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1 LINDA BROPHY: Good afternoon, I

2 think we will begin now. If you would

3 take your seat, we will be ready to

4 begin the CDER portion of the program.

5 I\'m honored to introduce

6 Dr. Woodcock, and she has a CDER

7 message.

8 JANET WOODCOCK: Thanks, Linda.

9 Good afternoon everyone, again. I\'m

10 very interested and I hope I will be

11 able to hear from people and what their

12 affiliation is and where you all come

13 from and what your interests are during

14 the course of the rest of this session.

15 Because some of you may not

16 really know much about what we\'re doing

17 or who we are in the Center for Drug

18 Evaluation and Research, CDER, I\'m going

19 to very briefly go over some of the

20 things that we do and what I think the

21 current state of drug regulation is

22 right now, what are our strengths, what

23 are our challenges, and what questions

24 are we seeking input on. I\'m going to

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1 talk about our level of performance,

2 answer basic tasks that the country has

3 asked us to do and I\'m going to discuss

4 some of the challenges that we face

5 right now, and some of them you\'ve heard

6 about already during the interactive

7 session with Dr. Henney. And finally,

8 I\'m going to talk about the questions

9 that were asked in that session and were

10 put up on the screen, but discuss them

11 in the CDER context and the context of

12 drug regulation. How are they relevant

13 to drug regulation, and I hope we\'ll

14 hear from you about that.

15 As far as our level of

16 performance, I decided to use some of

17 the charts from the Report to the Nation

18 that we just passed out to people so you

19 will be able to refer to that and that

20 will provide some context about what I\'m

21 going to show you.

22 Basically, I think my message

23 is that our core programs in the Center

24 that we operate are performing

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1 efficiently and effectively and they\'re

2 serving the purposes that they were

3 intended for. However, of course, like

4 everything else, they could use some

5 improvement.

6 If you look at New Drug

7 Applications, this is the new medicine

8 of different kinds that are coming on

9 the market and changes to old medicines

10 and dosage forms and stuff.

11 It does not look totally

12 focused here. How is that; is that okay

13 for everyone (indicating)?

14 You can see that the line is a

15 number of new applications and they have

16 gone up considerably. And the time that

17 it\'s taking us to approve them \-- let\'s

18 start over at the 1993 on the left, and

19 then to the right \-- has dropped

20 considerably. And this is the effect of

21 the Prescription Drug User Fee Program,

22 the user fee paid by industry to

23 increase money, and the goals and

24 timelines that were set for us. You can

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1 study this chart, if you\'re interested,

2 more thoroughly in the book.

3 And then if you look at whether

4 we\'re meeting our goals on the New Drug

5 Application as far as the goals that

6 were established under the User Fee

7 Program, which were ambitious time goals

8 for how fast we would review

9 applications, and most people really

10 didn\'t think that the Center would be

11 able to meet these time goals, you can

12 see, since 1996, we have been a hundred

13 percent on time with our New Drug

14 Application Review. And it may be in

15 the future we may miss one or two, but

16 that would usually be for a very good

17 reason.

18 Now, most important to the

19 public office, are some, not all, but

20 some of the new molecular entities.

21 These are completely new methods that

22 are entering the U.S. market for the

23 first time. How are we doing on those?

24 What you see here is that,

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1 since 1993, the number of new molecular

2 entities that are approved that are

3 going into the market have increased,

4 although it peeked in \'96 and has gone

5 down a little bit since then, just not

6 surprising that the \'96 peek was a

7 result of the Prescription Drug Usage

8 Program. We have approved a great

9 number of new molecular entities and,

10 just as important, a review time for

11 these new medicines is the same. It has

12 fallen to about a year, which is our

13 goal, and it\'s about the same in the

14 overall New Drug application.

15 Now, equally important and

16 previously neglected was looking at new

17 uses of old medicines. Many of these

18 new uses of medicines that were already

19 on the market never came to an

20 application before the agency. They

21 were never really studied and they were

22 simply adopted into medical practice.

23 It became what you call an off-label

24 usage. This is not necessarily good for

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1 the medical practitioner or for the

2 public because we need to have the drug

3 studied for these uses and get the very

4 best information possible on the label

5 so people can refer to it.

6 And I think really good news

7 here is that the industry is studying

8 these uses and it\'s submitting them to

9 the agency. Last year, we had 124 of

10 these new uses for already-approved

11 medicines submitted to the agency, and

12 you can see that our review time is

13 dropping for them, as well. It has

14 dropped down to under a year and we

15 expect an increase of improvement in new

16 uses.

17 Now, equally important in a

18 different way is our Generic Drug

19 Program. The Generic Drug Program has

20 economic corpse to the public because

21 this brings competition and lowers drug

22 prices. And the affordability of

23 medicines is one of the issues, one of

24 the new issues that\'s really emerging

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1 now, the affordability of medicine for

2 the public. And you can see here,

3 again, the line is the actual number

4 that has been submitted to us in this

5 case, the number of generic approvals,

6 actually.

7 The number of generic approvals

8 was 344 last year, if you count all the

9 different dosage strengths and so on.

10 We\'re approving almost one generic drug

11 everyday. So, our Generic Drug Program

12 is doing very well. If you look at the

13 bars which show the review times,

14 similar to the other graphs, you can see

15 that the review time for generic drugs

16 has dropped remarkably over the last

17 years in the absence of any User Fee

18 Program and in the face of the great

19 escalation with the number of generic

20 drugs that are being submitted to the

21 agency. So, we\'re extremely proud of

22 our performance in this area because we

23 haven\'t been supported by any additional

24 funding.

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1 I must say, in the context of

2 what we talked about in the earlier

3 session, which is the statutory review

4 time, that the fact we need a plan to

5 come in compliance with our statutory

6 obligations, review time, which is the

7 time to tell a company whether or not

8 their generic drug application is

9 approved or not after it\'s submitted, is

10 180 days under the statute. That is

11 different than the time to approval

12 because the generic drugs may go through

13 a number of cycles before they\'re

14 actually approved, but we only get about

15 half of the generic drug applicants and

16 answer in the 180-day timeframe. So,

17 obviously, there are improvements that

18 we can do there, but we think, from the

19 point of view of the firms, and we were

20 interested to hear what they think, that

21 getting the overall time of getting onto

22 the market down is more important,

23 actually, because that gets the drug out

24 on the market and available to provide

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1 competition.

