to the

10 reference listed drug under reasonable conditions

11 of us. You know, what we have been doing for many

12 years is good but it hasn't really been a true

13 equivalence statement, based on a true statement of

14 equivalence. And, what we are trying to do here is

15 perhaps improve that somewhat so that we can with

16 total confidence say that these two are equivalent

17 under reasonable conditions of use.

18 DR. LEE: Jurgen?

19 DR. VENITZ: I would like to follow-up on

20 that because I am still trying to understand what

21 it is that you are exactly proposing. You are

22 saying for any non-Class I drug, regardless of the

23 label of the reference drug, a generic has to show

24 fasting and fed bioequivalence?

25 DR. CONNER: No, that is not what we are

130

1 saying at all. We are saying that based on the

2 label of the reference listed drug, should that

3 label contain any statement about a food effect and

4 most, if not all, of the modern drugs that were

5 recently approved, within the last few years, will

6 have some type of statement about food effect. If

7 you look at, you know, twenty years ago, NDAs or

8 products that are still out, a lot of them didn't

9 do food studies or they didn't think it was worth

10 putting in the labeling, and so forth, a statement

11 about food in those old products may be totally

12 absent. Those would not trigger us to ask for a

13 food study. But any statement of a food effect in

14 the reference listed drug labeling will trigger a

15 question about whether it is bioequivalent in the

16 fed state as well. And, based on the type of

17 product or the type of drug substance we are

18 proposing dealing with it in different ways. You

19 know, if it is a Class I drug we will deal with,

20 you know, what the first part of the discussion

21 was. If it is not a Class I, then we will do a

22 food study, which we would do today. The only

23 question is how should we power that study, and how

24 should we analyze it, and what kind of conclusion

25 can we come up with based on that approach.

131

1 DR. VENITZ: So, as long as there is any

2 statement but it says there is no food effect, then

3 the official bioequivalence for the fed state--

4 DR. CONNER: Yes.

5 DR. VENITZ: --or if there is a food

6 effect.

7 DR. CONNER: I can tell you during the

8 five, seven, twelve years, whatever, we went

9 through a lot of discussion, a lot of proposals to

10 perhaps not make it such a label-based trigger for

11 having food considerations. We looked at a lot of

12 information on whether the original effect was drug

13 substance related, formulation related and so

14 forth, the assumption being, well, if we can

15 absolutely prove it is drug substance food effect

16 it is going to be the same for a generic versus

17 not. We went through a lot of this and had some

18 proposals to do that, but we finally figured out

19 that 99 percent of the time we don't know or are

20 unable to determine. So, we seldom, if ever, have

21 the data to answer it and we would end up doing

22 food studies virtually for everything anyway.

23 DR. VENITZ: But the consequence then of

24 having done a generic fed study and having failed

25 that study would be the generic would not be

132

1 approved or you would relabel?

2 DR. CONNER: No, the generic would not be

3 approved without a passing study. But that is true

4 today. I mean, with the criteria that we are

5 looking at today, and really the major change here

6 is not doing more studies but simply how we are

7 doing the studies that the generic sponsor would do

8 anyway.

9 DR. VENITZ: And how would that compare to

10 the NDA route?

11 DR. CONNER: I mean, what we are talking

12 about here is a bioequivalence study, which is one

13 of the few studies that is done to get a generic

14 product on the market. The NDA has literally

15 sometimes hundreds of studies of different types,

16 many of them bioavailability, a lot of them

17 clinical studies, studies on a lot of aspects of

18 the drug substance and drug product and how it

19 performs clinically. With a generic you

20 essentially have anywhere from one to perhaps three

21 or four, at the maximum, small in vivo studies to

22 be able to make the decision to approve that and

23 put it on the market.

24 DR. VENITZ: But in terms of assessing a

25 food effect you would use the same approach

133

1 basically?

2 DR. CONNER: We are not assessing a food

3 effect.

4 DR. VENITZ: No, I understand, but I am

5 saying if you are in an NDA situation so you are

6 not talking about generic bioequivalence and you

7 want to assess the food effect you would use the

8 same approach?

9 DR. CONNER: A very similar one.

10 DR. PAREKH: But the final decision is not

11 that of non-approval for NDAs. The final decision

12 is if you fall within this window you can say in

13 the label that there is no food effect.

14 DR. LEE: Let's come back to question

15 number two. Art?

16 DR. KIBBE: Just to go down another

17 wonderful side path, you decided to limit the

18 waiving of a food study to an immediate release

19 because you can get good dissolution data that

20 would overlap on immediate release, as well as the

21 fact that the Class I drug is highly soluble, and

22 what-have-you. But if I make a sustained release

23 product out of a Class I drug and someone else does

24 and we have clearly overlapping dissolution data,

25 and the criteria that we are looking at clearly is

134

1 the effect of food on dosage form, is there

2 evidence that there will be a problem with food

3 when you have delayed release products?

4 DR. HUSSAIN: I think to answer that

5 question, if I look at the example of theophylline

6 controlled release, modified release, the mechanism

7 for dose dumping there was different. Jerry Skelly

8 and others have actually done in vitro work that

9 actually showed that could be predicted. But our

10 confidence in in vitro is not at that level at this

11 point to go in that direction. So.

12 DR. KIBBE: If it is not an effect on the

13 drug moiety itself, the active ingredient, then it

14 is a matter of how confident you are in the

15 formulations being truly similar even if they give

16 the same dissolution profiles.

17 DR. HUSSAIN: The question is can you rely

18 on in vitro dissolution to understand the complex

19 mechanisms. Our answer is no, not at this time.

20 DR. LEE: Marv?

21 DR. MEYER: I tried to jot down the

22 reasons why not to use confidence limits. One, no

23 one takes drugs with a meal of any type. Well,

24 that is obviously not true and since we don't know

25 what type let's use the worst condition, confidence

135

1 limits are not a valid measurement of

2 bioequivalence. I think if they are good enough

3 for fasted, they are good enough for fed. Highly

4 variable drugs will pose a problem, and if they

5 somehow scrape by fasted they may not scrape by

6 fed. Well, that is an economic issue and that is a

7 statistical issue and it may be that we need to

8 change the stats for both fed and fasted to somehow

9 capture a point estimate and the variability of the

10 reference relative to the test, or vice versa but

11 that is a side issue. Too many failures. Well, we

12 have shown here that about five out of 40 would

13 fail marginally. With a proper designed study they

14 wouldn't. There would be like two or three out of

15 40. It would cost too much money; too many

16 subjects. We would have to again change our

17 statistics. I think FDA can't worry about public

18 health in the context of a $50,000 or $10,000

19 bioequivalence studies that some sponsor may have

20 to conduct. Numbers of subjects, we are still only

21 talking 30, 40 subjects. So, I think the reasons

22 why not to have confidence limits aren't

23 substantiated, and I have always felt that if

24 fasted need confidence limits, then fed need

25 confidence limits.

136

1 DR. LEE: Other points of opinion?

2 DR. MOYE: I guess I should say on the

3 record that at the conclusion of this session I

4 will turn over a synopsis of an alternative

5 analysis that would avoid the indirect approach of

6 confidence intervals, and would allow one to now

7 include this measure of variability that has been

8 excluded from the analyses.

9 DR. LEE: So you will have this synopsis

10 as food for thought.

11 DR. MOYE: As an admissible alternative.

12 DR. PAREKH: This is just for the record,

13 Dr. Meyer, you asked a question earlier about the

14 point estimates. For the two products that failed

15 on AUC the point estimates were 1.22 and 1.20. For

16 the three that didn't make it on Cmax, it was 0.86,

17 0.87 and 0.88.

18 DR. LEE: Are you satisfied?

19 DR. MEYER: Yes.

20 DR. LEE: Are there any other ideas or

21 suggestions, opinions? If not, thank you very

22 much. That concludes the agenda item on food

23 effect of BE studies. Now we are into the public

24 hearing. We have three submissions. The first two

25 cannot make it here, and we do have the last person

137

1 here, Russ Rackley. For the record, I have asked

2 Kathy to read the first two, and you all have that

3 in your notes.

4 Open Public Hearing

5 MS. REEDY: Yes, the right side of your

6 red folder has your agenda, your questions and the

7 open public hearing submissions in writing. On the

8 left side are the slides that were submitted in

9 advance. For the slides that were not submitted in

10 advance, they may show up at the time of their

11 presentation.

12 But for the open public hearing, the first

13 submission is from Brian Kearney, senior scientist,

14 clinical pharmacology, Gilead Sciences.

15 Guidance for industry food effect

16 bioavailability and fed bioequivalence studies,

17 commentary on the following issues is not currently

18 included in the draft guidance and FDA

19 Pharmaceutical Advisory Committee perspectives

20 would be much appreciate. One, please comment on

21 the acceptability/utility of parallel study designs

22 and/or secondary statistical analyses of PK data,

23 collected across studies, to evaluate food effects.

24 For example, could pharmacokinetic data derived

25 from fed studies in later stage PK studies b

138

1 compared to fasted, reference data from a previous,

2 formal crossover food effect study?

3 Two, while single dose studies are

4 preferred as they are the most sensitive to food

5 bioavailability effects, please comment on the role

6 and acceptability of steady state comparisons for

7 compounds with a short elimination half-life and/or

8 with predictable, reproducible PK profiles. Those

9 are Brian's comments.

10 The next is David Fox, writing to present

11 the views of Abbott Laboratories on a matter

12 scheduled for discussion at the upcoming meeting of

13 the Food and Drug Administration's Advisory

14 Committee for Pharmacologic Science on May 7th and

15 8th, 2002.

16 Specifically, we wish to comment on the

17 draft guidance document titled, "Food Effect

18 Bioavailability and Fed Bioequivalence Studies:

19 Study Design, Data Analysis and Labeling." We ask

20 that the committee carefully consider our written

21 submission in the course of its deliberations.

22 The food effect guidance recognizes that

23 foods and beverages often have a clinically

24 significant effect on the bioavailability of an

25 active drug ingredient or on the bioequivalence of

139

1 two different formulations of the same active

2 ingredient. Food effect guidance at 2. A growing

3 number of drug products now bear labeling that

4 describes a significant food effect, a trend which

5 Abbott believes is good for patients. Food effect

6 labeling contributes to consistent and more

7 accurate dosing and can help patients adopt a

8 routine set of conditions under which they take

9 their medicines.

10 Second, the food effect guidance

11 recognizes the need for bioequivalence studies

12 under fed conditions, particularly where the

13 reference of the pioneer product bears food effect

14 labeling. Food effect guidance at 4.

15 Food effects may be formulation specific,

16 and two different versions of the same drug may

17 react differently in the presence of food. In

18 fact, two products may react differently depending

19 on the quantity or type of food used. And, he uses

20 a reference discussing an example of two products,

21 each with the same active ingredient and dosage

22 form that had clinically significant

23 bioavailability differences depending on whether

24 the drugs were taken with chocolate milk, apple

25 juice or orange juice. For these reasons, the

140

1 guidance endorses the need for well-controlled and

2 well-designed fed bioequivalence studies where the

3 reference product has a noted food effect. Food

4 effect guidance at 3, noting that the mechanism by

5 which food may affect bioavailability is often

6 unknown and cannot be determined by physical

7 inspection of in vitro study.

8 Abbott agrees and compliments the agency

9 for recognizing these points. Abbott's

10 concern,however, is that the agency has not gone

11 far enough to address the variable bioavailability

12 seen by many drugs under different meal conditions,

13 nor has the agency taken steps to ensure that

14 bioequivalence studies performed by applicants

15 under abbreviated new drug applications follow the

16 same meal conditions used in the study of the

17 reference drug product. Instead, the agency

18 recommends only the use of a high-fat, high-calorie

19 test meal to provide the greatest effects on

20 gastrointestinal physiology so that systemic drug

21 availability is maximally affected, food effect

22 guidance at 6.

23 For a product with a known sensitivity to

24 food, the agency's approach in many instances is

25 likely to mask or obliterate important formulation

141

1 differences. The better approach, we suggest, is

2 to require fed bioequivalence studies under the

3 meal conditions suggested in the labeling or, if

4 the labeling is not specific, under the meal

5 conditions likely to be followed by patients who

6 use the drug. Alternatively, the sponsor of a

7 bioequivalence study should follow the meal

8 conditions that were used to support the efficacy

9 of the reference drug product. Patients on a

10 low-fat diet who are instructed to take their

11 medications with meals should be assured that a

12 generic substitute will behave the same under

13 low-fat conditions as the pioneer.

14 Finally, while the food effect guidance

15 allows for the use of other test meals, food effect

16 guidance at 7, the guidance puts the decision

17 within the discretion of the sponsor. It is the

18 generic drug sponsor's choice, for example, to

19 conduct a bioequivalence study with a test meal

20 other than the maximum 50 percent fat meal

21 described introduction he guidance. Abbott

22 disagrees with this approach. The guidance must

23 recommend the use of a test meal that closely

24 reflects the labeled conditions of use or the

25 conditions under which the reference drug was

142

1 studied. In fact, by allowing the sponsor to

2 select the test meal, FDA invites the real risk

3 that the sponsor may use food selection to drive or

4 optimize the showing of bioequivalence.

5 In short, the agency's thinking on the

6 need for bioequivalence studies is pointed in the

7 right direction but, at this stage, is too general.

8 For products that are food-sensitive, it may be

9 impossible to know in advance whether the product

10 will behave in a linear or predictable way under

11 different meal conditions. Simply comparing two

12 products under fasting and high-fat conditions may

13 be insufficient, especially when the drug is

14 labeled for us under low-fat or other dietary

15 conditions. Food effects are not yes/no

16 propositions. Far too little is known about food

17 effects for FDA to assume the use of one type of

18 meal for all drug products.

19 For these reasons, we respectfully request

20 that the committee consider three related points.

21 The first, the need for fed bioequivalence studies

22 under conditions other than the maximum 50 percent

23 fat meal described in the food effect guidance.

24 Secondly, the need for fed bioequivalence studies

25 under the conditions of use recommended or

143

1 described in the labeling; and, thirdly, the need

2 for fed bioequivalence studies that follow the same

3 study design used in the clinical testing of the

4 pioneer product. We greatly appreciate your

5 attention to this issue.

6 DR. LEE: Thank you very much, Kathy, for

7 reading it, and I don't think we can ask any

8 questions because the presenter is not here. So,

9 next I would like to invite Dr. Rackley, from Mylan

10 Laboratories to give a ten-minute presentation. He

11 is going to be speaking on behalf of the Generic

12 Pharmaceutical Association.

13 DR. RACKLEY: Thank you. It is an honor

14 to be here to speak before you today on behalf of

15 the Generic Pharmaceutical Association.

16 [Slide]

17 ANDAs have been approved and marketed

18 since around 1985 with no documented safety issues.

19 The demonstrated safety and wide acceptance of

20 these products by the general public are indicative

21 of the robustness and adequacy of the current

22 approval process. We propose that the current

23 system for the evaluation of bioequivalent drug

24 products be maintained.

25 [Slide]

144

1 For current fasting bioequivalency studies

2 this represents a standard bioavailability

3 comparison of test and reference drug products.

4 Ninety percent confidence intervals are well

5 accepted as demonstration of bioequivalence.

6 [Slide]

7 For current fed bioequivalency studies,

8 the OGD breakfast represents an extreme food

9 condition. The standard breakfast allows for

10 effect of food on GI motility, the effect of food

11 on the bioavailability of the drug in vivo, the

12 effect of food on the formulation of the drug.

13 [Slide]

14 Point estimate criteria is well-accepted

15 for the fed studies as further confirmation of

16 bioequivalence. The requirement for 90 percent

17 confidence intervals for a food effect study does

18 not improve the safety of the generic drug product.

19 [Slide]

20 Regarding post meal administration,

21 logistically it is difficult for everyone to

22 consume a standardized breakfast in exactly 30

23 minutes and then immediately take the dosage form.

24 Study subjects should be allowed to consume the

25 standard meal within 30 minutes and the dosage form

145

1 will be administered 30 minutes after the start of

2 the meal.

3 [Slide]

4 Pharmacokinetic parameters to assess

5 bioequivalence, AUC and Cmax should remain the

6 primary parameters upon which to assess similarity

7 of rate and extent of absorption. Expectation of

8 Tmax to be comparable is vague and tends to be

9 subjective. Tmax should be provided for

10 information purposes only, and not held to a

11 statistical criteria.

12 [Slide]

13 Regarding sprinkle studies and special

14 foods, if a dosage form is shown to be

15 bioequivalent after a stringent fasting study and

16 similarity is confirmed by a fed study, there is no

17 reason to believe that it will not be bioequivalent

18 when taken with a small amount of food.

19 We acknowledge there are no examples where

20 vehicle has had a significant effect on

21 bioequivalency, and these should be well documented

22 in labeling under dosage and administration.

23 [Slide]

24 However, requirements to demonstrate

25 bioequivalence, when taken with special foods or

146

1 vehicles, will lead to anecdotal stories and open a

2 flood gate for an infinite number of study

3 requirements for generic approval. There is no

4 doubt that this will be taken advantage of to delay

5 generic approvals.