2 Now, what about once they\'re on

3 the market, and I was talking about a

4 premarket review program? Then we have

5 marketed drugs. We regulate advertising

6 and promotion of drugs with a very small

7 staff of about 25 people. We try, as

8 Dr. Henney said, to make sure that

9 broadcast print, all other types of

10 advertisements for drugs, the

11 advertisements that are appearing in

12 professional journals, the launching

13 campaigns and so on, make sure they are

14 balanced and not misleading and make

15 sure that the correct information is

16 presented there and that whether doctor,

17 pharmacist, nurse, or patient, they

18 don\'t walk away with a false impression

19 after looking at that ad. And we think

20 we\'re doing a good job there, but as you

21 heard, there are a lot of questions,

22 especially in the direct consumer area.

23 There were a lot of questions

24 about adverse events or balance for

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1 drugs. Once drugs are out on the

2 market, there are going to be a lot of

3 expected adverse events and there are

4 going to be some new ones that are rare,

5 or when the drug is being tried for new

6 uses, or different populations or drug

7 interactions.

8 We have built a new computer

9 system in the last three years which we

10 call AERS, Adverse Event Reporting

11 System. It\'s a state-of-the-art system

12 that\'s capable of handling this flood of

13 reports that come in. Under the

14 International Conference for

15 Harmonization, which is a three-region,

16 Japan, Europe, and the United States

17 regulators plus industry collaboration,

18 we\'ve developed a harmonized terminology

19 for the efforts to end MedDRA, which is

20 a common name in all these regions for,

21 say, a heart attack or whatever. You

22 know, people have a hundred different

23 ways to describe that. This is one step

24 of setting up a worldwide safety network

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1 for drugs, and it\'s actually functioning

2 very well.

3 Our computer system uses this

4 measure of terminology. And we hope,

5 within the next 18 months, we will be

6 able to have the adverse events

7 submitted electronically to us through

8 our electronic gateway at the agency and

9 go directly into our computer system,

10 and we\'re piloting this activity right

11 now with some people from industry some

12 industry sponsors. But there\'s much

13 more that we need to do in adverse

14 defense surveillance, as people brought

15 up, and I think this is one area where

16 the agency needs to be more active in

17 drug regulation.

18 Product quality surveillance,

19 we do a great deal with this. Product

20 quality in lifeline is very good in the

21 United States, much better than many

22 other countries you may visit. In the

23 United States, you could be very sure

24 that what you\'re getting is what it says

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1 on the bottle and that its strength is

2 correct and that it will not crumble

3 into dust and so forth.

4 And those of you who travel

5 widely, know that isn\'t always the case

6 everywhere.

7 For example, in test products,

8 and we evaluate imported products, an

9 enforcer is becoming a big issue. Just

10 like globalization of the food supply,

11 globalization of the drug supply, and

12 especially involve drugs made all over

13 the world and self industries and so

14 forth, and it proposes a challenge for

15 our field to figure out how to police

16 all this.

17 Nevertheless, every regulated

18 entity that makes approved drugs has to

19 send in manufacturing supplements to the

20 Center every time they change their

21 processes in significant ways. And you

22 can see that, last year, it looked like

23 we approved 1375 of these supplements.

24 This is a PDUFA goal because it\'s very

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1 important to the industry for

2 competitiveness to be able to modernize

3 and to keep the plans up-to-date. So,

4 it\'s important that we turn around these

5 applications quickly and evaluate them.

6 Our average there was five months, about

7 five months to approve a manufacturing

8 supplement. We\'re going to have more

9 ambitious deadlines under the newly

10 approved PDUFA agreement.

11 For generic drugs, I call this

12 the gift that keeps on giving. Every

13 time we approve a generic drug, we

14 inherit from the field force the

15 regulation of yet another set of

16 manufacturing sites and processes. For

17 generic drugs, we receive 3,000

18 manufacturing supplements, and we expect

19 that to keep on growing if generic

20 competition remains healthy in the

21 United States, and this is a significant

22 challenge for us.

23 What about drug safety?

24 There\'s been a lot questions raised in

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1 the newspapers about the safety of

2 medicines, especially giving the record

3 of faster review that I just talked

4 about. People are wondering about the

5 standards left or are we making a more

6 cursory review. That is not the case.

7 We have more staff and I think we\'re

8 actually going to hire quality review

9 now because science has improved. And

10 actually, the number of patients that

11 are evaluated in NDA is growing and the

12 sophistication of drug evaluation is

13 increasing.

14 Drug recalls are actually down,

15 physics on drug recalls and those are in

16 your book. And also, the rate of market

17 withdrawal of new drugs, the actual time

18 when a drug is approved and on the

19 market and something terrible happens

20 that the drug has to be taken off the

21 market, actually, that has decreased

22 slightly. Although I would say it\'s not

23 statistically different than before, but

24 certainly lower, and it\'s quite

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1 different than in previous decades.

2 However, we\'re approving more

3 drugs nowadays and it\'s quite possible

4 that in the future, with these 30 new

5 drugs that are coming on the market, 30

6 to 40 every year, that one of them,

7 again, we will find some unacceptable

8 rare side effect that occurs after

9 marketing.

10 Linda, you\'re keeping me on

11 time here; am I right? I\'m almost done.

12 Are there key activities that

13 the Center engages in that affect all

14 our stakeholders that you should know

15 about? We talked a little bit about

16 international harmonization, but it\'s an

17 extremely important activity that we\'re

18 increasingly engaging in and spending

19 more and more time every year in working

20 with regulatory authorities around the

21 world to try to develop common

22 standards, to try to train regulators in

23 underdeveloped countries. And again,

24 our field does a lot of work in this

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1 area.

2 Another challenge that people

3 came up to me during the break and asked

4 me about is our transition to an

5 electronic environment. We made a

6 commitment to go to a hamberless

7 submission and review system by the year

8 2002. We have recently published, about

9 three months ago, a guidance which

10 allows the terms to submit totally

11 electronic NDA, New Drug Application.

12 This, we have no paper that we would

13 keep, although it might have some paper

14 copies and different things to aid the

15 reviewers. The archive copy now can be

16 completely electronic.

17 We have had, for the past

18 couple of years, a guidance for the case

19 report form and case report tabulations

20 parts of the NDA, which are where the

21 clinical data is listed. This has, so

22 far, we think, saved about 12 million

23 pages of paper that have been submitted

24 to you which would have been submitted

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1 to the agency otherwise. But this

2 raises significant challenges for us and

3 it\'s going to challenge the industry

4 because we will start out and have

5 voluntary submission by electronic, and

6 eventually, we\'re going to have two

7 processes side-by-side, it\'s too

8 expensive. And eventually, we\'re going

9 to be going to require an electronic

10 submission, but it won\'t happen for a

11 long time. People will get plenty of

12 warning. You should be thinking about

13 that.

14 Regulatory Research is very

15 important to that part of the science

16 base that Dr. Henney was talking about.

17 We learn so much when we have time and

18 some small dollars to go back into our

19 database.

20 What are the implications of

21 our regulatory position? What are the

22 consequences of the path that we took?