6 [Slide]

7 Standard breakfast, the FDA standard

8 breakfast is adequate for demonstration of food

9 effect on bioavailability. The use of alternate or

10 unusual food studies may be used as a tactic to

11 further delay generic approvals.

12 [Slide]

13 In conclusion, the current approach for

14 performing food effect bioavailability studies

15 using a standardized meal is adequate. Unless the

16 current methods and criteria represent a danger to

17 public safety, we, as responsible scientists and

18 citizens, should challenge unreasonable regulations

19 and requirements. The existing fasting BE and fed

20 BA studies are time-tested methods. Changes to

21 these methods increase the burden to the industry,

22 delays approvals and does not seem to be justified.

23 DR. LEE: Thank you. Are there questions

24 for Dr. Rackley?

25 DR. SHARGEL: Dr. Meyer mentioned about

147

1 variability drugs, where you have a highly variable

2 drug it would seem to me that food effect and

3 trying to match 90 percent confidence intervals

4 would be very tough. How do you feel about that,

5 or widening the intervals past the 90 percent

6 confidence intervals, from 0.8 to 1.25?

7 DR. RACKLEY: Clearly, a highly variable

8 drug product would have had to be powered

9 adequately, probably with large numbers of

10 subjects, in a fasting study. If the same

11 inter-subject CV were to be held or shown for the

12 same drug products in a fed study you would likely

13 be doing, again, huge size studies. So, where

14 there is 10 percent of studies that might not pass

15 confidence intervals, you might also factor in that

16 some of these studies might have to be done with

17 perhaps even over 100 subjects to do a fed study,

18 whereas today they demonstrate or reaffirm what a

19 rigorous, stringent fasting bio study has

20 demonstrated.

21 DR. LEE: Larry?

22 DR. LESKO: Are you aware of any evidence

23 that food can reduce the variability in a highly

24 variable drug case where a drug is highly variable

25 under fasting conditions, but when you give it with

148

1 fed the variability actually is reduced? I mean,

2 as a general assumption the variability is going to

3 go up with food, and I would say we haven't seen

4 that in the analysis of our own data. When Ameeta

5 showed the ANDA data where 35 out of 40

6 applications met confidence intervals, it suggested

7 that the variability did not change compared to the

8 fasting studies, or else not that high number would

9 have passed. So, I am not sure of the assumption

10 that food increases variability, unless we have

11 some evidence to suggest that is one that is

12 necessarily valid. Perhaps in the FDA survey that

13 was done with 40 drug products, or if they want to

14 add more to it, they would provide those point

15 estimates and what the estimates for inter-subject

16 variability were under fasted and fed conditions.

17 That is just a thought. I mean, the data is out

18 there. There is plenty of it that comes in every

19 year.

20 DR. RACKLEY: I guess one question I was

21 going to ask about our own database is what was the

22 size of the fasting studies for the corresponding

23 applications for which you showed fed data. In

24 other words, was the fasting study larger or the

25 same size?

149

1 DR. CONNER: I don't know the exact

2 numbers that correspond to these 40 but generally

3 what we usually see is around a 24-subject study

4 for most products. You know, we might see up to

5 36. The highly variable drugs are, you know,

6 special. Fortunately, in the scheme of things they

7 are a relatively small problem but they are a very

8 special problem which we have to deal with for

9 fasting studies as well. I mean, for most drugs

10 that are very highly variable we are talking about

11 60 or 80 subjects, but there is a very small subset

12 where it is over 100, if not more. So, we are

13 currently thinking or working on ways to do

14 different types of analysis, say, with perhaps the

15 ideas on scaling that came out of the individual

16 bioequivalence efforts, but those things are not

17 ready yet. We still have a lot of work to do on

18 working that out, but we hope to eventually have a

19 way of dealing specifically with highly variable

20 drugs whether we are doing a fasting or a fed study

21 that will, you know, come in with a valid approach

22 at a reasonable sample size.

23 DR. LEE: Very well, thank you. Let me

24 summarize this morning. I think this morning we

25 have witnessed the progressive approach to

150

1 reexamine the guidance as science evolves, as drugs

2 change, and so forth. I think we can come to some

3 cautious conclusions, and I think we are kind of

4 cautious because we, as scientists, always think

5 about exceptions. Also, as a member of the

6 committee I would like to suggest thinking about

7 meals, new composition, as a possibility to see how

8 far that thinking would go. As you can hear from

9 our discussion, what is the intent of the guidance

10 to look at the food effect.

11 On that note, I think we are ahead of

12 schedule but in fear of a long discussion this

13 afternoon--yes, Art?

14 DR. KIBBE: One quick question. Am I

15 right as I read the guidance that you have

16 eliminated now therapeutic index drugs a priori

17 from consideration, or did you just eliminate the

18 ones that don't meet the criteria for high

19 solubility? The therapeutic index is an indication

20 of their interaction with the receptors and not

21 necessarily an indication of the nature of the

22 chemical itself or the dosage form.

23 DR. LESKO: When you say eliminate,

24 eliminate from what?

25 DR. KIBBE: I thought there was a

151

1 statement in there.

2 DR. LESKO: The waiver of NTIs in the food

3 guidance is similar to what we did in the BCS

4 fasting guidance, and I believe they are excluded

5 from bio waivers in both guidances.

6 DR. KIBBE: But my point is that that

7 isn't necessarily necessary. If the therapeutic

8 index is a function of the way the drug behaves in

9 the body and our guidances are a way of helping us

10 determine equivalence between products, then I am

11 having a hard time getting my hand around

12 eliminating a narrow therapeutic index drug from a

13 waiver just because when you give it, no matter who

14 makes it, no matter how it is administered, it is

15 the way that it works in the body that is at issue

16 and not the dosage form.

17 DR. LESKO: I think that is a good

18 question and it is probably an open question. We

19 have discussed it here in this committee and it was

20 related to the level of certainty about the science

21 that you wanted to be careful about expanding this

22 to each and every drug, even those that have narrow

23 therapeutic index. On a scientific basis,

24 mechanistically speaking, you are right in arguing

25 that they should not necessarily be excluded

152

1 because the therapeutic index is related to the

2 pharmacology and not the pharmaceutics of the

3 dosage form. You know, it is something if the

4 committee feels we should revisit, I think we can

5 do that.

6 DR. VENITZ: But I would argue all we are

7 doing is risk management. The stakes are higher.

8 That is what it really comes down to.

9 DR. MEYER: It is okay to continue a

10 little bit with the proposed guidance, or do you

11 want to break?

12 DR. LEE: What would you like to bring up?

13 DR. MEYER: Well, I have a couple of

14 questions. Dr. Rackley raised the issue of

15 sprinkles and special vehicles.

16 DR. LEE: Sure.

17 DR. MEYER: That wasn't one of the

18 questions we should deal with. Can we comment now?

19 DR. LEE: Go ahead.

20 DR. MEYER: I guess my one question about

21 the sprinkles is it seems to make sense if it

22 passes a high-fat meal, why also make people put it

23 on apple sauce and swallow the sprinkles? Is there

24 evidence to suggest that that is a problem?

25 DR. CONNER: I don't view that they are

153

1 studying two totally different things. With the

2 sprinkle it is I think most of the time it pertains

3 to beaded, modified release dosage forms, which

4 depend on their mechanism of release with a coating

5 or some other mechanism that, on direct and perhaps

6 slightly prolonged contact with the food of given

7 properties--pH, fat content and so forth--we are

8 talking about not mixed up in the milieu of the

9 stomach but in actual direct contact, dumped in and

10 mixed into this food, that there is at least a

11 possibility that that coating could be broken down

12 where you wouldn't necessarily see an effect when

13 it is mixed up with stomach contents, and so forth.

14 And, for these type of products often it

15 is stated in the labeling that they are labeled to

16 be given this way. If you have ever worked at

17 hospitals or had small children that had to take

18 this type of dosage form, you know that frequently

19 they are dumped into food and left around perhaps

20 for half an hour, an hour on normal use. So, the

21 worry is that at some point that mechanism that we

22 depend on is disrupted. Now, in a bioequivalence

23 sense what we worry about is not that both products

24 are going to be disrupted in the same way; we are

25 worried that we could have a differential effect.

154

1 If I put the innovator product in apple sauce, it

2 is perfectly stable; no breakdown; you take it

3 after five or ten minutes, and then I put the

4 generic in and it immediately dissolves, you know,

5 I have a real problem with that because those two

6 products are not going to be bioequivalent under

7 those conditions. A lot of people say, well, it is

8 the same thing as the food study we have always

9 done. I think it is a very direct challenge of the

10 coating or mechanism of modified release by direct

11 and very concentrated contact with the food. That

12 is the rationale for doing it.

13 DR. MEYER: It almost seems like that

14 could be studied in vitro with apple sauce mix in a

15 basket, or something.

16 DR. CONNER: I can imagine pouring the

17 apple sauce after the dissolution. You know,

18 theoretically I am not saying that you couldn't

19 develop some kind of in vitro method to get at

20 this. I don't really think that we know enough

21 about it to know what the properties are or how we

22 should approach that. If people have some research

23 or some ideas in mind, we would love to see the

24 data on that. But right now the most direct way of

25 studying this is with an in vivo study. Perhaps

155

1 later on we can develop a system to do it in vitro

2 in a valid way. We are just uncertain of how to

3 approach that with our current knowledge.

4 DR. SHEK: There is at least on case for a

5 liquid where it makes a difference with what type

6 of juice you are using.

7 DR. HUSSAIN: In that case I think it is

8 far more complex. I would rather not discuss that

9 particular case here.

10 DR. LESKO: It is worth mentioning one

11 thing, the problem you were going to bring up is

12 with a fairly old product, I believe. But nowadays

13 any NDA that comes in that wants to make a claim

14 about administering the drug with food, either

15 sprinkles or orange juice, or whatever it is, is

16 going to have to have some evidence to make that

17 claim in the label. Whereas, in the past I don't

18 think we appreciated all the various mechanisms of

19 interactions and we sometimes let some of that go

20 with the vehicles. But I think that has changed

21 today and the label is pretty much going to reflect

22 the evidence that company submits.

23 DR. LEE: Marv, a second point?

24 DR. MEYER: Yes, the one about special

25 vehicles, if the label of the reference listed drug

156

1 says apple juice, orange juice, grapefruit jelly,

2 what-have-you does not affect the absorption, as I

3 read this guidance the generic has to do all of the

4 above to show that they do not affect the generic

5 formulation. Is that a reasonable thing for us to

6 be allowing to happen?

7 DR. LESKO: My sense would be it would

8 have to be case by case. You would have to look at

9 the reference listed product and see what data is

10 available that supported that claim in the label

11 and with there is any mechanistic reason that a

12 study needs to be done. I wouldn't generalize on

13 that issue.

14 DR. MEYER: But the guidance does

15 generalize.

16 DR. LESKO: I think the guidance makes

17 some recommendations rather than exclude it, and

18 you would have to interpret that I think on a case

19 by case basis.

20 DR. KIBBE: Just following up on that,

21 would the generic company then who sees that type

22 of labeling on a product they wish to duplicate do

23 well to talk to you about whether they need to do

24 that study or not before they even go down that

25 road?

157

1 DR. LESKO: I would. I think Dale is

2 going to comment, but I think it might be something

3 we can clarify and deal with because I think we

4 know what the intent is. It is a matter of getting

5 the right words around it.

6 DR. CONNER: It comes up with our recent

7 experience with certain products, which we don't

8 want to talk about today. Fortunately for us,

9 these products that are covered by that are very

10 few and far between. I think we are not dealing

11 with a huge number here. So, we wanted to really

12 leave ourselves the option of dealing with these

13 problems, not only option but the ability to deal

14 with these problems as we saw them. You know,

15 should we see a very complex dosage form or a

16 liquid dosage form or one that needs to be mixed

17 with a beverage, we will have the ability and the

18 sponsors will know that that is a potential problem

19 and they can put that into their thinking as far as

20 how they develop their dosage form, whether it be

21 the original innovator dosage form or a generic,

22 about how to approach that and what to ask us about

23 and what they would like to propose themselves. It

24 really just puts both the FDA and the industry on

25 notice that this is a potential issue and that they

158

1 need to work it out prior to being approved.

2 DR. HUSSAIN: Vince, just to sort of

3 clarify, I think if we discuss that example it

4 brings up the issue of a particular product, and so

5 forth. I think it would be a good question and I

6 think we will go back and consider it maybe at the

7 next meeting. We could actually make that a case

8 study for discussion because for that to happen, I

9 think the key sponsors would need to be present in

10 the room.

11 DR. LEE: Certainly, I think so. As

12 science evolves and we know more about something,

13 you know, what should we do about it? Yes, Leon?

14 DR. SHARGEL: Yes, I agree. You know, for

15 specialized diets the guidance sort of leaves open

16 possibilities of last minute labeling changes,

17 which certainly slows entry of generic products. I

18 think it needs to be clarified a little bit more

19 clearly when a food is required for specialized

20 issues, and I think the innovator who is making the

21 claim when there is an issue should actually show

22 data.

23 DR. LEE: Thank you very much for the

24 discussion. I think that we are going to move on

25 to the afternoon about the BCS and I don't know

159

1 what this discussion is going to lead to. It

2 hopefully won't lead us to come back to revisit the

3 food effect today but maybe in a future session.

4 Kathy does have some announcements to make.

5 MS. REEDY: For those who have contracted

6 for the convenience of having your sandwiches here,

7 in the building, they will be directly across the

8 hall. For those consultants, members and guests

9 who have not yet done so, you may do so by finding

10 Beverly O'Neal and handing her $10.00. For all

11 others, it is a lovely day and there are a number

12 of sandwich shops in the neighborhood.

13 DR. LEE: Thank you. We will come back at

14 1:15.

15 [Whereupon, at 12:05 p.m., the proceedings

16 were recessed for lunch, to reconvene at 1:20 p.m.]

160

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

2 DR. LEE: Welcome back. We heard about

3 BCS all morning. So, this afternoon we will find

4 out what exactly BCS is, for those of you who don't

5 know about it. More importantly, we want to talk

6 about the next steps. These are not baby steps;

7 these might be giant steps. We have Lawrence Yu,

8 Acting Deputy Director of Science, OGD/OPS, to

9 introduce the topic.

10 Biopharmaceutics Classification System - Next Steps

11 Introduction and Overview

12 DR. YU: Good afternoon. Dr. Vincent Lee,

13 Chairman of the FDA Advisory Committee for

14 Pharmaceutical Science, members of the FDA Advisory

15 Committee for Pharmaceutical Science, my FDA

16 colleagues and distinguished guests, this afternoon

17 we will cover the biopharmaceutics classification

18 system - next steps.

19 [Slide]

20 We will have three presentations. Dr.

21 Gordon Amidon, chairman and professor of

22 pharmaceutics at the University of Michigan, will

23 give a talk entitled history and applications of

24 the biopharmaceutics classification system. Dr.

25 Jack Cook, from Pfizer, will give a second talk

161

1 entitled the industrial experience with the BCS. I

2 will give the third talk entitled regulatory

3 implementation and potential extension of the

4 biopharmaceutics classification system.

5 [Slide]

6 Following the three presentations there

7 will be two questions which have been slightly

8 modified. The first question is should the agency

9 consider revising the pH range of the solubility

10 class boundary to be consistent with the

11 dissolution pH range?

12 The second question is should the agency

13 consider expanding the application of the BCS based

14 biowaivers to rapidly dissolving and immediate

15 release products of the BCS Class III drugs,

16 namely, highly soluble and permeable drugs? With

17 that introduction, I will turn the podium to Prof.

18 Gordon Amidon.

19 Presentations

20 DR. AMIDON: Thank you, Lawrence. It is a

21 pleasure to be here, talking about and seeing the

22 evolution of the biopharmaceutics classification

23 system, something that I have worked on I think for

24 almost 15 years. At least if you count the very,

25 very beginnings for an FDA workshop on dissolution

162

1 and absorption, since 1988, I believe, so it has

2 been a long time and I will show some of that

3 history. Then, to see the application of BCS this

4 morning being used as a basis for providing waivers

5 for Class I drugs, waiver of food studies for Class

6 I drugs, I think of that as a superb extension of

7 and use of the BCS concept because how else could

8 you come to that conclusion without having a

9 mechanism for biowaivers? So, I think that is a

10 superb application and I was pleased to see that go

11 so well.

12 [Slide]

13 The process of BCS is based on looking at

14 the systemic availability versus the absorption

15 processes controlling appearance of drug into the

16 plasma, and transitioning from the systemic

17 availability view to the absorption view, and then

18 using that, in turn, to set standards for drugs.

19 Because if we can ensure absorption, we will also

20 ensure systemic availability. The advantage of

21 ensuring absorption is that now we can talk about

22 processes in the gastrointestinal tract and develop

23 scientific hypotheses to formulate and proceed.

24 That process led then to the guidance, the

25 so-called BCS guidance which says waiver of in vivo

163

1 bioavailability and bioequivalence trials. I think

2 that choice of terms I am fairly happy with because

3 it says waiver of in vivo bioavailability and

4 bioequivalence trials. We are not waiving

5 bioequivalence. No one has ever proposed that, and

6 I think bioequivalence, Cmax and AUC is the gold

7 standard and BCS doesn't change that. It provides

8 alternatives to ensuring in vivo bioequivalence.

9 Our goal is to ensure bioequivalence and to meet

10 that standard. In fact, I will argue that I think

11 it is clear that for BCS Class I drugs that

12 dissolve rapidly the in vitro standard is actually

13 a better standard. It is not as good; it is not a

14 substitute; it is actually better because the in

15 vivo test is not very accurate.

16 [Slide]

17 BCS is a scientific framework for

18 classifying drugs based on their aqueous solubility

19 and intestinal permeability. This is fairly

20 straightforward. I will say a little bit about the

21 science today and the extensions. I do want to

22 provide some overview of the process that was

23 involved in moving this guidance along.

24 When I became involved in bioequivalence

25 in the mid to late '80's, it was Cmax and AUC,

164

1 empirical; you do the test and reference and get

2 the result; do the statistics and you pass or fail;

3 and that was kind of the end of the story. When we

4 developed the concept of BCS we also needed a

5 database and scientific support to develop the

6 standard.

7 [Slide]

8 So we began some research with the support

9 of the FDA, at that time the Office of Generic

10 Drugs in 1990 at Michigan and Uppsala and at

11 Maryland. Over the period of the next five years

12 that led to substantial research. The first

13 application of BCS was incorporation actually into

14 one of the SUPAC guidances in 1995. We actually

15 formed a working group at the FDA. I think we made

16 our first presentation to the ACP panel around

17 1996. I can't read that well. In 1996 we made our

18 first presentation and proposal to this committee

19 regarding biowaivers and the BCS approach. It was

20 supported at that time and led to more research.

21 Also, at that time I took leave of absence and

22 spent four months at the FDA, working with Ajaz and

23 Larry.

24 I should say at the very beginning that

25 Larry Lesko was the initiator with me. He referred

165

1 to himself as the grandfather when he passed me

2 this morning after the BCS discussion. If he is

3 the grandfather, what does that make me, Larry? I

4 was trying to think that maybe we could be

5 grandparents but that doesn't work somehow. But we

6 worked on this over about a five- or six-year

7 period, building up the science and the draft

8 guidance.

9 The actual draft guidance was drafter in

10 1995 with Ajaz. So, Ajaz was instrumental. He

11 came in, in 1995 to replace Larry because Larry

12 moved up and took on other responsibilities and

13 Ajaz did a superb job writing the draft guidance.

14 I say that so that if there are any problems with

15 it, it is Ajaz' problem.

16 Many of the extensions, I would say we are

17 talking about today, were discussed at that time.

18 I can't say all of them because I can't remember

19 everything. But in the process of developing the

20 guidance we came up with what we thought were the

21 most conservative and sure-thing in terms of

22 biowaivers because if we were going to change the

23 paradigm of biopharmaceutics we wanted to do it

24 carefully so that it is accepted. We don't want to

25 make a mistake going out there with that first

166

1 application for biowaivers. So, we ended up with a

2 very conservative guidance.

3 [Slide]

4 The actual draft guidance was published in

5 February of 1999 and then the final guidance was

6 published in August of 2000. You can see the

7 number of workshops and scientific discussions we

8 have had--the U.S., Europe and Japan, as well as

9 Latin America, including a workshop at PAHO, the

10 Pan American Health Organization, because this

11 guidance is important in developing countries as

12 they develop or phase in bioequivalence standards

13 throughout the Americas. So, there is a great deal

14 of interest in this approach.

15 [Slide]

16 There was a lot of discussion and I think

17 I can say it is generally accepted. At least we

18 have been out talking about it enough so no one

19 stands up and argues with me anymore. This is kind

20 of the principle of bioequivalence as I think of

21 it, kind of like the central dogma in biology which

22 we now know is wrong because one gene produces more

23 than one protein. At any rate, this is the dogma,

24 similar plasma levels, similar pharmacodynamics;

25 similar in vivo dissolution, similar plasma levels.

167

1 That is similar in vivo dissolution. Then, in

2 vitro dissolution can match in vivo dissolution.

3 Oftentimes when we talk about dissolution, we use

4 that term too generically, like cancer. You know,

5 there are so many different versions of it.

6 Dissolution in what? So, what we want to do is

7 establish a BE or bioequivalence type dissolution

8 methodology which would be more complex and more

9 elaborate perhaps than the usual QC or quality

10 control dissolution methodology that would be used

11 when you make major changes in your formulation

12 that engender a bioequivalence question.

13 [Slide]

14 So, we have changed from systemic view to

15 the fraction absorbed view. Marvin, I think your

16 point was well taken this morning that

17 bioavailability is much easier than fraction

18 absorbed. It can be very hard and sometimes even

19 impossible if your drug is unstable in the

20 gastrointestinal tract and the metabolite or active

21 compound, like an ACE inhibitor, is not well

22 absorbed. So, it can be impossible almost to

23 determine what actually is the fraction absorbed.

24 But in the majority of cases you can determine it

25 by mass balance studies or IV and oral excretion

168

1 studies or bioavailability.

2 Now, the initial rationale for the BCS

3 waiver was the following: If a drug dissolves

4 rapidly like a solution and becomes essentially a

5 solution in the gastrointestinal tract,

6 particularly the stomach, a rapidly dissolving

7 drug, then the rate-determining step for absorption

8 is gastric emptying. It is not a formulation

9 difference; it is gastric emptying. So, on the

10 basis of that rationale, if gastric emptying is a

11 slow step for a high solubility, high permeability,

12 rapidly dissolving drug, plasma levels tell you no

13 information about formulation differences.

14 Consequently, an in vivo test is not the best test

15 for ensuring in vivo bioavailability. In this case

16 then a dissolution test would be more than an

17 adequate surrogate for an in vivo test. And, that

18 is where the waivers are currently allowed for a

19 high solubility, high permeability, rapidly

20 dissolving drug.

21 [Slide]

22 As you think about extensions of BCS, we

23 are going to propose several extensions. We had

24 one workshop on January 31, February 1 on

25 extensions. We have had one meeting at the FDA

169

1 with the internal working group on extensions, and

2 I would say there is a list of about six or eight

3 areas we are considering for extensions, of which

4 the two that we are proposing today represent what

5 we think are the next steps that we should take.

6 [Slide]

7 I will say a few things about other areas

8 of extensions and illustrate them. First is the

9 extension to Class III drugs, which are high

10 solubility but low permeability. Those are drugs

11 like atenolol which are less than about 50 percent

12 absorbed, or maybe 60 or 70 percent absorbed. So,

13 the remainder of the drug is in the intestine the

14 whole time. Fifty percent of the atenolol dose is

15 in the colon all the time, or just about that,

16 because the majority of the residence time is in

17 the colon. That means the colon permeability has

18 to be pretty small.

19 So, there is position-dependent

20 permeability along the gastrointestinal tract.

21 While we think if a drug like cimetidine or

22 ranitidine dissolves very rapidly in the stomach, a

23 waiver should be allowed for those drugs, but they

24 must dissolve in the stomach. So, we think

25 probably a tighter dissolution specification is

170

1 important for low permeability drugs because of the

2 position-dependent permeability, in most cases,

3 along the gastrointestinal

4 tract--position-dependent in the very least. We

5 know some drugs are absorbed in the duodenum

6 jejunum because we have plasma levels, and we know

7 that it is in the colon all the time and it is not

8 completely absorbed. So, there is clearly

9 position-dependent permeability, although evidence

10 for colon permeability is much harder to obtain.

11 It can be obtained but it is much harder.

12 A third area of discussion is low

13 solubility drugs or so-called Class II drugs that

14 dissolve rapidly in the gastrointestinal tract.

15 This is more problematical. Let's say there are

16 more scientific issues here and we are not ready to

17 make a proposal in the area of low solubility

18 drugs, but I will give you one example of my own

19 thinking, and that is if you take salicylic acids

20 like NSAIDs, ibuprofen, ketoprofen, the high

21 permeability drugs, we have measured most of them

22 in humans, all of them in animals and they dissolve

23 very rapidly at pH 6.8 because they ionize. The

24 ionize around pH 4-5. So, the solubility goes up

25 by two orders of magnitude in the intestine. In

171

1 this case dissolution occurs after emptying but it

2 is still a very fast process. So, if we think of

3 it kinetically, yes, there is a small effect of

4 dissolution on absorption but the principal

5 rate-determining step is in gastric emptying. So,

6 I think for Class II drugs, there are some Class II

7 drugs where we can extend biowaivers but that

8 requires more evidence and more debate and

9 discussion and we are not going to propose that

10 today.

11 [Slide]

12 Here is the equation that started my

13 career down this track, for those of you who are

14 interested in it. I am very partial to this triple

15 interval because no one has ever asked me a

16 question on this thing, but that is good. When I

17 had to give my first presentation in 1988, I was a

18 late addition to a program on dissolution and

19 absorption and had to talk about dissolution at an

20 AAPS workshop. I came to the conclusion I was a

21 late addition because it was a workshop on

22 dissolution and no one wanted to stand up and talk

23 about dissolution and absorption and

24 bioavailability and bioequivalence, and I was still

25 young at the time so I didn't know enough to say

172

1 no.

2 So, I wondered how do I handle it and I

3 concluded in the morning before the presentation

4 that if I showed this I would be safe. And, it

5 worked and I have been safe ever since. Basically,

6 it says that the determining factors are

7 permeability and concentration. Absorption is

8 occurring along the gastrointestinal tract. So,

9 you have to add up absorption processes across the

10 whole surface of the intestine. So, this is just a

11 surface integral and then you have to add it up

12 over time as well. But the key factors are

13 permeability and concentration, and in the limiting

14 case the highest concentration is solubility. So,

15 that is very simply Fick's first law. The two

16 critical variables are permeability and solubility.

17 Now, when I was on sabbatical at the FDA

18 in 1990-91, thinking about looking at dissolution,

19 working with Vinod Shah and Jerry Skelly at the

20 time, looking at how dissolution was used to set

21 regulatory standards, we had a regulatory issue

22 regarding carbamazepine at the time. So, I began

23 to think about is there a way--I could see that in

24 the struggle to come up with a guidance for

25 dissolution you would write a guidance that would

173

1 be so general that it was useless and it was a

2 product by product regulatory basis, so I thought

3 is there some way to kind of capture drug products

4 into categories that would be simpler to manage and

5 handle? Over the next couple of years, it took me

6 about two years to realize that the place to start

7 was Fick's first law. My major professor would be

8 appalled at that, Bill Laguchi who taught me Fick's

9 first law, but it took me two years to realize that

10 the starting point for predicting absorption is

11 Fick's first law, and that is P X C, Fick's first

12 law applied to a membrane.

13 [Slide]

14 At any rate, the waiver is applied to high

15 solubility drugs. We take the definition of high

16 solubility of a drug that the highest strength must

17 dissolve in a glass of water. What are you going

18 to use for high solubility? What is your reference

19 point? You have to come up with something

20 practical. This seems very practical to me, the

21 highest dose. Then I learned that sometimes you

22 can dose two of the highest strengths and

23 bioequivalence requirements currently use strength.

24 So, we then used highest dose strength but then

25 that was confusing too. The highest strength must

174

1 dissolve, the highest marketed strength must

2 dissolve in a glass of water. That is a high

3 solubility drug. I think it is a very practical

4 definition.

5 High permeability, we decided to define

6 high permeability and well absorbed as a drug that

7 is absorbed to 90 percent or more. Maybe we drew

8 that bar a little high, and one of the areas of

9 possible extensions is to change that to 85 percent

10 or 80 percent. We are looking at with that is

11 important or not from the point of view of the

12 database within the FDA. Further, if we extend

13 waivers to Class III drugs, which are low

14 permeability drugs, it makes this borderline a

15 little less critical perhaps in terms of drug

16 product regulation.

17 Then, the drug product must dissolve

18 rapidly. Based on theoretical simulation work done

19 at the time, we decided that 30 minutes would be

20 the upper limit for rapid dissolution even though

21 our simulation supported a 60-minute upper limit

22 for Class I drugs, high solubility, high

23 permeability drugs. But we chose 30 minutes, 15

24 minutes as a single point determination; 30

25 minutes, you would have to do a statistical

175

1 comparison using the F-2 metric.

2 [Slide]

3 This shows a partial database. Hussain

4 referred to a data base of about 25 drugs which is

5 being published over the past few years and over

6 the next couple of years, studied under virtually

7 identical conditions in normal subjects. So, we

8 have a permeability database that shows I think

9 around 15 or so of them. The high permeability

10 definition is appropriate metoprolol, approximately

11 where those red arrows are. Unfortunately,

12 metoprolol was mis-plotted on that plot but near

13 the intersection of the fraction absorbed curve and

14 the 90 percent line. So, we have used metoprolol

15 as our main reference compound. It is about at the

16 borderline between high and low permeability and it

17 is about 95 percent absorbed.

18 So, when we do permeability, and this is

19 permeability in humans, we almost always do it with

20 metoprolol being an internal standard. We

21 calculate permeability relative to metoprolol.

22 Yes, there are some potential interactions and they

23 are more theoretical than practical because we

24 rarely see them in vivo in humans or in animals.

25 So, we use metoprolol as a reference compound. If

176

1 the permeability in rat of CACO 2, if the

2 permeability is higher than metoprolol you have a

3 high permeability drug.

4 This allows you to determine the fraction

5 absorbed, the upper limit of the fraction absorbed.

6 The beauty of this is that in 1990 if you said you

7 could predict absorption people would have laughed

8 at you because no one even tried. Now we can

9 predict the upper limit. We just measure

10 permeability. That is the upper limit to systemic

11 availability. Systemic availability is always less

12 than or equal to fraction absorbed. So, from

13 preclinical data now we can predict how well we can

14 do the upper limit. Knowing the upper limit I

15 think is very important. We don't know the lower

16 limit. That is harder and it also includes

17 metabolism. So, the advantage of permeability is

18 that it can be scaled to preclinical animal and

19 even tissue culture methods for predicting

20 absorption.

21 Solubility, I didn't know what to say

22 about low solubility drugs so I put in my best

23 example here. When I think of low solubility and I

24 need a reference point of something that is low

25 solubility everyone would agree that marble is low

177

1 solubility. Right? I calculated the solubility of

2 Venus and she is ten mcg/ml, if I can remember my

3 old physical chemistry. As a reference point, a

4 drug like resiafulvin is about 15 mcg/ml. Some

5 other drugs, like glyburide are around 3 mcg/ml,

6 peroxicam about 7 mcg/ml.

7 So, I take about 10 mcg/ml as our

8 definition of a low solubility drug. But the

9 factors that we need to consider there in the

10 future are drugs like peroxicam which is actually a

11 high solubility drug at pH 6.8, not a pH 3 but pH

12 6. So, we will be looking at potential extensions

13 for drugs that ionize and dissolve in the

14 gastrointestinal tract in the future.

15 [Slide]

16 Just to illustrate kind of the effect of

17 dissolution, I think we have lost sight of the

18 importance of dissolution. So, I calculated the

19 dissolution times here based on the solubilities

20 and assumed particle size. Cimetidine dissolves in

21 one minute at 25 micron particle, typical particle

22 size. Glyburide, which has a thousand times lower

23 solubility, takes 30 hours to dissolve. That is

24 the reason dissolution is critical for glyburide

25 but for cimetidine it is not. This emphasizes

178

1 compartmentalizing the drugs because some are

2 simple and some are hard. Let's not try to

3 regulate everything by the hard rules. Let's try

4 to separate them out and say these are hard and

5 these are simple, and there are some drugs where we

6 may be doing in vivo studies forever because it is

7 too complicated. I also tried to calculate the

8 dissolution time for Venus. I had to use a

9 particle size for Venus so that meant I had to go

10 to the Louvre and see Venus because, you know, you

11 can't tell from pictures. Venus is a big lady, if

12 you have ever gone to the Louvre to see Venus. So,

13 I used a one meter particle size for Venus and I

14 calculated this number. I think it is like

15 million, billion, trillion, and I don't know what

16 the next number is. Does anyone know what the next

17 number is after trillion? One thousand trillion?

18 That is a long time although compared to the age of

19 the earth it is not so long. At any rate, this is

20 the reason solubility is so critical and why for

21 high solubility drugs the dissolution is very rapid

22 and there is not a problem with regard to

23 bioequivalence.