23 What did we learn about placebo controls

24 in this area? Are they necessary?

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1 Could we avoid them? Could we get

2 better guidance to people who follow on

3 afterwards, after 50 trials in

4 rheumatoid arthritis have been done?

5 Only the FDA has all that data

6 collected, and only if we have time to

7 do the regulatory research can we help

8 do our part to advance in the field.

9 This is something that has really taken

10 a hit in our constrained budget over the

11 past few years. So, I would say we\'re

12 not doing as good a job as we need to in

13 that area, but we do our best.

14 Other challenges that are

15 affecting us, the Modernization Act that

16 you heard about that was passed by

17 Congress made some new regulatory

18 schemes for certain areas. One of them

19 is pharmacy compounding, and since were

20 in the School of Pharmacy, I think this

21 is a relevant talk in here. There is

22 now a new regulatory scheme for

23 compounding of drugs, how drugs will be

24 remade available to pharmacists, how

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1 there will be a coalition between the

2 State Board of Pharmacy and FDA to

3 regulate these activities, etcetera,

4 which drugs will be not permitted to be

5 compounded. And we\'re holding a series

6 of advisory committees and other

7 actions. All of this is on our website

8 and I urge those of you who are involved

9 in pharmacy to be involved in this

10 because we need all the input we can

11 get. This is a very controversial area.

12 Positron emission tomography is

13 a new technology that is creating

14 diagnostic agents that are being used in

15 patients. We were charged with

16 developing a regulatory scheme. Health

17 economic information was already eluded

18 to, I think, in the previous session, a

19 reprint of off-label uses is either

20 other changes in the Modernization Act.

21 We also have the radio pharmaceuticals,

22 which we have already published a new

23 guidance and composed ranks on, and in

24 the reauthorization of Prescription Drug

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1 User Fee Act, we\'ve been very busy since

2 that bill was passed. To do all this

3 performance under our ever-shrinking

4 budgetary resources, it has been a

5 tremendous challenge for the people in

6 the Center, and we really do need all

7 the ideas of everyone.

8 The globalization of industry,

9 I don\'t think many of us really

10 recognized how fast this is happening

11 and the profound impact it is having.

12 And the Internet, it\'s been in the

13 papers lately, selling drugs on the

14 Internet, maybe without a prescription

15 even.

16 Internet pharmacies, these are

17 all the information age and the

18 challenges of that age are bringing new

19 challenges to the FDA in the way we

20 traditionally regulated it.

21 Now, how am I doing as far as

22 time?

23 Then the questions, what

24 actions do you propose we take, and I\'m

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1 speaking for CDER now, from the CDER

2 prospective, to expand our capability to

3 incorporate science into our decision

4 making.

5 We hold right now, for example,

6 about 52, I think, scientific advisory

7 meetings ever year, bringing in experts

8 in different subspecialty areas. Most

9 of these are focused, though, on

10 specific products. Occasionally,

11 they\'re focused on guidance development.

12 Are there ways, especially

13 inexpensive ways, that we can better

14 harness or incorporate the science that

15 exists out there into our decision

16 making? Are there ideas or suggestions

17 that you have?

18 We have been having to curtail

19 sending our scientists out for exchange

20 programs, for sabbaticals, for learning,

21 for training, because of budgetary

22 constraints. And given that we can\'t do

23 that right now, what other possibilities

24 do we have?

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1 This is similar in the exchange

2 and integration of scientific

3 information to better enable FDA to meet

4 its public health responsibility

5 throughout a product\'s life cycle. This

6 is particularly germane to what happens

7 to a drug product after it\'s approved.

8 And there were a lot of questions and

9 discussions about that, I think, in the

10 earlier session.

11 Now, how do we incorporate, how

12 do we get all that information about

13 product use and consequences of product

14 use into our decision-making at the

15 agency? There may be other thoughts

16 that you have.

17 This is something very dear to

18 my heart, a concept of balancing risk

19 against benefit in public health

20 decision making. We feel that the

21 people, stakeholders in this particular

22 issue, need to really have a

23 conversation about this because this is

24 a systems issue and no one party is in

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1 charge of balancing risk to benefits.

2 It has to happen all through the chain

3 and we need to figure out how to

4 incorporate the understanding of the

5 people who are assuming the risk and

6 their judgement as well as educating

7 them to the point that they can have a

8 voice in the risk and benefit analysis

9 if not all throughout everything from

10 approval of the drug all the way to the

11 use of the medicine. Now, this is very

12 hard for a stakeholder to do; so, I will

13 be interested in what you all have to

14 say.

15 When we had our stakeholders

16 meeting last year, people told us that

17 their issue was the most important.

18 That\'s very typical for a public agency,

19 is that each stakeholder feels they have

20 very important issues that the agency

21 should make a top priority, but clearly,

22 it is necessary for us to prioritize

23 issues, and that\'s very difficult for

24 us. We end up trying to put a little

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1 bit of resources into every part of our

2 program. And any time we try to draw

3 back, for example, because a program is

4 working very effectively and

5 satisfactorily and there are other areas

6 that we deem have greater risk, then the

7 stakeholder for that particular area,

8 both internal to the agency as well as

9 external, cry foul and we\'re backing off

10 on our public health responsibilities.

11 And I think, well, what about these guys

12 over here? You know, there are all

13 these problems, but no, this area is

14 fine and it should continue whatever

15 investment of resources is invested in

16 it. This is a very significant problem

17 that we have.

18 Almost done, Linda.

19 The last question was, what

20 additional actions do you propose for

21 enhancing the communication process that

22 allows for ongoing feedback evaluation

23 and evolution of our modernization

24 efforts?

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1 Now, I feel, in particular,

2 that CDER has made a tremendous effort

3 in the last five years to modernize all

4 our processes. We have tried to

5 communicate with all our stakeholders.

6 We have been much more successful in

7 communicating with some groups, such

8 industry, than others who are more

9 diffused, such as consumers, and who

10 have a very broad range of interests and

11 concerns. Whatever suggestions you

12 might have for enhancing our

13 communications, we would appreciate,

14 particularly if they weren\'t too

15 expensive.

16 In summary, and I haven\'t gone

17 over all our programs \-- I shortened

18 this a lot from last year \-- I think

19 it\'s fair to say that we\'re performing

20 at a high level. We\'re performing very

21 well against the tasks that we were set

22 out, especially our traditionally

23 defined tasks some of the newer tasks

24 that we clearly recognize are important,

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1 such as communicating more effectively

2 with the outside world, we\'re doing

3 them, but we certainly aren\'t doing them

4 at a high level. So, I think our report

5 card is mixed but for our core, we\'re

6 performing very well. We face numerous

7 challenges as the world changes and as

8 our job is somewhat redefined and we

9 invite your suggestions and comments,

10 and that is really one of the purposes

11 of this meeting. So, I thank you for

12 your attention.