24 [Slide]

25 The waivers of in vivo, so-called

179

1 biowaivers, and I will emphasize this again,

2 biowaivers are not waiving bioequivalence. They

3 are waiving the in vivo test. They are

4 substituting another test which is as good or

5 better. We require bioequivalence. The question

6 is what test. Either a single point of 15 minutes

7 or a minimum of three points if there is 85 percent

8 dissolution at 30 minutes. Then, three pH's,

9 simulated gastric fluid, simulated intestinal fluid

10 and then an intermediate pH of 4.5 because that is

11 a pH which a drug sees as a transition from the

12 stomach to the duodenum and jejunum. In the

13 duodenum you have the mixing of gastric acid from

14 the stomach and the pancreatic bicarbonate secreted

15 from the pancreas through the common bile duct, and

16 also duodenum mucosal secretions. So, there is a

17 tremendous pH fluctuation in the upper duodenum and

18 so we included pH 4.5. So, the drug must dissolve

19 rapidly at those three pH's. We felt that was a

20 very safe criteria for allowing waivers from in

21 vivo bioequivalence.

22 [Slide]

23 Just by way of reference, I included here

24 one slide on the gastric emptying work that we

25 actually did via intubation, where we intubated

180

1 humans and measured gastric emptying of a liquid.

2 Here we used volumes of 50 ml and 200 ml of liquid

3 and then measured the gastric emptying rate. We

4 monitored motility, phase 1, 2 and 3, and then the

5 overall mean. The overall mean for the 50 ml

6 volume was around 22 minutes and the overall mean

7 for gastric emptying for the 200 ml volume was

8 about 12 minutes. So, the gastric half emptying

9 time was typical volume we would administer.

10 Actually a glass of water, the FDA requirement, is

11 8 oz. So, we used 200 ml here because this was a

12 long time ago. The gastric emptying time is about

13 12 minutes.

14 That was the basis for choosing a

15 15-minute, 85 percent dissolution time. Other data

16 from the literature--Ian Wilding has done a lot of

17 that from pharm profiles; and Bob Davis in

18 Nottingham. So, the gastric emptying time is very

19 well established so we felt very confident in the

20 gastric emptying time. We used 200 ml. I have

21 come to realize that that is actually closer to the

22 official Japanese glass of water which is 6 oz.

23 When I realized that I immediately thought of

24 harmonization. Do you think we could ever

25 harmonize a glass of water? This is an example of

181

1 cultural differences. No matter what we, as

2 scientists think might be possible, I doubt that we

3 are going to get cultures to change their official

4 glass of water.

5 [Slide]

6 I think I can summarize by saying there

7 has been strong support or at least very limited

8 resistance. I would like to think of it as strong

9 support but I will take limited resistance for BCS

10 and biowaivers. There have been some concerns

11 expressed at the workshop and commentaries on the

12 BCS guidance. For example, there is some

13 inconsistency between the solubility and

14 dissolution specifications. In particular, for

15 solubility we specify up to pH 7.5 while for

16 dissolution we only require a pH of 6.8. We think

17 we should harmonize those, and one of our proposals

18 is to look at the implications of changing the pH

19 7.5 solubility to pH 6.8.

20 Also, there are many completely absorbed

21 drugs whose systemic availability is less than 90

22 percent. That is kind of a paraphrase. That is

23 like what Marvin was saying this morning.

24 Bioavailability is easy. Fraction absorbed can be

25 hard. So, there is this concern out there that

182

1 fraction absorbed is actually hard to measure.

2 Probably you have to do radiolabeled studies. You

3 can use animal data for radiolabeled studies. You

4 need to do IV and oral because some drugs may be

5 excreted in the feces as well as the urine. You

6 need to measure generally your unchanged drug in

7 the urine, and the ratio IV to oral can be used to

8 estimate fraction absorbed if it is not too highly

9 metabolized. But estimating fraction absorbed is a

10 little tricky. Nevertheless, from the point of

11 view of the scientific approach, focusing on

12 fraction absorbed from the point of view of setting

13 dissolution standards is the correct view, I

14 believe, and fraction absorbed is what we want to

15 regulate.

16 Systemic availability contains absorption

17 plus metabolism. Generally metabolism is not a

18 formulation factors. Yes, you can add some things

19 and that is another factor. So, the systemic

20 availability complicates regulations because of the

21 metabolism variability. So, this allows us to

22 separate out. While we can't solve and simplify

23 all drug products this way, we can simplify I think

24 quite a number of them.

25 The third point is that we are overly

183

1 conservative. I think everyone agrees with that

2 and we should apply waivers to Class III drugs as

3 well.

4 [Slide]

5 More broadly, this kind of summarizes the

6 extension issues that we have been debating for the

7 past--well, I would say it started in 1995 when

8 Ajaz was drafting the guidance. Changing the pH

9 for solubility determination to 6.8 from 7.5;

10 reduce the permeability class boundary from 90 to

11 85 percent. We are not proposing that today

12 because, quite frankly, we are not sure about that.

13 We need a rationale to come to the committee and

14 there are a couple of different ways of doing that

15 using actual compounds and data, but we are not

16 prepared to do that today.

17 Class II, we feel these require extensive

18 research and they, again, are not subjects for

19 extension at this point in time for this

20 intermediate solubility class of drugs that

21 dissolve in the intestine. If there is one

22 solubility you want to know, it has to be the

23 solubility in the intestine for oral delivery

24 because that is where the drug is absorbed. So, pH

25 6.5 or 6.8 to be consistent. So, the solubility of

184

1 pH 6.8 is the single most important solubility for

2 oral delivery. If a drug dissolves rapidly at pH

3 6.8 it may be a candidate for waiver as well but,

4 again, that is going to require more studies.

5 Then you could ask the question about

6 surfactant. What about if it dissolves rapidly in

7 the presence of surfactants? Again, the Class II

8 drugs represent more complicated formulations,

9 perhaps more complicated dissolution

10 methodologies--not perhaps, more complicated

11 dissolution methodologies.

12 Then, for the Class III drugs the high

13 solubility, the low permeability drugs we want to

14 allow waivers if there is 85 percent dissolved in

15 15 minutes. So, again, it is a matter of getting

16 data and evidence to support that.

17 [Slide]

18 To conclude, I think we have established a

19 new paradigm. It has been a long process, starting

20 more than ten years ago with public discussion and

21 debate, including the support of this committee and

22 the FDA and the support of research, external

23 research as well as the many internal meetings in

24 developing the consensus in moving this new

25 paradigm in bioequivalence ahead.

185

1 I think one of the big advantages, of

2 course, is it reduces unnecessary in vivo studies.

3 I didn't realize, this was in the code of the

4 Federal Register, somebody gave me a new reference

5 today that the CFR says we don't want to do

6 unnecessary human studies. I didn't know that that

7 was in there so I have to add that to my slides.

8 But it reduces unnecessary human studies, and it is

9 based on scientific principles that allow us to

10 formulate a hypothesis, do some tests and move

11 ahead.

12 To conclude, I guess it is a great

13 pleasure for me to be here, talking to this

14 committee again and seeing the progress that we

15 have made over the past few years and seeing the

16 interest in extending and in building on it where

17 we can to improve, with our overall goal, of

18 course, of improving public health policy

19 standards. Thank you.

20 DR. COOK: For those that don't know me

21 and probably for those that do, I am Jack Cook,

22 with Pfizer Global R&D. My purpose today is to

23 show you that at least some in industry would

24 welcome additional guidance.

25 [Slide]

186

1 The agenda is that first I want to talk

2 about what I see are the benefits for industry with

3 the current guidance. Second, I want to talk about

4 the barriers because if you talk to Ajaz or

5 Lawrence you will find out that there have only

6 been six, plus or minus one, applications for

7 waivers so far. Finally, I want to talk about what

8 I see are the future benefits for the guidance.

9 [Slide]

10 First the benefits, the BCS guidance

11 allows bioequivalence to be shown by dissolution in

12 lieu of in vivo studies, but the question is will

13 it really save money, and at what cost?

14 [Slide]

15 I looked at the data availability at the

16 FDA web site, and I found over the period from

17 January 1998 to May of 2001 that there were 229

18 different NDA approvals, at the rate of about 67 a

19 year. Over the same time there were 466 ANDA

20 approvals, at a rate of 136 per year. NDAs, I

21 could find data from a recent study by DiMasi, that

22 about 90 percent of those are approved. Also, from

23 the DPQR site, we find that three to six studies

24 per NDA submitted their bioequivalence studies and

25 generics always get it right on the first time so I

187

1 assume that there is one bioequivalence study for

2 an ANDA. When you massage all of that data, you

3 get that industry as a whole performs 350 to 600

4 bioequivalence studies per year. That is probably

5 a little low estimate because it doesn't talk about

6 the drugs that didn't make it to market, and it

7 doesn't talk about studies that aren't submitted.

8 But at least that was a starting idea of how many

9 studies are performed a year.

10 [Slide]

11 The next thing I wanted to look at is what

12 does it cost. At least at Pfizer, Ann Arbor, when

13 you consider the cost for packaging and maintaining

14 samples, the clinical cost to run a study, the

15 bioanalytical cost, the data analysis and report

16 generation or my yearly salary, and then the

17 internalization, it costs us about a quarter

18 million dollars a study to run.

19 [Slide]

20 Again, if you take that number, about 25

21 percent of all drugs are waiver candidates. I

22 don't have a slide on that but that comes from a

23 survey I did over the same period of time, looking

24 at potentially how many drugs are waiver

25 candidates--I should mention that very quickly.

188

1 What I did, I looked at labeling and additional

2 data that were out in the literature, decided that

3 a drug could be classified as highly soluble if I

4 could find that the highest strength was soluble at

5 some pH between 1 and 7.5, but there was no other

6 pH that would preclude it from being a highly

7 soluble drug. So, I didn't have extremely high

8 evidence of it being Class I but I couldn't

9 preclude it from it. So, it could be as many as 25

10 percent.

11 To me, for the permeability classification

12 there was enough data in the literature where it

13 would have to meet one of the BCS requirements.

14 Anyway, if you accept that number of 25 percent you

15 can find that the industry as a whole could save

16 between 22 and 38 million dollars a year.

17 [Slide]

18 If I were to apply that same thing to

19 Pfizer in Ann Arbor, we would find that it is

20 somewhere between half and one million dollars a

21 year at our site, considering that we do about 17

22 bioequivalence studies a year.

23 [Slide]

24 I call that direct savings. There are

25 some direct savings. It is not that unusual for us

189

1 to have bioequivalence studies that are

2 rate-limiting to submission. A typical scenario is

3 that we are changing the site of manufacture and we

4 want to include that bioequivalence study in our

5 submission. So, we, those that would do the in

6 vivo testing, end up being behind the eight ball as

7 rate limiting. Typically, it takes us about six

8 weeks to actually run the study and get the results

9 back. I won't talk about how long it takes us to

10 generate the report, but let's say six weeks to say

11 that we have a product going forward. Assuming

12 that we have peak sales of a drug of one billion

13 dollars, not one trillion dollars, a year, that

14 ends up being that there are 110 million dollars

15 that one can save by doing the in vitro testing

16 rather than the in vivo testing.

17 [Slide]

18 That is all well and good, I want to

19 assure you that there is a cost savings. If you go

20 out and do the formal testing of something to

21 classify something as an in vitro methodology you

22 do, indeed, save money. The characterization cost,

23 depending on how you choose to characterize your

24 compound as highly soluble, highly permeable, ends

25 up being between $10,000 and $60,000 per drug.

190

1 Then, to evaluate a formulation, because that is

2 the second step because not only to you have to

3 have a Class I drug but you have to do the in vitro

4 dissolution for the formulation, is about $15,000

5 per formulation. I have stolen this slide from

6 another talk, but it ends up that that total cost

7 of that $75,000 is far less than the quarter

8 million dollars it costs us to run a study.

9 [Slide]

10 A few years ago I had the opportunity to

11 try this at Pfizer, and I likened it to a favorite

12 poem of mine by Robert Frost, the Road Not Taken,

13 that talks about decision in life and I thought the

14 BCS was the more attractive road and chose to take

15 that less traveled path. I have good news with

16 drug X, which is that we were able to obtain a

17 waiver of in vivo studies and show that it met in

18 vitro bioequivalence requirements. We saved four

19 bioequivalence studies and, like the last line of

20 the Robert Frost poem, that has made all the

21 difference in that it saved Pfizer, Ann Arbor, one

22 million dollars.

23 [Slide]

24 So, why isn't everybody else jumping on

25 the bandwagon? We have seven applications but,

191

1 yet, a quarter of all drugs could potentially meet

2 BCS classification. There are a couple of barriers

3 that actually are not within the agency but within

4 industry itself. One is what I call wrong

5 attitudes, mainly because they don't agree with

6 me--

7 [Laughter]

8 --secondly, about wrong wiring. When I

9 first proposed going this different path within the

10 company, saying I don't want to run a traditional

11 in vivo bioequivalence study; I want to run an in

12 vitro bioequivalence study, it wasn't my decision

13 alone. I needed to take it to the head of my

14 department, the head of regulatory, the head of

15 formulations department.

16 [Slide]

17 To a person, this is the kind of response

18 I get, "you want to do what? Does the agency allow

19 such a thing?" I said, "well, sure they do. Here

20 is the guidance on it." "Has this been done

21 before?" I said, "no." They said, "what, are they

22 crazy?" There is a good scientific rationale

23 behind that.

24 [Slide]

25 So, some of the questions I get are "you

192

1 can't release a new product on the market without

2 testing." That is questioning the science. I do

3 point out that we have been doing this all along

4 with solutions, and the BCS Class I is something

5 that is very similar to solution; it is something

6 that is dissolving very rapidly, behaving very much

7 like a solution.

8 As I mentioned, "the FDA won't allow it."

9 They question the procedure. Actually, what I have

10 been doing to my colleagues in industry is

11 advocating that they get an advocate within the

12 agency to talk to their regulatory people within

13 the company and say that, yes, indeed, it can be

14 done. "Has this been done before?" Fear of the

15 unknown. I go all the time and talk about our

16 success with trying to encourage it.

17 [Slide]

18 There is another thing that kind of stops

19 industry from doing it and that is wrong wiring.

20 This is kind of a diagram of what is needed for BCS

21 classification as far as information flow.

22 Typically within a company, my colleagues in

23 preclinical, there is very good information usually

24 coming to me in the clinic. Chemistry provides

25 decent information with their formulation

193

1 scientists. What is actually needed for the BCS is

2 something like this, there has to be a lot more

3 talk across these inter-departments because we are

4 relying on information generated elsewhere. If I

5 am using preclinical data to help classify a

6 compound as highly permeable, chemical

7 characterization is the one that usually does the

8 full dissolution profile. So, we need to figure

9 out how to have better information flow.

10 The next thing I am doing is bringing

11 across dollar amounts. The size of the dollar sign

12 represents the change in costs for a department.

13 Red means that the costs for a department go up

14 when they decided to classify something this way.

15 For instance, chemical characterization has to do

16 more characterization on a compound than they are

17 used to. Green means where it saves. So, as you

18 can see, I am in clinical pharmacokinetics, I look

19 good and I can claim that we saved our company a

20 million dollars, but other parts of the company are

21 actually spending more. So, this is another

22 barrier that one has to overcome within industry

23 and is why it hasn't been used so much.

24 [Slide]

25 I am going to talk about that a little bit

194

1 when I talk about blue sky, how will industry

2 benefit from the proposals.

3 [Slide]

4 Change within a company is kind of like a

5 chemical reaction. To orient you on the slide, on

6 the Y axis is kind or resources, and going from the

7 old, on the left-hand side, to the new, on the

8 right, you can see that overall if I use the old

9 way, the in vivo bioequivalence, I actually have to

10 spend more resources than the new. But I have to

11 overcome this barrier of activation energy. I have

12 to change how data flows within a company. I have

13 to overcome some mind sets.

14 I submit that if there is benefit and it

15 is only slightly better than the activation energy,

16 that change is going to be slow in a company. They

17 are going to fail to see that for that little good

18 we have to change all these ways that we do things

19 within a company. On the other hand, if through

20 expanding the BCS we can provide a lot broader

21 application of it, those systems will change a lot

22 faster and we will see actually a far greater use

23 of BCS within industry.

24 [Slide]

25 In that same survey I looked at how many

195

1 drugs are potentially future candidates for BCS if

2 we were to include all highly soluble compounds.

3 From that survey we come with something like 45

4 percent of all candidates would be considered

5 highly soluble, with another 25 percent unknown.

6 So, given that some will fall out of that 45

7 percent, they may be replaced by the 25 percent and

8 I submit that that is probably not too

9 unreasonable. So, there is a great potential for

10 the number of candidates that the expansions

11 proposed today would cover.

12 [Slide]

13 I would like to leave you with a few

14 thoughts. First, we feel that the current guidance

15 is useful. Pfizer has saved over a million dollars

16 with it. The barriers right now within company on

17 changing paradigms result in the low rate of use

18 they have so far with the guidance. To overcome

19 that, one thing that will help is expanding the BCS

20 where more candidates will equal a greater savings,

21 and that will be very useful for companies and, as

22 I say, you will see it used a lot more. With that,

23 I will turn it back over to Lawrence.

24 DR. HUSSAIN: Vince, can I make a comment?

25 DR. LEE: Yes.

196

1 DR. HUSSAIN: I think one of the benefits

2 that I think needs to be on the table is the

3 concept of quality by design and I just want to

4 bring a formulator's perspective here. When the

5 work of a formulation development group starts, for

6 initial screening everything is based on in vitro

7 dissolution and we pick a dissolution that we think

8 might work. Actually, we have seen cases where

9 companies may go down the path and actually

10 optimize their formulation before they do the first

11 bio study and in that study the dissolution test

12 was all wrong to start with.