13 LINDA BROPHY: Thank you,

14 Janet. She certainly has given us a

15 context to have a conversation.

16 The next section of our

17 discussion this afternoon, we\'ll hear

18 from two of our stakeholders. We have

19 two stakeholder presentations.

20 The first is Dr. King, who is a

21 consultant from Paul G. King Consulting,

22 and he has come to speak to us for about

23 ten minutes.

24 PAUL G. KING: Well, I want to

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1 thank everyone for letting me have the

2 chance to say a few words. I guess I\'m

3 a contrarian in many respects.

4 Let me just start off by saying

5 I\'m not speaking for myself, I\'m not

6 speaking for industry and I\'m not

7 speaking for the agency. I\'m speaking

8 for the people who watch their children,

9 parents and friends suffer from the side

10 effects of the agency\'s failure to

11 protect the public from those in the

12 pharmaceutical industry, whose greed

13 outweighs their concerns for the public

14 health. That\'s who I\'m speaking to.

15 As a consultant, time and time

16 again, I have witnessed FDA-regulated

17 companies, large and small, deliberately

18 not comply with a law or regulation

19 simply so they could make more money.

20 They have done this because their

21 management was, and is, confident that

22 they will get away with their

23 noncompliance \-- or, if caught, profit

24 more than their overall cost. Though my

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1 heart goes out to the FDA in many

2 respects, its decision not to inspect

3 every drug establishment as often as

4 required by law is not only wrong, it\'s

5 illegal.

6 Beset by priorities, loss of

7 many knowledgeable personnel under REGO,

8 and underfunded, the agency has

9 attempted to balance conflicting

10 priorities instead of holding fast and

11 protecting public health by strictly

12 enforcing all of the current CGMP

13 regulations for drugs.

14 Emboldened by an FDA that holds

15 itself above the law and overlooks the

16 industry\'s deliberate noncompliance with

17 certain regulations, many firms, under

18 the same cost and manpower pressures

19 imposed on the FDA, have likewise

20 reduced their compliance program.

21 Given their agency\'s lead, why

22 should anyone be surprised that many of

23 the firms it regulates currently not

24 only ignore applicable laws and

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1 regulations, but are also pushing for

2 even more concessions?

3 For example, emboldened by

4 their success in getting the FDA to

5 ignore enforcement of key parts of the

6 drug CGMP\'s, the industry is now

7 pressuring the agency to allow skip lot

8 testing, although they know full well

9 that the CGMP regulations explicitly

10 require the testing of each batch.

11 Instead of wasting time

12 considering such initiatives, the agency

13 again needs to begin rigorously

14 enforcing compliance with all of the

15 drug CGMP regulations.

16 This bring the public

17 face-to-face with a major flaw in the

18 science-based questions posed to the

19 stakeholders.

20 As Dr. Henney has recognized,

21 without knowledgable personnel who

22 understand the true minimum requirements

23 of both the sciences and regulations

24 involved, the agency will continue to

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1 accept the pseudo science that some

2 firms submit as \"valid science\", and the

3 non-compliant or violative practices

4 that some firms are using.

5 Yet the reality today is that

6 agency personnel often lack the

7 education, training and/or experience in

8 the regulation they are supposed to be

9 administering or the fundamental

10 sciences that they\'re supposed to

11 understand or both required for them to

12 properly discharge their duties.

13 Beyond hiring people that have

14 the expertise it lacks and simply

15 \"providing training\", what should the

16 agency course of action be today to

17 address these recognized deficiencies?

18 First, the agency needs to

19 initially and continually establish the

20 fundamental metric-based competency of

21 its management, review, inspection and

22 testing personnel in the applicable

23 requirements of the statutes and

24 regulations as well as the fundamentals

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1 of all aspects of inspection science and

2 statistics.

3 To do this, the agency needs to

4 provide continual training and

5 metric-based assessments of all such

6 personnel to assure that said personnel,

7 \"A\", understand the requirements of all

8 applicable regulations, \"B\", properly

9 assess the science submitted or applied

10 and, \"C\", determine that the science

11 submitted or applied is valid science

12 that truly meets the minimum

13 requirements of the current good

14 manufacturing practices regulation.

15 Second, before attempting to

16 expand its use of science, the agency

17 needs to ensure that all firms

18 incorporate fundamentally sound science

19 in all areas of their submission.

20 Minimally, all existing and

21 pending drug establishments\' submissions

22 need to be audited and shown to provide

23 scientific proof that, \"A\", their

24 in-process and batch-release

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1 specifications are such that they

2 assure, with a high level of confidence,

3 that every article in each releasable

4 batch will, if tested, comply with the

5 USP\'s lifetime standards, but the law

6 requires that; \"(\'B\')\" All critical

7 control points in each process step of

8 each batch of every product need to be

9 identified and properly controlled using

10 valid inspection plans, most of the

11 inspection plans that I see are just

12 nonsense; \"C\", all samples tested are of

13 appropriate size and representative of

14 the batch from which they were taken;

15 and \"D\", the number of representative

16 samples tested is sufficient to satisfy

17 the statistical minimums required under

18 21 CFR 211.165\[d\] For validly predicting

19 the lifetime quality of each batch not

20 just the present values for the samples

21 tested.

22 Third, until the agency can

23 provide the requisite in-depth ongoing

24 metric-based training of and establish

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1 the competency of each such employee,

2 the agency needs to seek out, learn

3 from, and rely upon written advice and

4 instructions but only from those outside

5 the agency who can prove that their

6 advice has applied sound science in

7 determining the true minimum

8 requirements for compliance with a given

9 drug CGMP as based supposedly on

10 science.

11 It\'s amazing. I understand, as

12 a scientist why the public in general

13 doesn\'t trust scientists. It\'s amazing

14 how cheaply some of us sell science to

15 make a buck.

16 The preceding is but a short

17 overview of some issues that this agency

18 must truly address if it wishes to

19 expand the agency\'s capability to

20 incorporate state-of-the-art science or

21 any science into its risk-based

22 decision-making and to facilitate the

23 exchange and integration of scientific

24 information to better enable the FDA to

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1 meet its public health responsibilities

2 throughout a product\'s life cycle if it

3 truly wants to protect the public.

4 In closing, let me thank the

5 agency for allowing me to speak to these

6 issues today. For those interested, my

7 formal response to all five stakeholder

8 questions is available on-line in the

9 docket, and also, there are 25 copies of

10 what I presented today more or less for

11 anyone who would like to have a written

12 copy. Thank you.

13 LINDA BROPHY: Our next speaker

14 is Dr. Totman.