13 So, focusing on the dissolution, relevant

14 dissolution, helps us to do the right thing the

15 first time and I think that is one of the

16 scientific benefits that is not always clear. So,

17 bringing more science to formulation development

18 and linking biopharmaceutics to formulation

19 development is another big benefit here.

20 Also, when I was working on the BCS I saw

21 18 bioequivalent studies in one NDA, and I am not

22 so concerned with the cost at this point. I am

23 more concerned that this is a new drug entity for

24 which the safety and efficacy has not been fully

25 evaluated and you are exposing normal, healthy

197

1 volunteers to a test which may not be adding all

2 the value. I think that is the motivation that

3 sort of drives us here.

4 DR. JUSKO: Could I ask Jack to clarify

5 one thing here?

6 DR. LEE: Certainly.

7 DR. JUSKO: The test compound that you

8 described, I presume you already had oral and IV

9 data for that compound.

10 DR. COOK: Actually, the way we classified

11 it as highly permeable is that this drug is

12 excreted virtually unchanged in the urine. So,

13 just by measuring urinary excretion we were able to

14 show that the bioavailability was above 90 percent.

15 DR. JUSKO: So it was a Class I compound?

16 DR. COOK: Oh, yes. This is a Class I

17 because that is the only way currently that you can

18 get a waiver for in vivo bioavailability. What we

19 are proposing today is to expand that further.

20 DR. JUSKO: Thank you.

21 DR. YU: Thanks, Dr. Amidon for the

22 excellent presentation for an overview and

23 applications of the biopharmaceutics classification

24 system, and Dr. Cook for an excellent presentation

25 on the industrial experience of the BCS.

198

1 I want to emphasize that the driving force

2 for us to have this current guidance and for future

3 extension is the science, the science behind the

4 philosophy driving this change. In the next twenty

5 minutes or so I will talk about two aspects. One

6 is regulatory implementations, and the second is

7 basically potential extensions of the BCS.

8 [Slide]

9 As you can see, this guidance was issued

10 in August, 2000. It is now about 18 months. This

11 guidance basically allows for biowaiver for highly

12 soluble, highly permeable and rapidly dissolving

13 and wide therapeutic window index drugs. There are

14 also characteristics of the drugs to ensure that

15 the solution is not the limiting step in terms of

16 oral drug substance process. Again, the

17 permeability is also not the rate-limiting step.

18 [Slide]

19 So, those characteristics allow them to

20 say that the gastrointestinal emptying is basically

21 the limiting step for these solid oral dose form

22 for BCS Class I drugs.

23 [Slide]

24 In terms of applications, basically this

25 guidance allows applications for BCS for

199

1 investigational drug applications for Phase I to

2 Phase II post-approval changes certainly as ANDA,

3 abbreviated new drug applications.

4 [Slide]

5 So far, we basically have received strong

6 scientific support. As Prof. Gordon Amidon pointed

7 out, there is very little resistance. Some

8 concerns expressed in the public workshops are that

9 we are too conservative or overly conservative with

10 respect to solubility class boundary with respect

11 to BCS Class III drugs, highly soluble and low

12 permeability drugs. Again, the submission activity

13 is relatively low. So far we have received a total

14 of about five NDAs, ANDAs and post-approval

15 changes.

16 [Slide]

17 I want to discuss with you some of the

18 experience we have had with this current BCS

19 guidance. This slide shows you basically the

20 experience with the solubility . The pH range for

21 solubility studies is 1.2, or sometimes we say 1.0

22 HCL to 7.5. Temperature is 37 degrees. The

23 solubility is basically the highest strength

24 divided by 250 at all relevant pH's. For example,

25 for diazepam what you are really looking for is

200

1 lowest solubility, in this case a pH of 7.4, to

2 determine whether this drug belongs to Class I or

3 belongs to another class, Class II or IV. So,

4 there are solubility studies, relevant pH, relevant

5 temperature, and determined by the lowest

6 solubility at all relevant pH's from 1.2 to 7.5.

7 [Slide]

8 I want to discuss with you the experience

9 with permeability. So far, the applications we

10 have received classify permeability based on the

11 following methods: pharmacokinetic studies in

12 humans. For example, bioavailability is basically

13 90 percent or above. To ensure the permeability of

14 this drug, that it is highly permeable.

15 We also received applications using an in

16 vitro cell culture model. We sometimes receive

17 inquiry about the literature method or literature

18 data. I have to point out that the agency has

19 little experience to accept literature data as the

20 sole evidence to support or to classify

21 permeability for the regulatory purpose.

22 [Slide]

23 In these four slides I took advantage of

24 the new technology and I just added them this

25 morning in the hope of addressing the concerns,

201

1 especially Dr. Marvin Meyer's concern about

2 permeability classification. It is not in your

3 handout. First I want to point out that the

4 permeability classification, especially the extent

5 of intestinal absorption, is not bioavailability.

6 Just because bioavailability or extent of

7 absorption includes the extent of drug input into

8 the system added to circulation, so it includes

9 everything, especially for example the solution,

10 metabolism and so on.

11 However, for the purpose of the BCS, you

12 use the extent of intestinal absorption which means

13 extent of drug across the intestinal membrane is

14 not considered a factor of solubility, for example,

15 metabolism is subject to hepatic metabolism. So,

16 we only consider one step here, the extent of drug

17 across membrane. While the bioavailability

18 considers many, many processes involved, including

19 the solution, gastric emptying, GI motility,

20 hepatic metabolism, and so on. So, there is a

21 difference between extent of drug absorption and

22 extent of intestinal absorption for the BCS

23 biopharmaceutics permeability classification

24 purpose, the extent of intestinal absorption.

25 [Slide]

202

1 In the guidance we basically specify a

2 number of methods. You can use any method you

3 would like to classify the drug in terms of

4 permeability class boundary in terms of

5 permeability class membership. So, there is a list

6 of a number of methods availability specified in

7 the guidance, including in vivo intestinal

8 perfusion in humans; including pharmacokinetic

9 studies for example in humans; including in vivo

10 and in situ intestinal perfusion in animals and,

11 certainly, we also include the in vitro cell

12 culture model.

13 [Slide]

14 I just want to elaborate to give you an

15 idea, if you use an in vitro method or an in situ

16 method, in order for this method to qualify to pass

17 the permeability of drugs for the regulatory

18 purpose, the sponsor is required to demonstrate

19 that he has established the so-called system

20 suitability, so basically to show the link or

21 relationship between the permeability, for example,

22 cell culture permeability, and extent of intestinal

23 absorption for 20 representative drugs. For

24 example, you have to have a drug, certainly for

25 these 20 drugs you have to spread from low, medium

203

1 and high. So, you have a certain range from low to

2 medium and high. You also have to show the in

3 vitro method integrity, for example using mannitol

4 or dextran as a marker. In the case of the cell

5 culture models, you have to show that the cell

6 culture model expresses the transporter for

7 example, in this case Pgp, P-glycoprotein

8 transporter.

9 [Slide]

10 In order for this specific model to

11 qualify for regulatory purposes with respect to the

12 permeability classification, you need to establish

13 the correlation between the extent of intestinal

14 absorption and in vitro cell culture permeability

15 in this case. This was done at the FDA lab, and

16 Donna Volpe is the investigator and actually she is

17 sitting in the audience.

18 As you can see here, for these 20 drugs we

19 pretty much get very reasonable correlations

20 between the extent of intestinal absorption and

21 apparent CACO 2 cell permeability. With this

22 establishment, this specific model in a specific

23 sponsor's lab can be utilized for class

24 permeability of drugs. Now, if you use the same

25 principle in a different lab you have to requalify.

204

1 So, we put in relatively conservative criteria in

2 place to make sure the data that come from sponsors

3 does show that the permeability of a specific drug

4 is highly permeable or poorly permeable.

5 [Slide]

6 Again, even with the permeability method,

7 not only do you need to show that the cell culture

8 establishes the system suitability to show that the

9 drug is highly permeable, you are also required to

10 do stability studies to make sure this drug which

11 you are measuring in an in vitro system is stable.

12 These are the recommendations in this slide based

13 on the guidance. For example, you need to show

14 that the drug is stable in simulated intestinal

15 fluid. You need to show that the drug is stable in

16 simulated gastric fluid. Certainly, for stability

17 purposes you need to use stability indicating

18 assay, validated assay. The guidance suggests at

19 this point that the drug is stable if less than

20 five percent is degraded in both small intestinal

21 fluid and the gastric fluid.

22 [Slide]

23 Basically, this is our view in terms of

24 regulatory implementation and some of the

25 challenges and issues we have faced so far.

205

1 Next I want to discuss with you the

2 revisions and extensions with respect to solubility

3 class boundary and with respect to biowaiver

4 extensions, especially for BCS Class III drugs.

5 The objective here, again, is to have a science

6 based in vitro solution to BE standards. Again, I

7 want to emphasize here that the driving force for

8 us to have extensions or to have the current

9 guidance is science. It is the science.

10 Let's talk about the first proposal

11 change, solubility class boundary. Currently, the

12 pH range in defined solubility is 1.2 to 7.5. The

13 potential future direction is for a pH range from

14 1.2 to 6.8 in defined solubility.

15 [Slide]

16 Basically, this is the GI tract here. You

17 have a pH in the stomach, pH in the small

18 intestine; pH in the jejunum. The pH range in the

19 stomach is 1.4 to 2.1 under fasting condition. The

20 pH range for the duodenum is 4.9 to 6.4. The pH

21 range in the jejunum is 4.4 to 6.6. Finally, the

22 pH range in the ilium is 6.5 to 7.4.

23 Let's look at how long it takes for drug

24 solid dosage forms to get into the ilium where the

25 pH is relatively high, as you can see, at 7.5. On

206

1 average, in terms of residence time it is 85

2 minutes for a drug particles to go through the

3 stomach, duodenum, jejunum and to the ilium. So,

4 it takes 85 minutes for a drug solid dosage form or

5 drug particles to get there.

6 Now let's look at what are our in vitro

7 dissolution criteria. Our in vitro dissolution

8 criteria is 85 percent dissolved in 30 minutes.

9 So, by the time the drug gets to the ilium it is

10 likely all the drug is dissolved. Intuitively we

11 would think if all the drug is dissolved, why do we

12 need this criteria? That is first.

13 Second, in our current dissolution testing

14 for BCS, we have a dissolution test at pH 1.2 or

15 0.1 HCL, 4.5 and 6.8. So, in this regard to have

16 consistency between solubility and dissolution

17 class boundary it seems reasonable to reduce the pH

18 requirement from 7.5 to 6.8.

19 [Slide]

20 Now let's move on the next potential

21 extension, which is BCS Class III drugs. Currently

22 we have a biowaiver for BCS Class I, namely highly

23 soluble and highly permeable. One proposal is a

24 wavier to highly soluble and poorly permeable

25 drugs.

207

1 [Slide]

2 So, the question we ask is why do we

3 choose Class III, why not Class II or Class IV?

4 For Class III drugs it is highly soluble and poorly

5 permeable drugs in rapid dissolving dosage forms

6 which essentially behave like a solution if the

7 dissolution of a solid oral dosage form dissolves

8 rapidly. It essentially behaves like a solution.

9 Let's look at the solution requirements

10 here. The FDA policy on oral solutions is

11 basically if bioequivalence is self-evident

12 biowaiver can be granted, and no in vivo

13 demonstration is needed if the test solution

14 contains no inactive ingredients or other changes

15 in formulation from the reference product that may

16 significantly affect the absorption of the active

17 moiety or active ingredients. So, only if the

18 excipients do not affect absorption.

19 [Slide]

20 Now let's look further in terms of

21 mechanistically. Again, you can dose oral dosage

22 forms such as tablets or capsules. A solution is

23 certainly a liquid dosage form. When the solid

24 tablet comes to the stomach or the solution comes

25 to the stomach, what happens for the solution is

208

1 basically gastric emptying, the emptying from the

2 stomach to the small intestine. However, for solid

3 products there is one process which is the

4 dissolution. So, there is a difference in terms of

5 the process in the stomach. But when it comes to

6 the small intestine there is not much difference

7 there. The drugs in solution get absorbed. So,

8 basically in the small intestine or in the colon

9 there is basically a process in terms of

10 mechanistic absorption which is the same for oral

11 solutions or for solid dosage forms.

12 [Slide]

13 Now let's look at the next assumption

14 here. We say if the test product equals a simple

15 solution, if we can show it, and if we have

16 reference products which equal a simple solution

17 then automatically you say the test product equals

18 the reference product if there are two criteria

19 here, they are rapidly dissolving and the second

20 criterion is no excipient effect on oral drug

21 absorption. No excipient effect.

22 [Slide]

23 This is basically a list of potential BCS

24 Class II drugs. I say potential because there is

25 no concrete information to support yes or no and so

209

1 I say potential. This is a list of BCS Class III

2 drugs.

3 [Slide]

4 So the hypothesis here is if two immediate

5 release solid dosage forms dissolve rapidly at all

6 physiologically relevant conditions and contain no

7 excipients that may potentially affect the oral

8 drug absorption of the BCS Class III drugs, then

9 the bioequivalence of these two solid IR products

10 is assured and biowaiver can be granted.

11 [Slide]

12 This is basically the proposal for studies

13 or data collection to test the hypothesis.

14 Certainly we can collect data from human

15 bioequivalence studies to compare a simple solution

16 with two solid dosage forms of at least ten model

17 BCS Class III drugs to show that those data may

18 confirm the literature, the NDA or ANDA or FDA

19 internal studies, maybe unpublished data. We are

20 thinking about going through the PQRI to collect

21 the unpublished data from the sponsors and, if

22 necessary, to do relevant in vitro dissolution and

23 cell culture studies.

24 There are two potential issues here. The

25 first issue is transport which we touched on in the

210

1 morning. As you can see, there is much in vitro

2 evidence to show that transport may affect the

3 absorption of a certain number of drugs. On the

4 other side, we though if dose proportionality is

5 shown over the range from the lowest to the highest

6 strengths, we can conclude that the effect of the

7 transporter may not be significant with respect to

8 the bioequivalence. It may be still significant in

9 terms of drug-drug interaction but with respect to

10 bioequivalence this may not be significant.

11 [Slide]

12 The next question is the potential effect

13 of excipients. Excipients of oral drug absorption

14 can certainly affect GI motility. They can affect

15 permeability. In order to minimize the risk of the

16 bioinequivalence caused by the excipients, we

17 basically have two options.

18 Option number one, we basically identify

19 and exclude excipients that may affect the

20 absorption or pharmacokinetics. In other words, at

21 this point we consider all excipients acceptable;

22 we identify one, we basically exclude it. That is

23 the first option.

24 The second option is we basically exclude

25 every single excipient at this point. We basically

211

1 include them when we find specific excipients have

2 no effect whatsoever on oral drug absorption in

3 vitro and in vivo. So far we have tested a number

4 of products and if they had no effect we included

5 them. So, basically those are the two options we

6 have.

7 [Slide]

8 With that, I conclude my talk and with the

9 following questions we want feasibility and input

10 from you. Thank you very much. Thank you for your

11 attention.

12 DR. LEE: Thank you, Lawrence. Ajaz?

13 Committee Discussion

14 DR. HUSSAIN: Just a perspective that I

15 wanted to share with the committee before we start

16 deliberations. When we put together the first

17 guidance that was published in August of 2000, what

18 were the reasons why we did not include Class III

19 is sort of the one thing which I wanted to point

20 out. The other thing which I wanted to point out

21 which I will address first is our regulations

22 currently allow waiver of in vivo studies when you

23 have in vitro and in vivo correlations. For

24 immediate release dosage forms we don't have that

25 option because correlations are usually not present

212

1 or not apparent because dissolution in many cases

2 tends to be not rate limiting.

3 So, in vitro and in vivo correlations have

4 not actually been very useful for most immediate

5 release dosage forms. There are a few exceptions.

6 So for the BCS based biowaivers, when you think

7 about it, we are making decisions on in vitro

8 dissolution as a source of comparison in absence of

9 such correlations. So the thought process and the

10 justification is based on mechanistic underpinning

11 of that.

12 If I look at Class III drugs, what sort of

13 held us back for recommending waiver in the first

14 instance when we looked at it was the issue of

15 permeability being a mechanism by which you

16 essentially have the same conditions in vivo. So,

17 the volume differences for dissolution in vitro and

18 in are sort of one reason behind that sort of

19 holding back from that recommendation.

20 Also, keep in mind that solution

21 bioequivalence has always been waived, or options

22 have been available for solutions, and some of the

23 work we did suggested that the way we evaluate

24 excipients would have to be tightened up. So, if

25 you look at the bioavailability, bioequivalence

213

1 guidance we actually use a higher standard for

2 solubility forms whereby we limit it to highly

3 permeable drugs because that is sort of protected

4 against some of the excipient effects. In the new

5 guidance that we issues on BA/BE it actually

6 pointed out some of the issues with respect to

7 sorbitol or osmotic ingredients for solution drugs

8 because we have been seeing cases were a solution

9 actually has lower bioavailability than a tablet,

10 and you have one example in your handout. Those

11 are sort of the motivations and thought processes

12 that held us back at that point. So.

13 DR. LEE: Thank you. Are there any

14 questions for the presenters? Yes?

15 DR. RODRIGUEZ-HORNEDO: Yes, maybe a point

16 of clarification, how do you define or how do you

17 classify a compound that is ionizable so that the

18 pH determines its solubility? It is not clear to

19 me from the reading material.

20 DR. YU: Solubility over the pH range is

21 defined as 1.2 to 7.5. So, if it is ionizable, for

22 example as a free base, the solubility will be much

23 higher at the low pH; the solubility will be lower

24 at the high pH. So, actually whether this drug is

25 highly soluble or not is determined by the high pH.

214

1 On the contrary, for acid, for example, the

2 solubility will be lower at the low pH and higher

3 at the high pH so that basically determines whether

4 this compound belong to high solubility or not by

5 the low pH. Essentially in terms of ionizable, we

6 basically ensure that it matches the solubility of

7 all pH's to determine whether it is highly soluble

8 or not.

9 DR. RODRIGUEZ-HORNEDO: So, it is

10 determined by the minimum solubility of the

11 compound at any pH?

12 DR. YU: Correct, absolutely, yes.

13 DR. RODRIGUEZ-HORNEDO: If I may ask a

14 question that is related to something we are going

15 to be discussing tomorrow, I guess then the

16 classification is also dependent on the solid state

17 of the material.

18 DR. YU: Absolutely.

19 DR. RODRIGUEZ-HORNEDO: So, if you have an

20 amorphous compound versus a crystalline compound it

21 will change the solubility. The classification may

22 change depending on solid state structure.

23 DR. HUSSAIN: Well, I think this is sort

24 of an equilibrium solubility.

25 DR. AMIDON: Solid state properties,

215

1 particularly if they can change when the dosage

2 form is introduced into the gastrointestinal tract,

3 are problematical. I think when we use solubility

4 here we think of it as approximate equilibrium

5 solubility. But, in reality, we are only

6 interested if the drug stays in solution for over,

7 you know, four to six, eight hours in the

8 gastrointestinal tract. We don't need to wait

9 days; in days the drug is out of the GI tract. So,

10 in some ways we think of this as kind of a kinetic

11 solubility, but to a physical chemist that is an

12 oxymoron, right, because solubility is equilibrium

13 by definition. So, we think of equilibrium

14 solubility. So, amorphous compounds or compounds

15 like carbamazepine which hydrate and change their

16 physical form in contact with water have to be

17 handled more carefully.

18 DR. LEE: Yes, Gloria?

19 DR. ANDERSON: On page three of your

20 presentation you have solubility equal to greater

21 than highest strength per 250 ml at all pH's. Is

22 there a number that you associate with solubility

23 that is highly soluble, not very soluble, or does

24 this high strength refer to the dosage?

25 DR. AMIDON: That is a good question. We

216

1 are asked that frequently. We use the term high

2 solubility of a drug to be one whose highest

3 strength dissolves in a glass of water. That is

4 not really solubility. That is what we are calling

5 a high solubility drug. You know, if your drug

6 dose is 250 mg and it has to dissolve in 250 ml, 1

7 mg/ml would be a high solubility drug. But if your

8 dose is lower, then you could go to a lower

9 solubility. So, the actual solubility changes with

10 dose. The solubility limit changes with dose.

11 DR. ANDERSON: And from drug to drug.

12 DR. AMIDON: And from drug to drug, yes.

13 DR. LEE: Joe, you have a question?

14 DR. BLOOM: Basically when it is called

15 high solubility it is depending on dose.

16 DR. COOK: It depends on the highest

17 formulation strength one would make. So, it is

18 drug specific and it is the highest strength, and

19 whether that strength will dissolve in 250 ml or

20 not at all relevant pH's. So, you can't think of

21 it as a milligram/ml; it is just a yes or no.

22 DR. KIBBE: And that applies to the

23 highest strength that is available whether or not

24 there are multiple strengths. No one can get a

25 waiver for a 5 mg tablet when a 50 mg won't meet

217

1 that criteria? Is that right?

2 DR. COOK: Currently.

3 DR. LESKO: I think it is important to be

4 clear. The solubility is based on the highest

5 approved strength. If you can imagine a

6 bioequivalent situation where there is a reference

7 product approved and somebody is looking at an

8 abbreviated new drug application, the highest

9 strength that is approved would be the reference

10 for solubility determination. That is different

11 than the highest dose that may be approved if, for

12 example, somebody can administer two tablets or

13 three tablets within the range of an approved dose.

14 That is not what we are talking about. We are

15 talking about the strength of the tablet. We are

16 trying to mimic a bioequivalence study where you

17 compare a tablet of drug that is a test to a tablet

18 of a drug that is a reference, and that is what we

19 want to compare at the highest strength.

20 DR. KIBBE: If four products are

21 commercially available from the innovator, four

22 dosage strengths, 2 mg, 5 mg, 10 mg and 20 mg, then

23 your decision to allow people to get a waiver is

24 going to be based on the highest one whether or not

25 they want to market the highest one or not?

218

1 DR. LESKO: That is correct.

2 DR. KIBBE: Even though they want to

3 market the 2 mg, they can't claim that the 2 mg

4 would meet your criteria and, therefore, it should

5 get a waiver.

6 DR. HUSSAIN: That is the way it is right

7 now.

8 DR. LESKO: You didn't say what the

9 highest approved strength was, but if 20 was the

10 highest approved strength, then that would be the

11 basis for the solubility determination.

12 DR. KIBBE: Regardless of what the company

13 wants to market?

14 DR. LESKO: Well, if they want to market

15 10 mg and they don't market 20 mg, then 10 mg would

16 be the reference.

17 DR. KIBBE: That is my point.

18 DR. LESKO: Yes.

19 DR. KIBBE: That just changed the answer,

20 I think. If there is a company on the market that

21 has four strengths and the highest strength is not

22 a very popular strength but it is on the market as

23 the innovator, and I want to only come in as a

24 generic and market the bottom two strengths, which

25 represent 80 percent of the market, I don't have to

219

1 have, to get a waiver, that the highest strength is

2 soluble at 250 ml. I only have to have the highest

3 strength I want to market that is soluble at 250.

4 DR. LESKO: That is correct.

5 DR. LEE: Has there been any thought about

6 using dose numbers in all these kind of

7 descriptives?

8 DR. AMIDON: Well, yes, actually if the

9 dose number is less than one than you are a high

10 solubility drug. So, really that is the way I

11 think of it.

12 DR. LEE: Yes, Bill?

13 DR. JUSKO: This is a very illuminating

14 set of presentations and I have learned a lot from

15 it. My first, somewhat facetious, comment is,

16 Gordon, I wonder why in your triple integral you

17 didn't include the upper limits of the A variable?

18 [Laughter]

19 We will talk about that later.

20 DR. AMIDON: you are the only one that has

21 ever asked that question. It is not really written

22 right but no one has ever noticed. It really

23 should be a vector integral, quite frankly. It

24 should be a vector integral written over the

25 surface of the intestine, yes.

220

1 DR. JUSKO: That makes everything clear!

2 [Laughter]

3 Speaking computationally, faculty members

4 in our department teach students about Lapinsky's

5 rule of five. I wondered if there is some role in

6 all of what you are doing for a computational

7 approach, structure activity kinds of calculations

8 to address estimations of permeability values.

9 DR. AMIDON: Yes, I actually use them all

10 the time. The question is what evidence would you

11 want to bring to the FDA. I think within industry,

12 if I don't have an experimental partition

13 coefficient I would calculate one just using some

14 software program. I mean, it is one of the first

15 things I do to determine kind of what the

16 permeability of this drug might be. So, I find it

17 a very useful qualitative tool. I know that there

18 has been some interest. Well, Lawrence has actually

19 done some computational work when he was with

20 Glaxo. I think the FDA is very concerned about

21 making decisions based on some computational

22 result, but I personally use them all the time,

23 yes.

24 DR. COOK: As somebody who may work for a

25 company who looks into this, we find it very useful

221

1 for candidate selection, realizing that compounds

2 with the desirable absorption characteristics are

3 ones that likely make to market. If you can have

4 activity plus it is well absorbed, you have

5 something that you should actually fast-track

6 through the system. Our experience is that they

7 have been very useful at that stage. The

8 correlations haven't been precise enough to where

9 we feel comfortable saying for sure it is a Class I

10 compound, and to, you know, absolutely predict it

11 is above 90 and, therefore, do other tests. But

12 some day maybe.

13 DR. JUSKO: In the graphs that I saw

14 showing the non-linear relationship between

15 fraction absorbed and permeability, there was a lot

16 of data on the high side and only three or four

17 points, some complicated by metabolism issues,

18 indicating small fraction absorbed when

19 permeability was low. Plus, the relationship was

20 very steep. So, that makes people wonder how

21 reliable predictions are going to be if the

22 critical information has such a steep profile.

23 DR. COOK: Well, thank goodness, the area

24 of interest is actually the flat part of the curve

25 because if you look at where metoprolol is, that is

222

1 kind of where it starts the flat part of the curve

2 and you have to be there or greater to be

3 considered a highly permeable compound. I think

4 most people agree that that is really hard on that

5 area of the curve where a little bit of

6 insensitivity in your assay measurement could

7 result in a big change. Here, we are on the flat

8 part of the curve and are less susceptible to that.

9 DR. HUSSAIN: I think that is an excellent

10 point.

11 When we were putting in the class boundary that

12 actually came as a decision-making point. The

13 reason we said 90 and above is because of that.

14 Originally I think we thought of 80 and that is the

15 steep part of the curve, and one of the criteria

16 for 90 percent as the boundary was driven by that.

17 At the same time, I think for assessment

18 of permeability one of the recommendations in our

19 guidance is actually to use an internal standard, a

20 known high permeability internal standard so that

21 you can say it is better than that. That is how we

22 addressed that.

23 DR. JUSKO: That is what I didn't quite

24 understand from Dr. Yu's presentation, whether he

25 was indicating that the companies needed to study

223

1 all 20 drugs and establish the profile or could

2 just use the indicator drug as a cut-off.

3 DR. HUSSAIN: The recommendation is to

4 actually establish your own system with all 20

5 drugs; demonstrate suitability, and once you have

6 demonstrated suitability of the method, because lab

7 to lab variability is significant in some of those

8 things so we wanted every lab to define suitability

9 and then, after that you could use one of the

10 internal standards.

11 DR. JUSKO: In these recommendations you

12 are going by cell culture systems. I wonder, is

13 there no room for animal data? Win Chao has shown

14 a very nice correlation between fraction absorbed

15 of a large number of drugs in rats and man.

16 DR. HUSSAIN: I think with respect to

17 extent of absorption, animal data is allowed with

18 respect to perfusion experiments in direct methods

19 of permeability. We stopped short of using extent

20 of absorption in rat. I know we had that

21 discussion with Prof. Win Chao and he had about 100

22 compounds. So, we stopped short of that in our

23 recommendations in the guidance. But animal

24 perfusion experiments truly are okay. They

25 qualify. So.

224

1 DR. YU: In fact, I have a similar plot

2 which is from rat instead of CACO 2, also 18 drugs.

3 DR. LEE: Jurgen?

4 DR. VENITZ: I am very supportive of the

5 approach and I want to congratulate Gordon and the

6 FDA for moving it along as far as you have. Very

7 much like Marvin, I have some concern about the

8 permeability assessment based on in vitro data. I

9 guess I am wondering whether you have any

10 experience with misclassification using the human

11 in vivo as your gold standard. In other words, if

12 you know you have bioavailability of 90 percent or

13 above, you have a high permeability drug. How does

14 that compare to the in vitro predictions based on

15 CACO 2 cells lines?

16 DR. HUSSAIN: I don't have any experience

17 where we have found that problem occur. We are

18 actually in the process of publishing a validation

19 study, our own data, on in vitro studies, and Donna

20 will be here who has done that work. So, I don't

21 have an example.

22 DR. VENITZ: I know of one that was

23 supposed to be a poor permeability drug and it

24 turned out to be a high permeability drug--

25 DR. HUSSAIN: Cimetidine would sort of

225

1 come to my mind as probably an example where I

2 think extent of absorption in vivo in humans, the

3 data would suggest it is either 100 percent or

4 slightly less than that. But under CACO 2 and

5 other perfusion studies, it comes out as low

6 permeability. So, misclassification is on the

7 lower side.

8 DR. COOK: Yes, I would echo that. I did

9 an informal survey of some other companies and that

10 is what their indication was, that more often than

11 not the CACO 2 system was very conservative.

12 DR. VENITZ: With your proposal that

13 wouldn't be a big deal because you are lumping one

14 and three together. So, it doesn't make a

15 difference in terms of the waiver. But as it

16 currently exists, that would make a big difference

17 in terms of with you are waiving or not.

18 DR. AMIDON: it would only make a

19 difference in the dissolution standard you would

20 have to meet.

21 DR. VENITZ: Right. The second question I

22 have for you is about this Class III extension. Do

23 you have any experimental evidence, other than the

24 theoretical considerations that you went through,

25 to suggest that for a Class III compound we can

226

1 safely waive it and still show in vivo

2 bioequivalence.

3 DR. YU: This is basically for

4 information. We are considering those extensions

5 and we will come back with the data next time. We

6 will come back next time to this same committee

7 with data.

8 DR. LEE: So, Lawrence, you understand

9 correctly that probably the high end of the Class

10 III would be more like the low end of the Class I?

11 DR. YU: Yes.

12 DR. LEE: Therefore, you can waive it?

13 DR. YU: Yes.

14 DR. AMIDON: I think there are some drugs

15 where there have bee intubation studies, you know,

16 gastric, duodenal, jejunum. So some of those data

17 sets are availability for at least one or maybe two

18 Class III drugs in published literature. There is

19 more data also in NDAs. I think, for example, that

20 type of data showing site dependence would be one

21 set of data.

22 DR. VENITZ: Since you are going to go out

23 and come back, that would be the kind of data I

24 would like to see to support it experimentally, not

25 just theoretically saying we think Class III is

227

1 fine.

2 DR. YU: Absolutely. We are looking, for

3 example, at the evidence which would show

4 bioequivalence between solid oral dosage forms

5 versus a solution. We have about seven or eight

6 drugs right now. We intend to collect at least ten

7 drugs to deny or confirm the hypothesis we

8 discussed here today.

9 DR. LEE: Larry?

10 DR. LESKO: Yes, I wanted to answer that

11 last question because when we were doing the

12 research at the University of Maryland as part of

13 the scientific basis for the SUPAC guidance we had

14 two drugs from this class, the class that we are

15 talking about today, Class III with the high

16 solubility, low permeability, and Lawrence had them

17 on one of his slides, cimetidine and ranitidine.

18 Those were another two drugs which we tried,

19 through various manufacturing method changes, to

20 sort of ruin the formulations, create big

21 differences in dissolution but in vitro they were

22 very robust in terms of bioequivalence. So, I

23 think that is some evidence that would support what

24 Lawrence is talking about.

25 DR. VENITZ: So, you showed that the two

228

1 different solubility forms were bioequivalent in

2 vivo?

3 DR. LESKO: Yes.

4 DR. VENITZ: What about comparing the

5 solution to a solid dosage form?

6 DR. HUSSAIN: Well, I think that is what

7 Lawrence is proposing now but we don't have

8 prospective data on that now. We have some

9 in-house data but I think Lawrence is proposing to

10 do some studies comparing solution to tablet, and

11 so forth. So, that is one of the sets of

12 experiments that we probably will bring back to

13 this committee.

14 The other experiment that is ongoing right

15 now, we have completed the manufacturing and so

16 forth, and actually the studies have begun at

17 Tennessee, the biostudies. That is to create

18 formulations of a low permeability drug. We took a

19 low solubility, low permeability drug, furosemide,

20 and created dissolution profiles which are very

21 different and actually induced a pH sensitivity in

22 that. I don't know when those studies will be

23 completed but they have already begun. So.