15 Dr. Totman comes from Consumer

16 Healthcare Products to represent the

17 Association.

18 LORNA C. TOTMAN: Thank you for

19 giving me the opportunity to speak

20 today. As you heard, I\'m Lorna Totman,

21 director of Scientific Affairs for the

22 Consumer Healthcare Products

23 Association, CHPA, which was formerly

24 known as the Nonprescription Drug

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1 Manufacturer\'s Association. The

2 Association, founded in 1881, represents

3 the manufacturers and distributors of

4 national and store brand nonprescription

5 medicines and dietary supplements.

6 CHPA\'s membership comprises over 200

7 companies involved in the manufacture

8 and distribution of those self-care

9 products and their related services.

10 CHPA appreciates FDA\'s outreach

11 to its stakeholders. Dr. Bill Soller,

12 Senior Vice President and Director of

13 Science and Technology, joined

14 Commissioner Henney in the studio in

15 Rockville, Maryland for today\'s video

16 conference, and Joe Doss, our Senior

17 Vice President and Director of Public

18 Affairs, is speaking in the Center for

19 Food Safety and Applied Nutrition public

20 meeting in Chicago. We have submitted

21 written comments in a letter to the

22 designated docket.

23 My comments today on behalf of

24 CHPA mainly addresses the first of FDA\'s

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1 questions about ways the Agency can

2 expand its capability to incorporate

3 state-of-the-art science into its

4 risk-based decision-making.

5 In answering, we would draw

6 your attention to the switch of drugs

7 from prescription to over-the-counter

8 status. The public health history of Rx

9 to OTC switch has been exemplary. Since

10 the beginning of the OTC Review in 1972

11 and through the subsequent further

12 development of the OTC NDA process of

13 drug approval, about 80 ingredients,

14 dosage forms, dosages and indications

15 have been switched from Rx only to OTC.

16 These switch products are a remarkable

17 success story, providing significant

18 cost savings to the public health system

19 and important self-care therapeutics for

20 the consumer. Examples are fluoride,

21 vaginal antifungals,

22 nicotine-replacement therapy, cromolyn

23 sodium for prevention of allergy

24 symptoms, among many others.

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1 Importantly, under the Durham

2 Humphrey Amendments to the FD&C Act, if

3 a drug cannot be safely used without

4 medical supervision, it must be labeled

5 for sale and dispensed only by a

6 prescription from a licensed

7 practitioner. Otherwise, it is OTC, not

8 restricted to Rx status.

9 Hence, by law and regulation in

10 the United States, drugs are

11 prescription by exception. In other

12 words, if it can be OTC, it must be OTC.

13 The law does not, however, state the

14 approach FDA should take in determining

15 if medical supervision is needed for a

16 drug\'s safe use. In making decisions

17 about OTC availability, FDA\'s Center for

18 Drug Evaluation and Research uses a

19 case-by-case, weight-of-the-evidence,

20 dialogue and data-driven process. This

21 approach is entirely consistent with the

22 legal mandate that, if a product can be

23 OTC, it must be OTC.

24 The science that provides the

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1 foundation for Rx to OTC switch

2 decisions has developed and improved

3 over the years. Each novel Rx to OTC

4 switch product has been characterized by

5 a full array of data including, for

6 example, studies related to

7 post-marketing surveillance of the Rx

8 parent, the post-marketing experience in

9 other countries, dose-ranging studies,

10 long-term safety studies, OTC actual use

11 studies, label comprehension studies,

12 and specialized safety studies in

13 enriched populations.

14 FDA has demanded an

15 ever-increasing database to support more

16 complicated switch decisions. Hence,

17 the proposition that a product or

18 condition can be switched to OTC or

19 self-care status can be regarded as a

20 testable hypothesis. In other words,

21 the basis for the decision is usually

22 distilled to a basic question or

23 questions that, if tested, would

24 contribute meaningfully to OTC

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1 benefit/risk decisions pertaining to OTC

2 availability. A sponsoring company with

3 a switch candidate, working with FDA,

4 will define study designs to answer

5 specific questions about the drug

6 product\'s safety or effectiveness in the

7 prospective OTC setting.

8 With this approach, the need

9 for a health professional as a learned

10 intermediary in the use of any drug for

11 a potential or actual OTC condition is a

12 testable hypothesis. Scientific and

13 clinical data \-- not medical opinion

14 alone \-- are the drivers for expanding

15 the OTC paradigm with novel Rx to OTC

16 switches.

17 However, in September of 1997,

18 CDER issued a Guidance for Industry on

19 the OTC Treatment of

20 Hypercholesterolemia that stated: \"It

21 is CDER\'s view that a health care

22 practitioner supervision in the

23 diagnosis and ongoing management of

24 hypercholesterolemia is essential for

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1 safe and effective use of drug products

2 to treat this condition and this

3 supervision is assured within the

4 context of prescription access to the

5 appropriate drugs for the individual

6 patient. CDER, therefore, believes that

7 drugs for the treatment of

8 hypercholesterolemia should not be sold

9 OTC in the United States.\"

10 This decision was made after

11 review by an FDA advisory committee of a

12 comprehensive, well-designed,

13 well-conducted actual use study that

14 showed a remarkable set of study results

15 supporting the safety and effectiveness

16 of Questran for OTC use, as well as an

17 equally remarkable level of interest by

18 the American public in having widely

19 available cholesterol-lowering agents.

20 CDER should adopt a policy that

21 would require the agency to fully

22 explain its negative switch decisions,

23 in order to identify limitations and

24 omissions in the sponsoring company\'s

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1 submission. A sponsoring company would

2 have the opportunity to determine what

3 further, if any, state-of-the-art

4 research to undertake to support a

5 re-proposal for OTC availability of a

6 prescription drug active ingredient.

7 Commissioner Henney said today the

8 agency\'s policies need to be grounded in

9 science \-- and that\'s the point I\'m

10 making. By maintaining switch as a

11 data-driven, science-based process, FDA

12 would be assured of having the best

13 science to support its benefit-risk

14 decisions about OTC availability of drug

15 products.

16 In the process of developing

17 such a CDER policy, the negative

18 guidance on OTC cholesterol drugs would

19 be appropriately rescinded and

20 presumably amended. FDA should instead

21 explain in detail the specific questions

22 that would have to be answered by

23 well-designed research before drugs for

24 high cholesterol can be made available

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1 without a prescription. This is the

2 only way to preserve the dialogue and

3 data-driven process that has

4 characterized Rx to OTC switch over the

5 last 25 years.

6 And now I\'ll shift gears a bit

7 to comment on another important way FDA

8 can enhance its science capability.

9 Partnership interactions between the

10 agency and industry give FDA\'s drug

11 reviewers and compliance personnel

12 access to evolving scientific and

13 technical advances in the field of

14 self-care.

15 CHPA has a long-standing

16 partnership with the CDER Office of

17 Compliance in conducting joint

18 educational efforts, including CHPA\'s

19 annual Manufacturing Controls Seminar,

20 industry briefings, Small Business

21 seminars, and regional meetings on

22 specific issues identified as being

23 manufacturing problem areas at the time.

24 These invaluable sessions have

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1 demonstrated an important approach to

2 building the science base of the

3 agency, through the collaboration of FDA

4 with leading industry scientific and

5 technical experts.

6 Our goal in these programs is

7 to address current problem areas or

8 evolving technology issues and create,

9 with the agency, educational meetings

10 that raise awareness about the

11 identified issues, establish a higher

12 level of understanding of the agency\'s

13 expectations for current Good

14 Manufacturing Practices, and disseminate

15 scientific advances in the production of

16 quality drug products. Such jointly

17 developed educational meetings allow the

18 agency to make use of state-of-the-art

19 scientific expertise already available

20 in the industry.

21 These efforts have an important

22 beneficial effect on product quality. A

23 notable example of their practical

24 benefits was seen following the 1988

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1 joint regional seminars on label

2 mix-ups. The frequency of what had been

3 the number one cause of product recalls

4 dropped dramatically. We also

5 understand that our educational efforts

6 and those of other associations are

7 regarded by the Office of Compliance as

8 effective preventive compliance

9 programs.

10 CHPA also holds an annual

11 Research and Scientific Development

12 Conference, with a great deal of

13 cooperation and participation by CDER

14 staff. This is an outstanding meeting

15 because it enables the limits of OTC

16 availability to be explored both

17 conceptually and in practical exercises

18 with hypothetical switch candidates or

19 therapeutic categories. Our scientific

20 conferences, and ones that may be

21 sponsored by the Drug Information

22 Association, The Parenteral Drugs

23 Association or other industry groups,

24 bring together scientists from FDA and

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1 the regulated industries for invaluable

2 intellectual exchanges. Participants

3 are energized and invigorated by

4 attending as well as having the

5 opportunity to share new scientific

6 information.

7 We ask FDA to maintain a

8 commitment to educational partnerships

9 with industry.

10 In sum, CHPA requests that FDA

11 develop a policy within CDER to require

12 the agency to fully explain each

13 negative switch decision by identifying

14 the limitations and omissions in the

15 sponsoring company\'s submission, amend

16 its guidance on OTC cholesterol drugs to

17 omit a declaration that such drugs

18 should not be available OTC and,

19 instead, elaborate on the specific

20 questions that would have to be answered

21 before a favorable decision could be

22 made for nonprescription status and

23 continue the agency\'s commitment to

24 educational partnerships with industry.

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1 Thank you.

2 LINDA BROPHY: Thank you,

3 Dr. Totman.

4 Now, we\'re in the section of

5 the session where we would like to

6 invite the FDA panelist to come up and

7 they can take their place, their plates

8 are in place.

9 While they do that, let me just

10 warn you in response to the remaining

11 section here for our afternoon together,

12 we have in place four microphones

13 located on the floor. In order for

14 individuals to hear us all in the room

15 as well as for the captioner on the

16 videotape, I would really like to

17 encourage individuals, if you have a

18 question to please find your way to a

19 microphone and ask your question into

20 the microphone.

21 My name is Linda Brophy and I

22 will be monitoring this section of the

23 panel, and let me just quickly run down

24 our list of panelists who are from FDA.

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1 We have Dr. Nancy Smith from CDER,

2 Dr. Janet Woodcock from CDER, we have

3 Susan Setterberg from ORA, and Douglas

4 Ellsworth from ORA.

5 So, if you would like to begin

6 now, if you have questions, please find

7 your way to a microphone and speak

8 slowly and clearly and we will have our

9 panelists here to engage in a

10 conversation.

11 SANDY HARRISON: Hi, my name is

12 Sandy Harrison. I\'m a student at Temple

13 University School of Pharmacy. My

14 question is about direct to consumer

15 advertising for prescription drugs.

16 Dr. Woodcock mentioned how DeeDee Mac

17 (ph) does a very good job considering

18 the constraints in their resources and

19 for most prescription drugs the

20 promotional material would not review

21 until the product is promotionally

22 launched, but because of that, there can

23 be some problems afterwards and changes

24 may have to be made. It would seem that

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1 that would be more costly for the

2 companies to have to go and revise their

3 ads. Perhaps, looking at the PDUFA

4 program and its success with user fees

5 for expedited review process, do you

6 think there could be some mechanism that

7 we could have for a user fee for

8 promotional materials so that they could

9 be reviewed in advance of the product

10 launch perhaps that may even save the

11 companies money?

12 JANET WOODCOCK: We will review

13 launch materials in advance of the

14 product launch, although there have been

15 complaints about the timeliness of that

16 review. And we have provided some user

17 fee funding in that area since that is a

18 premarketing activity. For post-market

19 advertisement, I think there would be

20 tremendous reluctance to have FDA

21 prereview and I don\'t think there would

22 be any enthusiasm for a User Fee Program

23 for that. In some ways, the message

24 gets out once the promotional material

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1 is out there.

2 So, do you feel that generally,

3 some of the direct consumer information

4 is not balanced that\'s out there?

5 SANDY HARRISON: Yes, I think

6 it\'s not balanced. I think some of it

7 is not balanced and it\'s also confusing

8 for the general lay public, which

9 doesn\'t have a scientific background,

10 that the industry or people at FDA may

11 have. And I also think because of the

12 power of broadcast as a print media

13 these ads are very persuasive and it had

14 been mentioned before about opening a

15 dialogue with the patient and their care

16 giver, you\'ve already created an

17 impression in a person\'s mind about the

18 products before you even get to speak

19 about it. That\'s what my concern is,

20 that things that may be misleading will

21 get out to the public, as it has already

22 been done.

23 JANET WOODCOCK: One of the

24 problems we\'ve had is the brief summary

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1 requirement. It\'s gibberish right now,

2 often, that is attached to the ad.

3 There is a requirement that a brief

4 summary of the risk and benefits and

5 everything be attached to the ad, and we

6 have great difficulty creating something

7 that would be more \-- give more

8 information, you know, in lay language.

9 Yeah, it would be more user-friendly for

10 consumers in directed to consumer

11 advertising. I think that\'s a

12 challenge we\'re going to have to meet

13 somehow and figure out how to do that

14 because that labelling information is

15 fairly balanced, although I noticed it

16 doesn\'t include the indication, which is

17 very good.

18 But to get to your point, I

19 mean there are two sides to this, as

20 Jane Henney said. On one side, we know

21 that there\'s vast numbers of people in

22 this country who it\'s a sin of omission.