24 The solution as a standard I think is also

25 important because when we were doing the BCS

229

1 guidance we looked at excipients. I think

2 excipients come back as an issue, and we were

3 collecting data with solution, simple solution that

4 was established, and I think from that we

5 identified about 50 excipients which are commonly

6 used which don't seem to have an effect. So, we

7 could build a basis for that and I think that was

8 one of the questions Lawrence posed, should we

9 identify excipients which may be potential

10 problems. That is what we tried to do in the first

11 guidance. I think that is the easier route because

12 for solid dosage forms there are only about 50

13 common excipients and you can make all sorts of

14 dosage forms with those 50 excipients. Of those,

15 the potential problems were surfactants, sodium

16 laurel sulfate, and so forth. And, we have

17 supportive data to say it may not really be an

18 issue in vivo. So, that database also could be

19 brought back.

20 DR. JUSKO: Do you think you can ever

21 really be conclusive about the excipients? Because

22 there could be a very specific interaction between

23 a particular excipient and a drug based on their

24 distinct chemical features.

25 DR. HUSSAIN: We that interaction be a

230

1 chemical or physical interaction, or an interaction

2 at a transport or absorption level? I think our

3 focus is more on the absorption because that is

4 where the concern is. If it is a physical

5 interaction or a chemical interaction, it sort of

6 comes out as a stability issue rather than a bio

7 issue in some cases. So, there would be different

8 ways of addressing chemical interactions.

9 DR. JUSKO: Might one manufacturer use a

10 particular excipient in their product and someone

11 use a different one, and then there would be a

12 potential difference?

13 DR. HUSSAIN: That is possible. For oral

14 products you could have different excipients.

15 DR. LEE: Particularly with the Class IV

16 drugs. Well, shall we keep this conversation

17 going? Marv has a question.

18 DR. MEYER: Yes, one question perhaps to

19 Lawrence. Is there a greater potential for an

20 error to be made for the Class III than Class I? I

21 am asking from the standpoint of your table. If

22 you take a drug, Class I by definition is 90

23 percent fraction absorbed, the most we can go up to

24 is 100 percent. If you take glycinopril, it is 30

25 percent fraction absorbed, and that goes up to 40

231

1 percent. Now, you have a third increase in the

2 available drug. As you get down in FA you have

3 bigger orders of change if you do something to

4 cause a change.

5 DR. YU: That is why the effect of the

6 excipients is kind of critical.

7 DR. MEYER: Whatever. The formulation,

8 whatever you didn't see because you didn't do the

9 biostudy causes it to go from 30 percent to 40

10 percent or 30 percent to 20 percent. That is a

11 bigger change than 90 to 100 or 90 to 80.

12 DR. COOK: If I could jump in, you could

13 have a change the other way and have a drug that is

14 100 percent and all of a sudden it goes down to 10

15 percent. So, it is just depending on whether you

16 are looking at increased chance of adverse events

17 or a loss of therapeutic benefit. But I think the

18 risk is there--

19 DR. HUSSAIN: Jack, sort of a different

20 perspective on that, I think with the rapid

21 dissolution the likelihood is minimized the other

22 way around. I think the excipients with sodium

23 laurel sulfate, and so forth, I think the concern

24 that Marv raised was one of the reasons for holding

25 it back to highly permeable drugs. If you have an

232

1 excipient like sodium laurel sulfate that can

2 enhance permeability what will happen with highly

3 permeable drugs? Very little. But for low

4 permeability drugs the margin of error is high.

5 DR. AMIDON: I just want to caution or

6 advise the committee to not think of excipient

7 effects as yes/no but to think of them as

8 dose-response curves and it is a matter of at what

9 dose and what level they are having an effect. We

10 know that sodium laurel sulfate at a very low

11 concentration has no effect and at a very high

12 concentration dissolves the intestine. So, it is a

13 dose-response curve issue. So, having thought a

14 lot about this excipient issue and interactions

15 with the gastrointestinal track, if we get into the

16 excipient issues we should proceed carefully and

17 mechanistically in evaluating those potential

18 implications.

19 DR. HUSSAIN: A different perspective that

20 I think also is important with excipients is if

21 excipients have significant interactions that

22 alters bioavailability it actually is a much larger

23 issue than bioequivalence. It becomes a label

24 issue because if it is an interaction that changes

25 bioavailability the potential for that interaction

233

1 will be there in the marketplace and I think we try

2 to avoid that, and I think the excipients that are

3 available generally, with a few exceptions, are

4 essentially from that perspective. The famous

5 example is sorbitol.

6 DR. LEE: Then I will just propose that we

7 take a 15-minute break so that we can maybe focus

8 and discuss some of the issues more. Will you

9 please come back at 3:15?

10 [Brief recess]

11 DR. LEE: Lawrence posed two questions to

12 the committee. Actually, I should inform the

13 audience that I began to form study groups in the

14 committee to look at the issues. I have four

15 individuals working this particular topic, Bill

16 Jusko, Leon Shargel, Lemuel Moye and myself. Right

17 after lunch I delegated my responsibilities to Bill

18 and he is going to be the lead correspondent.

19 DR. JUSKO: Are you going to put the

20 questions back up that we are to focus on? We have

21 all heard from this morning's and this afternoon's

22 discussion about the BCS classification system and

23 the guidance that is in place for Class I drugs.

24 It was interesting to learn this afternoon how few

25 companies have actually taken advantage of this

234

1 classification system and proceeded to use it, with

2 only five or six having been indicated.

3 The discussion this afternoon provided

4 much more illumination of the basic scientific

5 ideas and regulatory approaches to dealing with the

6 BCS system, and we were asked to focus on two

7 particular questions. Within the second question,

8 it appears that there is plenty of room for

9 recommendations as to how to proceed with the

10 second question.

11 But let's go to the first one since it is

12 the easier one to deal with. We were shown that

13 there are discrepancies in the pH values used to

14 determine solubility versus dissolution. So, the

15 first question is should the agency consider

16 revising the pH range of the solubility class

17 boundary to be consistent with the dissolution pH

18 range?

19 In my own view, the answer is quite

20 obvious that one should seek consistency. Perhaps

21 other members of the committee would like to

22 provide their comments.

23 DR. MEYER: How about changing the other

24 one to 7.5, have the same range but have 1 to 7.5

25 instead of 1 to 6.8?

235

1 DR. AMIDON: Can we comment?

2 DR. LEE: Sure.

3 DR. AMIDON: I think one element there,

4 Marv, would be the harmonization also with Europe.

5 At a workshop we had at the end of January with

6 European representatives--6.8 is kind of an

7 international standard, U.S., Europe, Japan for

8 dissolution studies, simulated intestinal fluid.

9 So, I think it is partly also that, harmonization

10 to kind of the world standard. I think if we were

11 to go from 6.8 to 7.5 we would have some problems.

12 DR. KIBBE: Yes, I remember when I was a

13 young child my mother always telling me that you

14 don't do things because everybody else did them.

15 So, we have a harmonized number but the question

16 really is, is it missing information or not? That

17 is really the bottom line. Would we really miss

18 out on something important if we left out going up

19 to the physiological pH which exists at the

20 terminal end of the GI tract? If w are clear that

21 we are not going to lose anything, then it is okay.

22 If we are worried that we are, then we should

23 extend the other to 7.5 instead of cutting back to

24 6.8. That is the question I think.

25 DR. COOK: If I can comment on that, I

236

1 think the strongest evidence was when Lawrence put

2 up the slide about transit time, and it is 85

3 minutes to that terminal end but we are requiring

4 dissolution to be essentially complete within 30

5 minutes. So, it will never see the higher pH

6 before it is all dissolved.

7 DR. KIBBE: Your disease requirement is in

8 vitro dissolution and it is predictive of in vivo

9 dissolution, but in vivo dissolution of something

10 in 15 minutes might be 15 minutes and it might be

11 45 minutes. Okay. So, that still isn't a

12 guarantee. I am not saying that 7.5 is where we

13 ought to be, but I think we ought to know whether

14 we are losing any information.

15 DR. RODRIGUEZ-HORNEDO: I was going to

16 comment on that same point, and I struggled with

17 the way that the question is worded until I saw

18 Lawrence's slide with the pH in the different

19 regions of the GI tract. Maybe the question needs

20 to be reworded because it is not really a matter of

21 consistency with the dissolution range which should

22 specify that it is maybe the physiologically

23 relevant dissolution range. It wasn't clear if

24 this was an in vitro dissolution test that you were

25 trying to be consistent with, but what is more

237

1 important is that it is physiologically relevant.

2 So, with that in mind, my reaction is more positive

3 to the recommendation. However, my question still

4 relies on what about acids? Maybe you have weak

5 acids that are very poorly soluble at pH 7. Maybe

6 it is not relevant physiologically but I would like

7 you to address that. Are there any drugs or any

8 properties of drugs that are going to be of

9 concern?

10 DR. AMIDON: For borderline drugs? There

11 are a few NSAIDs. There may be. I think that is a

12 good example. What might this impact? I think it

13 is only a few drugs that it might actually impact.

14 I think that is a good point. I think our goal

15 here is to get the general view. We will come back

16 with the evidence in the future, and we are

17 interested in the type of evidence that the

18 committee thinks would be supportive of a positive

19 answer to this question one. For what types of

20 drugs would this have an impact?

21 I think I would agree. Harmonization is a

22 secondary issue. The question is reflecting the

23 physiological process and having a valid BE type

24 dissolution. So, I agree completely. On the other

25 hand, other things being equal, we would want to

238

1 harmonize rather than disharmonize--other things

2 being equal.

3 Ultimately, it is dissolution that counts,

4 not solubility. Our dissolution standard is based

5 currently on 6.8. So, dissolution is what counts.

6 Solubility is one of the factors determining the

7 dissolution rate but the dissolution rate is what

8 counts.

9 DR. HUSSAIN: One point that I think needs

10 to be kept in mind is the initial introduction of

11 BCS was in SUPAC which covered all drugs. The BCS

12 guidance, though focused on methods for

13 classifying, focused on waivers of highly soluble,

14 highly permeable. So, I think that is the

15 disconnect that we tend to see, that is, the range

16 of 1.2 to 7.5 is because it comes from the SUPAC

17 guidance and the rapid dissolution criteria that we

18 developed were for the BCS waiver guidance only.

19 So, that is how we will have to resolve that.

20 DR. LEE: Okay, so we have answered the

21 first question.

22 DR. JUSKO: I think we have resolved the

23 first question reasonably well. To summarize, I

24 think the answer to that is the inclination is to

25 have them both be determined at pH 6.8 but look

239

1 into the possibility that there may be unusual

2 circumstances where pH 7.4 would be particularly

3 relevant.

4 The second question is should the agency

5 expand the application of BCS-based biowaivers to

6 rapidly dissolving, immediate release products of

7 BCS Class III drugs? That question is a more

8 profound one and appears to be connected directly

9 to the list of proposed studies and data collection

10 efforts to test the hypothesis that this is

11 achievable, and it would be good to look again at

12 one of the slides from Dr. Yu. That one.

13 [Slide]

14 Clearly, it is premature that anyone go

15 directly to implementing this type of policy, and I

16 think we are at a stage where the committee is

17 probably recommending that a number of studies be

18 done to investigate and confirm that this is a

19 reasonable thing to do. This list of studies was

20 proposed and I would welcome comments from other

21 people on the committee.

22 DR. SHARGEL: One, it does strike me as

23 being a reasonable approach. I think, if I

24 understand this correctly, the premise is that

25 these drugs would rapidly dissolve and would be

240

1 very similar to giving it as a solution almost for

2 the time spent in the gastrointestinal tract. So,

3 the issue then becomes if you have a solution of

4 the drug would the excipients in a solid dosage

5 form make any difference in the permeability realm.

6 That is the issue I think as to make this a

7 universal kind of approach.

8 DR. YU: That is correct.

9 DR. HUSSAIN: I just want to make sure

10 that you are not committing to do those studies

11 with our money. We will take this recommendation

12 to PQRI and have industry do those studies.

13 [Laughter]

14 DR. JUSKO: With all the money that Pfizer

15 has saved, I am sure they are going to be the ones

16 to fund it.

17 [Laughter]

18 DR. COOK: That is how I got my salary all

19 the way up to $20,000 a year!

20 DR. LEE: Well, I think it is a serious

21 question and I think underlying this is the meaning

22 of permeability. I think I have heard repeatedly

23 throughout the day that while we are very

24 comfortable with dissolution solubilities being

25 unambiguous, when it comes to permeability that is

241

1 not so. Since someone else is going to pay for it,

2 we may as well address this issue more seriously.

3 What do we mean by permeability?

4 DR. YU: Yes, for BCS Class III drugs we

5 will collect a number of drugs and cover a wider

6 span of permeability. From there we will answer

7 some of the questions and some of the concerns with

8 respect to BCS biowaiver for Class III drugs. For

9 example, with internal studies we are proposing

10 intermediate permeability. Once we have the data,

11 I think the data will tell us which direction we

12 should go in. Thank you.

13 DR. HUSSAIN: I think one sort of point

14 that we would consider, I think is Hans Lennernas

15 has published on water, a glass of water. Water

16 has a permeability value which is fairly close to

17 metoprolol. It so happens that the permeability of

18 water itself is at the boundary. So, that has an

19 implication that when you give a glass of water and

20 a solid drug after an all-night fast, the glass of

21 water might get absorbed more quickly than the drug

22 has time to dissolve. I think we can bring that as

23 a sort of research question and address some of

24 that; some of the work that Gordon has done with

25 perfusion studies, and so forth, and what

242

1 implication that has.

2 DR. LEE: Yes, Larry?

3 DR. LESKO: If we look at that slide as a

4 way forward in anticipation of bringing results

5 back to the committee in the future, to get back to

6 the specific question about biowaivers, I wonder if

7 the committee members would have any thoughts on

8 what they would expect to see from these studies.

9 In other words, let's say I go out and I do a

10 comparative study of a solution versus these dosage

11 forms, would it be important to demonstrate strict

12 bioequivalence based on the 90 percent CI of 80 to

13 125? Would it be satisfactory to deal with the

14 point estimate? These are important considerations

15 in terms of designing and powering these studies to

16 address the question that we have. So, I wonder if

17 anyone has any thought on that.

18 The other part of this question is how we

19 select the solid dosage forms. Is there any advice

20 that committee members could give on the

21 identification of particular excipients that would

22 come to the forefront of people's mind that would

23 be worthwhile considering as part of the selection

24 process for the dosage forms. So, let's say that

25 we do come back in a year or something like that

243

1 and have data, we don't miss something that may be

2 particularly important in terms of potential

3 excipient effects.

4 DR. SHARGEL: Somehow, Larry, I am

5 compelled to talk about 90 confidence intervals and

6 bioequivalence. So, if you do the study I would

7 expect the same criteria would be held up.

8 MR. VENITZ: I would second that.

9 DR. BOEHLERT: I don't have a list of

10 excipients that you should be looking for, but I

11 certainly think that should be one thing you should

12 consider in doing these studies because, you know,

13 you keep repeating that excipients can have an

14 effect on oral absorption and I would like to

15 understand that better, where and how, so we could

16 begin to identify which excipients might be

17 problematic.

18 DR. LEE: Lawrence, have you shown us

19 those ten mono drugs? Did you provide a list?

20 DR. YU: Well, this is just the 12

21 potential BCS class drugs. We will come back with

22 some other drugs which are potentially Class III

23 drugs. That doesn't necessarily mean we will study

24 all ten. Maybe some data is already available from

25 NDAs and ANDAs.

244

1 DR. HUSSAIN: I think we have done two

2 studies, cimetidine and ranitidine, as Larry

3 pointed out. So, we have a good database on that

4 with manufacturing changes and dissolution changes

5 on two of those already. So, one could look at a

6 range of permeability values that could be selected

7 to account for that. At the end of the experiments

8 I think one aspect might be that you might need an

9 intermediate class of permeability because right

10 now you are going from 0-90, and I think when you

11 start going down to 20 and 30 percent, that is

12 where you start having problems. So, a range of

13 permeability values will help us maybe define and

14 intermediate permeability class.

15 DR. KIBBE: Is there less concern for a

16 company who decides to change the site of

17 manufacture from point A to point B and saying,

18 okay, it is a Class III and I am just going to show

19 you that I have the same dissolution

20 characteristics because I have just transferred my

21 process than with a second company who has a new

22 formulation and wants to do a biostudy? Would that

23 delineation help us move Class III's where we could

24 waive it in one case and not necessarily in

25 another?

245

1 DR. HUSSAIN: Well, I think SUPAC scale-up

2 and post-approval change actually did that. It

3 brought a risk-based approach or three-tier

4 approach for that. For example, for site changes

5 alone with no other changes, for a immediate

6 release dosage form it is qualification based on

7 dissolution alone. If you have other types of

8 changes, BCS comes in when there are excipient

9 changes, and so forth.

10 DR. RODRIGUEZ-HORNEDO: My observation is

11 that most of these compounds are weakly basic.

12 Right? Almost all of them?

13 DR. LESKO: Hydrochlorothiazide is a weak

14 acid, I believe.

15 DR. RODRIGUEZ-HORNEDO: Yes. Most of them

16 are weakly basic, and I am coming back to that

17 issue of pH dependence on solubility. I know it is

18 not the main issue here with the permeability but

19 maybe something that hasn't been addressed is the

20 pH dependence of the permeability. Is that of

21 concern?

22 DR. COOK: I don't know if this list was

23 proposed to take the ten drugs from. I think we

24 could take it back. We want to look at acids and

25 bases, and we want to look at a range of

246

1 permeability that probably even exceeds what we

2 have here to provide the best data. So, I don't

3 think I would get too hung up in saying that these

4 are the model compounds that one would use. It is

5 better to use a broader range that encompasses more

6 things so we will have more confidence in the

7 results.

8 DR. AMIDON: That is a good question about

9 pH dependence. The pH 6.5 with the perfusing

10 system that we use in humans provides a reference

11 permeability, kind of like a thermodynamic PK; it

12 is not really what is going on in solution but it

13 is what you use to move ahead. So, we measure this

14 reference PK. We have done permeability studies in

15 humans with alpha methyldopa a long time ago, and

16 that is pH dependent. It parallels that in

17 animals, and there is a variety of reasons for that

18 pH dependence. From the point of view of

19 predicting drug absorption and drug absorption

20 variability, it would be very important. So, I

21 would want to know that as a development scientist.

22 I don't see how it would help in a regulatory

23 classification or decision-making process. We take

24 the mean pH of about 6.5 for the human intestine

25 and say, okay, we are going to use that as our

247

1 reference value and stay with that. It gets to

2 cumbersome otherwise.

3 But for some of these drugs, I know

4 because we have studied hydrochlorothiazide, they

5 are very pH dependent, and we have also done

6 furosemide. So, the actual operative permeability

7 of pH 6.5, the permeability decreases there greatly

8 because it is ionizing. It is probably absorbed.

9 It has a very sharp absorption window because it is

10 the permeability, solubility procedure that counts.

11 Solubility is going up, permeability is going down.

12 I think that is why it is a highly variable drug.

13 It is not bioequivalent to itself, at least in one

14 study, because of the variability so we are getting

15 into problem drugs here--I should say variable

16 drugs. I am interested in the pH dependence, but I

17 can't justify it on the basis of regulatory use.

18 DR. LEE: It seems to me that this is an

19 ideal situation for forming a subcommittee to work

20 with Lawrence to just design a study. Right? The

21 choice of drugs, excipients, in vivo, in vitro,

22 other kind of parameters.

23 DR. YU: That is an excellent suggestion,

24 yes.

25 DR. JUSKO: I think it would also be good

248

1 to keep in mind making maximum use of complementary

2 information, like structure activity types of

3 predictions, as well as the data gathered from

4 animal studies so that one has more than one

5 measurement to base any anticipated results on.

6 DR. YU: This comes to my favorite topic,

7 my true research interest is in the structure

8 activity relationships. As long as my boss says

9 okay, do it, we will do it. Definitely.

10 DR. LEE: I thought you were going to say

11 you would do simulation studies.

12 DR. YU: Yes, we will do simulation

13 studies.

14 DR. LEE: Maybe that is the place to

15 start.

16 DR. LESKO: I want to get to the proposed

17 research because it is such a key to moving

18 forward. One of my concerns, and maybe I will ask

19 Lawrence to comment on this, is what is the

20 possibility or probability that you will be able to

21 find two solid dosage forms of these Class III

22 drugs that meet the rapid dissolution

23 characteristics that are being proposed for it? Is

24 this a study that is sort of Jack Cook's blue sky,

25 or is this a study where you can actually go into

249

1 the marketplace and find these things, or is it a

2 set of studies where you would actually have to

3 formulate the products to meet the rapid

4 dissolution criteria, or all of the above?

5 DR. COOK: Larry, would you consider a

6 solution versus tablet sufficient? That way, I

7 only need to compare those two rather than two

8 solid formulations?

9 DR. LESKO: Well, let's say we are doing

10 two tablets, but as I understand this research, if

11 you are going to go into the marketplace to find

12 those solid dosage forms, tablets, whatever, they

13 aren't necessarily formulated to be rapid

14 dissolution.

15 DR. COOK: That is why I was suggesting a

16 solution which is, for a highly soluble compound, a

17 lot easier to formulate and compare that to a

18 tablet. So, you have one that is extremely rapidly

19 dissolving, the solution, and then the tablet and

20 you can probably look at the excipients in that as

21 well.

22 DR. LESKO: So the tablet would be rapid

23 dissolution as well, 15 minutes?

24 DR. COOK: Well, it would have to be 15 or

25 30 minutes, whatever we propose. So, you would

250

1 have to make one formulation, is what I am saying,

2 rather than two.

3 DR. LESKO: I think actually that would be

4 a good idea because you are talking about ten drugs

5 with a comparative study, which is no less than

6 what we have for the original fasting study,

7 bioequivalence studies. In fact, it would exceed

8 it I think in terms of the total in vivo data to

9 support a biowaiver. But, again, that question

10 about what is the drug and what is the formulation,

11 and whether they are commercially available or not,

12 would be a limiting factor.

13 DR. YU: Certainly, I think we need to be

14 flexible, and we have limited research dollars. If

15 it is available on the market we will supply them

16 for the studies. That is the value of having a

17 subcommittee under the ACPS to get advice from the

18 members to see how best to utilize the money to get

19 the information we can get.

20 Secondly, we certainly want to utilize

21 what is out there in the literature and what is out

22 there in the NDAs and ANDAs. From there, we would

23 design--we only can conduct what is necessary to

24 address issues from those studies in NDAs or ANDAs

25 which we are not able to address.

251

1 DR. KIBBE: Larry, why can't you go to the

2 data the FDA already has and get the dissolution

3 profiles of all these products to start with? I

4 think it might be a little bit better if there were

5 two products out there that would give you relative

6 rapid dissolution. I think you would be better off

7 looking at them, and using as a fall-back a

8 procedure that isn't on the market, a solution.

9 DR. LESKO: Yes, I think the missing link

10 there is the dissolution studies that would not

11 necessarily be available in an application--

12 DR. KIBBE: Why not?

13 DR. LESKO: Well, because we are talking

14 about a very specific set of dissolution test

15 conditions to test a hypothesis of Class III.

16 Those dissolution conditions may not have been

17 studied as part of the normal drug development.

18 So, you can't just go back to the applications and

19 pull that information out. In almost all cases you

20 have to go to a laboratory and redo that to the

21 specifications that you would like to support the

22 hypothesis. But that is doable. I mean, that is

23 just reality; you just have to do it.

24 DR. YU: Absolutely. We actually

25 conducted a food effect study which was presented

252

1 this morning. When we selected a drug we purchased

2 the products and we did a lot of in vitro testing

3 before we selected these two specific products for

4 in vivo studies. It is doable and we have the

5 facility to do that within the agency.

6 DR. MEYER: It seems to me though that one

7 of the pieces of rationale I heard was that Class I

8 and Class III act like solutions. So, if we did

9 studies for low permeability drugs, solution versus

10 a marketed or experimental tablet, what-have-you,

11 just that two-way crossover, you would in a sense

12 prove whether the low permeability--while we know

13 it dissolves rapidly--also is sufficiently

14 permeable or permeability isn't a factor. So, that

15 seems to be a rational way of approaching it given

16 your initial hypothesis, solution versus tablet.

17 DR. YU: You are right. You are

18 absolutely correct, yes.

19 DR. MEYER: Can I raise one other

20 question? Just to kind of support the concept of I

21 think we still need to look at low permeability,

22 and that is that study that Ajaz had in his handout

23 from UT, ranitidine, sorbitol sucrose and

24 metoprolol, sorbitol sucrose, both solutions. And,

25 the metoprolol, which is highly permeable or

253

1 borderline high, had a confidence interval, sucrose

2 solution sorbitol 86-100 for AUC so it was

3 essentially bioequivalent, unchanged by sorbitol.

4 Whereas, ranitidine, which is low permeability,

5 dropped to 62 percent. So, the effect of sorbitol

6 was much greater on the low permeability ranitidine

7 than it was on the high permeability metoprolol.

8 So, we do have to worry about excipient effects.

9 Maybe this is the worst excipient known to man and

10 that is biasing our information, but maybe it isn't

11 so I think we still need to look closely at that.

12 DR. HUSSAIN: I think we would need to but

13 I think I would go back to what Gordon suggested in

14 a sense, for a solid oral dosage form it is the

15 dose of the excipient that is important. When you

16 think of a syrup you are looking at a tablespoonful

17 or two tablespoonfuls so sorbitol in a solution is

18 a much larger dose and a tablet is a much smaller

19 dose. So, that also I think is an issue that

20 should be considered. So. But I think Ian Wilding

21 has done the work with chewable tablets with

22 cimetidine. So. So, two grams of sorbitol with

23 mannitol had a dramatic effect on cimetidine. So.

24 DR. AMIDON: It may relate to the water

25 reabsorption and the absorbable versus not

254

1 absorbable excipients, and it would inhibit water

2 absorption which would slow down cimetidine's

3 absorption and if the transit is also speeded up

4 you can come up with a good rationale for the

5 mechanistic reasons, which suggests that maybe you

6 should classify excipients in some way. I mean, if

7 the excipient is absorbed, it is gone at some

8 point. So, maybe it is low permeability or

9 non-absorbable excipients that may have a problem

10 so you can perhaps reduce the problem that way. I

11 don't know.

12 DR. HUSSAIN: I think we talked about that

13 and actually low permeability, highly soluble

14 excipients are the ones which gave problems. If I

15 go back to Ian's work, and Ian could comment on

16 that, he actually did an experiment--Ian, correct

17 me if I am wrong--where he started with equal

18 osmotic pressure between sucrose, pyrophosphate and

19 sorbitol and mannitol, and showed that initial

20 osmotic pressure essentially.

21 DR. WILDING: We were trying to produce

22 osmotically equivalent concentrations of sodium

23 acid pyrophosphate, mannitol, the intention being

24 to try to work out what the mechanism was. As

25 Gordon indicates, I am sure there are mixed

255

1 mechanisms going on in terms of how the excipients

2 have their effect, but I am sure it is the

3 non-absorbable excipients that will have the key

4 issue in this regard.

5 I was just wondering as you were talking,

6 the choice of excipients that you use in the

7 context of these studies is obviously going to be

8 important. I wonder how much of the work, as Vince

9 indicated, could be done by modeling in advance to

10 create the matrix which is then tested by the human

11 biostudies. So, in looking at drugs for different

12 fraction absorbed in terms of Class III, given the

13 excipients' different release rates, trying to

14 build some form of modeling for that which then

15 forms the basis on which the human biostudies are

16 done. Because what you might find, if you are not

17 careful, is that human biostudies might not provide

18 the answer to the questions, which would be a waste

19 of time, money and effort.

20 DR. HUSSAIN: To that effect in the sense

21 of we worked with Jim Pauley last two years to look

22 at CACO 2 in vitro permeability experiments as a

23 screen to try to identify, hopefully, excipients

24 which might be affecting the permeability of the

25 membrane itself. I think from the literature and

256

1 from what Ian and we have done, we know the

2 osmotics. So, we are essentially looking at

3 several mechanisms by which these excipients can

4 exert an effect. So the studies we do and the

5 models we select, if they are mechanistically based

6 and based so we can actually get a hypothesis and

7 test that, would be far more meaningful than

8 randomly selecting those excipients.

9 DR. YU: Actually, we have done some

10 mathematical modeling work to simulate Ajaz' study

11 done at the University of Tennessee, to look at how

12 excipients in this particular case, sorbitol five

13 grams that one tablet will have, to look at how the

14 sorbitol affects oral drug absorption of

15 ranitidine. We have really nice results.

16 Certainly, we also want to evaluate it in the low

17 dose. I think those study results will all be

18 valuable in the future for how to address some of

19 the concerns expressed here. Thank you.

20 DR. HUSSAIN: One example that you have in

21 your handout is from my presentation. The drug is

22 atenolol, the tablet with a solution, and the

23 tablet has twice the bioavailability than the

24 solution. There is about 750 mg of sorbitol in

25 that. So, you know that even 750 mg in a solution

257

1 can reduce bioavailability by 50 percent compared

2 to a solid tablet. So, I think the thing which is

3 exciting to me is the major mechanisms by which

4 excipients exert their effect. As that happens, we

5 actually happen a means of doing hypothesis-based

6 testing underpinned by mechanistic basis for this.

7 DR. LEE: In other words, the excipients

8 can no longer be considered as inert.

9 DR. HUSSAIN: I don't want to alarm people

10 with that. I think we have to be very pragmatic.

11 I think some excipients have effect but I think

12 overall in a solid dosage form I don't think there

13 is a major concern. So.

14 DR. YU: The majority are inactive and

15 some of them, like sorbitol, may have some

16 concerns, yes.

17 DR. ANDERSON: Aren't you talking about

18 molecular interactions which are pH dependent,

19 particularly with those things that have all those

20 OH groups on them?

21 DR. YU: For solubility or permeability?

22 What aspect?

23 DR. ANDERSON: Well, if the solubility of

24 the drug is pH dependent, that is, if it has the

25 nitrogen or carboxylic acid group in it, and you

258

1 have all the OH's on the other things, whatever you

2 call them, you are talking about molecular

3 interactions which are pH dependent. The pH really

4 affects even those things with the OH groups on

5 them because the OH groups are basic as well.

6 DR. COOK: I guess that is another way of

7 looking at how you are classifying how the active

8 adjuvants, to steal somebody else's classification,

9 interact because not only are we worried about that

10 but things that change the physiology, whether it

11 be something that changes the osmolarity or

12 something that interacts with the membrane itself.

13 I guess the investigation of excipients is even

14 broader than just the molecular interaction.

15 DR. LEE: Bill?

16 DR. JUSKO: It sounds like there has been

17 considerable and very fruitful discussion about the

18 issues relating to these proposed studies. My

19 view, and I believe the committee believes that

20 there is good possible potential for future

21 biowaiver for the Class III agents, but before that

22 is done a very careful assessment of many of these

23 basic questions needs to be done. It appears that

24 an ample data set needs to be collected, and many

25 questions related to the role of excipients remain

259

1 to be resolved. So, there is great encouragement

2 from the committee to continue along this line.

3 DR. LEE: Well put. Maybe a future

4 committee will hear these results. Are there other

5 issues to be brought forth before this group? We

6 have had a very fruitful day.

7 DR. HUSSAIN: One issue, and I don't want

8 to be caught again like with the highly soluble,

9 highly permeable drugs, is the food effect. If we

10 go with a waiver for Class III, I think the logic

11 we be that we have to consider the food effect

12 alongside because otherwise it doesn't make sense.

13 So.

14 DR. LEE: That is for the record.

15 DR. HUSSAIN: So, this should also expand

16 to the food effect too at the same time.

17 DR. YU: You are absolutely right. We

18 will probably begin to collect the coefficient of

19 valence for a number of drugs compared under

20 fasting conditions and under fed conditions to see

21 if the valence becomes bigger or smaller, and how

22 to address this concern that we had this morning.

23 Thank you.

24 DR. LEE: We began the day talking about

25 subcommittees and I think this is an excellent idea

260

1 for clinical pharmacology, and not put a spotlight

2 on clinical pharmacology but also may serve as a

3 catalyst for other changes in the committee. Then

4 we went on to talk about a very interesting issue

5 about food effect on Class I drugs. I think the

6 committee is not that comfortable. Well, the

7 answer seems to be obvious but we don't have enough

8 evidence to support our gut feeling.

9 This afternoon I think we got a very good

10 understanding about the BCS Class I, Class III. I

11 don't want to repeat what Bill Jusko just talked

12 about. He put it very succinctly what needs to be

13 done. I think that we are going to hear about the

14 results of this work in a few years time, but the

15 committee, or at least I would like to see the use

16 of computation as a way to guide the experimental

17 design, and also to think about this permeability

18 more carefully, especially when we are encountering

19 more drugs that require transporters for

20 absorption.

21 DR. HUSSAIN: Let me go back to the issue

22 of the food effect waiver because that is an

23 important issue and I think I want to stress the

24 logic of the situation being such that it doesn't

25 make sense not to give waiver for fed studies for

261

1 Class I rapidly dissolving when we give the waiver

2 for fasting studies. I just want to stress that

3 fact because I heard from Marv that he is in

4 agreement with that. I really would like to have a

5 position of the committee on that one. So.

6 DR. LEE: That is the position.

7 DR. HUSSAIN: What is the position?

8 DR. LEE: What you just said.

9 [Laughter]

10 DR. HUSSAIN: So, the committee agrees

11 with Marv and the logic prevails?

12 DR. LEE: Right. What I have seen today,

13 shall we revise the guidance, reminded me very much

14 about curriculum revision. Tomorrow we can forget

15 about biology more or less, and we will focus on

16 some physical chemical issues. So, we begin

17 tomorrow at 8:30. Please plan on staying the

18 entire day because we have a full agenda, I mean

19 the committee members. You can leave the stuff

20 here because it is safe.

21 [Whereupon, at 4:00 p.m., the proceedings

22 were recessed, to reconvene at 8:30 a.m.,

23 Wednesday, May 8, 2002.]

24 - - -