23 They are being harmed, we know, by not

24 being treated with safe and easily

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1 available medicine to lower their

2 cholesterol to prevent recurrent

3 miocardialinfarction, etcetera,

4 etcetera.

5 On the other hand, there may be

6 people who are harmed by taking medicine

7 they don\'t really need or that are

8 inappropriate, and how we line our way

9 between those two people, is a very good

10 question.

11 LINDA BROPHY: Any other

12 questions?

13 JOHN VILLAUME: My name is John

14 Villaume. I\'m from Sanofi

15 Pharmaceutical. I apologize, I\'ve been

16 struggling on how to state this

17 precisely, but I can\'t. But it touches

18 on, I think, a lot of the recent

19 discussions, and that is concerns, risk

20 benefit evaluation, and especially in

21 the recent controversy about the adverse

22 experience reporting and withdraw of

23 drugs. And I just wondered whether, if

24 there\'s a problem or a weakness, it\'s

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1 not so much identifying adverse

2 experience \-- I think the FDA does that

3 very rapidly \-- but rather it is knowing

4 what to do with them and managing

5 expectations so that you can weigh the

6 risks and the benefits in providing a

7 framework for doing that even for FDA

8 advisory committees, which struggle with

9 that kind of decision-making. I just

10 wondered and would like to ask

11 Dr. Woodcock if you can give us your

12 thoughts on that. Is there an effort to

13 revise labeling to present that better

14 so that you can better understand the

15 benefits of the drug and the risks?

16 JANET WOODCOCK: I\'m glad you

17 asked that question. There are

18 certainly many efforts \-- and if anybody

19 wants to chip in, please.

20 As you know, we recently

21 revised the OTC labeling in conjunction

22 with the industry, and I think that will

23 help consumers understand what\'s in the

24 products and the benefits and the risks

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1 very well. We\'re going to try to do a

2 similar effort with the package insert

3 that\'s intended to communicate with the

4 health professionals. And we\'re going

5 to have to do that, again, through the

6 rule making. So, it will be quite a

7 long process but we\'re planning to

8 propose something on the package insert.

9 But the larger issue is how do

10 we, as health professionals, which many

11 of us in this room are, or manufacturers

12 or people who are in charge of producing

13 or testing or quality controlling

14 medicines, how do we manage that risk

15 and benefit balance all through the life

16 of the product from having it made to

17 having it taken by a patient? And as I

18 said, I think we need to have

19 conversation, and that\'s all the

20 different parties, about that issue, a

21 better framework.

22 We will be issuing a report in

23 a while, the FDA, as we have evaluated

24 and looked at this issue, and we have

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1 some ideas for ourselves where we can do

2 better, the FDA can do better. As

3 Dr. Henney said, we only do a part of

4 this. We make sure the risks and

5 benefits are well described and honestly

6 communicated in the label and in the

7 advertising, we hope, and that\'s our

8 role. And we also make a decision, if

9 the benefits for the population outweigh

10 the risks then we will approve the drug

11 for that population. But once the drug

12 is out there, then it\'s the nurses and

13 the pharmacists and the prescribers and

14 everyone else is in charge of managing

15 those risks that are described and using

16 that information and making sure that

17 the individual person taking a drug,

18 that the benefits should outweigh the

19 risks. And we know there are risks; and

20 so, we also need to make sure, as health

21 professionals, that the people who take

22 medicine know those risks and are aware

23 of what they are assuming.

24 It seems like there are many

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1 parts in this whole chain that need to

2 be strengthened and improved to maximize

3 the benefits in drugs and minimize the

4 harm although we know there is going to

5 be harm. So, I hope that, with our

6 report and so forth, we\'ll start a

7 conversation about this. That\'s what we

8 hope to do.

9 NANCY SMITH: I would like to

10 add that we, last summer, started a new

11 website where we\'re trying to post

12 information about all new products that

13 are approved in consumer-friendly

14 language. This was written following

15 the plain-language guideline and it is

16 designed so that a nonmedical, you know,

17 someone without a medical professional

18 background can understand.

19 We currently have posted all

20 products that have been approved since

21 January of 1998. There are 35 or 40

22 products now that are up there. We

23 realize, however, that this website will

24 not be as useful as it could be until we

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1 get enough information on all products,

2 not just the ones approved since 1998.

3 So, we\'re now beginning an effort and we

4 have determined that the easiest or the

5 best way to go about this is to begin

6 with the most commonly prescribed

7 medications.

8 So, hopefully, with the next

9 three or four months, we will have

10 information up on the top ten products,

11 and then we will be adding to it,

12 sequentially, as often as we can.

13 Again, the constraints in doing this are

14 time constraints. The information is

15 written by pharmacists within the FDA,

16 it then has to be approved by the

17 medical division that approved the

18 product, it has to be looked over by

19 them, it then goes to DeeDee Mac (ph),

20 and they look it over because they want

21 to make sure that we don\'t say anything

22 that we would not allow the firm to say

23 about the products.

24 So, it not only has to be

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1 written, but it has to go through two

2 levels of review so that it is

3 satisfactory to the medical division and

4 to DeeDee Mac, and so, it\'s a time

5 constraint getting more, but we are

6 trying to get more and more information

7 in consumer-friendly language which

8 should help patients themselves to be

9 able to weigh the risks and benefits for

10 themselves. As Dr. Woodcock said, the

11 agency weighs it on a population basis.

12 For this particular population does the

13 benefit outweigh the risk? But an

14 individual is looking at it from their

15 own prospective and it should help them.

16 JANET WOODCOCK: Well, I

17 appreciated the thoughts on the

18 over-the-counter switches as everyone

19 knows that the self-care and the ability

20 of people with access to medicine, and

21 it\'s a real important issue for the

22 population. So, it\'s been important to

23 me, I know that. Having other barrier,

24 an economic barrier and time barrier to

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1 seeking care in getting an intervention

2 is difficult and it doesn\'t keep some

3 people from getting important care that

4 they need. And the question is, we have

5 to balance that against the risks of

6 people misusing products, which, of

7 course, occurs in the prescription realm

8 as well as the over-the-counter realm.

9 So, I appreciate the input and we will

10 certainly take that into consideration.

11 STAN REYNOLDS: Good afternoon.

12 Stan Reynolds from Pennsylvania

13 Department of Healthcare Laboratories.

14 One of the things that we\'re

15 occasionally involved in is testing food

16 when it\'s suspected of causing human

17 illness. And quite often, we get

18 questions from the public when someone

19 says, \"I bought \'x\' \'y\' and \'z\', I have

20 concerns about it. Who do I talk to?\"

21 And one of things that we find

22 perplexing is that right now, there\'s

23 sort of niche line between the

24 responsibility of the FDA and the

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1 Department of Agriculture when it comes

2 to foods. And you know we\'re never

3 really certain on a given food product

4 whether to refer the people to the FDA

5 or the Department of Agriculture.

6 What we would like to know, do

7 you think, at any time in the near

8 future, you two agencies will get

9 together and come up with some clear

10 scheme as to who is responsible for

11 what; like, say, the Department of

12 Agriculture, unprocessed food, the FDA,

13 processed food, something like that?

14 Because right now, it is really very

15 confusing. I\'ll leave it to the panel.

16 SUSAN SETTERBERG: I\'ll take a

17 more generalized food.

18 Actually, there is some

19 guidance out there as to who does what.

20 And, generally speaking, if it\'s

21 poultry, any kind of beef, the meats,

22 other than game meats, it\'s ours. There

23 gets to be confusion when you\'re talking

24 about things like pizza that has

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1 pepperoni on it. It depends on how much

2 pepperoni.

3 But in any case, what I would

4 suggest to help immediately is that

5 anyone who has a complaint about a food

6 could call us through our consumer

7 complaint lines which are at each

8 district, and we will help them through

9 that quagmire. We are always interested

10 if they have a problem and we can help

11 them out. That\'s the best thing.

12 There is a lot of discussion

13 right now between USDA and FDA about

14 working together to be real clear about

15 who is going to do what where and making

16 sure that we\'re not redundant, who is in

17 a particular firm, we have set up

18 memorandum of understanding as to who is

19 going to do what where and, of course,

20 working with the states too. So, that

21 will get clarified more and more as we

22 work on the food safety initiative. We

23 work more closer together all the time,

24 but right now, I would suggest that

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1 folks call the consumer and complaint

2 coordinators and we could work that out

3 for them.

4 PENNY GILES: One of the questions

5 that you asked us was to come up with

6 ideas on how the FDA can better allocate

7 their resources for the minimize of

8 public risk. And unfortunately, I don\'t

9 have any great ideas, but I was curious

10 as to what you were thinking on that

11 issue right now. I\'m sure there\'s been

12 internal discussions and I\'m curious as

13 to what the FDA thinks those resources

14 should be allocated.

15 JANET WOODCOCK: Could you tell

16 us your name and affiliation?

17 PENNY GILES: My name is Penny

18 Giles and I\'m with Sheryclau (PH)

19 Corporation.

20 SUSAN SETTERBERG: Where we

21 think the allocations of our resources

22 should be, that\'s something we face all

23 the time and we make those judgments

24 almost every single day as we\'re trying

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1 to decide what area we are going to go

2 look at today, what job we need to do

3 today, where crisis is, a lot of what

4 we\'ve been doing lately is doing some

5 risk-based assessment priority setting

6 within all of our program areas. So, we

7 are attempting to hit the most important

8 things we can in every single program.

9 I think it has to be \-- my

10 opinion is it has to be a distribution

11 with expertise in all areas that we

12 regulate. So, it\'s hard to pick any one

13 particular place, but it has to be based

14 on the impact on the health and the

15 welfare of the people we service. So,

16 that\'s not a specific answer, but that\'s

17 kind of how we look at it.

18 JANET WOODCOCK: I\'d say that,

19 in CDER, we actually have looked at this

20 in some extent. And as I said in my

21 talk, it\'s very difficult. People are

22 really invested in whatever areas

23 they\'ve been doing as far as their

24 importance and their essentiality to

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1 health and it is very difficult for a

2 regulatory agency to determine the

3 effects of deterrence and how important

4 that is. Because you can always say,

5 well, there are no problems, but, oh,

6 that\'s because there\'s this tremendous

7 pressing so, if you cut it back, then

8 it\'s like speed limits or something.

9 You know, if you enforce the speed

10 limits then there are no wrecks, but

11 then, if you didn\'t enforce it, you

12 would have more problems. So clearly, I

13 would say that for medicines, most of

14 the most serious problems where there is

15 actually an injury and bodies in the

16 street, shall we say, is out in the use

17 of medicines in the community. That is

18 where the problems are, and people are

19 beginning to see that. I think that the

20 long time \-- where drug review took a

21 very long time convinced the intention

22 was focused on the time of review and

23 the lack of speed of review and so

24 forth, and that was the subject of

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1 discussion, but now it\'s really an issue

2 that is not an issue. So, people are

3 saying, well, these drugs are out there,

4 there are a lot of problems, there are

5 adverse there are medication errors,

6 there are unexpected adverse things of

7 drug interaction. We heard people

8 talking about this on the broadcast.

9 Now, that\'s more difficult to

10 deal with because we do not control many

11 of those things directly. Those are

12 things we are just players in; and

13 therefore, it is more difficult to

14 convince people that resources need to

15 be shifted in to those areas. And that

16 has long been my conviction and that is

17 what I think.

18 MICHAEL UMEN: Michael Umen of

19 Michael Umen Company. Just to reflect

20 back on the priority issues and where

21 the agency ought to focus, I did hear

22 Dr. Henney identify, at the beginning of

23 her presentation, by key areas of focus

24 beginning with \-- following the FDAMA

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1 mandates and ending up with aluminates

2 smoking amongst young people, and there

3 were three others in between that I

4 forgot, but at least there is some

5 overall agency directive there. But

6 I\'ve become enamored of some of the

7 polls I\'ve seen on television lately,

8 and in thinking out of the box, when you

9 ask the question of what action is being

10 proposed to enable FDA and its products.

11 Centers to focus resources on areas of

12 greatest risk to the public health, I

13 might say, why don\'t we ask them? Why

14 don\'t we iteratively consider some

15 polling? Because I know we, as health

16 care professionals seem to think we

17 know, but a lot of the way things get

18 misused or used, some kind of escape our

19 greatest guesses. So, some way of

20 asking them might be one way I proposed.

21 And I don\'t know what specific way, but

22 let\'s ask them.

23 Another comment I\'d offer just

24 in thinking about what I\'ve heard today

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1 and reflecting on another one of the

2 questions specifically about what action

3 to be proposed for education of the

4 public about the concept of balancing

5 risk against benefits and public health

6 decision-making.

7 I\'ve been involved in the drug

8 development approval business for about

9 25 years and I haven\'t seen too many

10 drugs that have been approved that have

11 been slam dunk no-brainers, this one is

12 absolutely a clean winner, no risks

13 benefits glaringly outweighing any

14 perceptible risk. They\'re often very

15 fine lines, and that causes some of

16 their business uncertainty and it also

17 causes some of the uncertainties they

18 think that the public thinks. So, I

19 think the public needs to be clearly

20 made more aware of the reality of this.

21 I\'ve been impressed by my

22 mother-in-law, who always asks me, \"did

23 you read this or did you read that?\"

24 She asked me, about ten years ago, \"did

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1 you read The Strong Medicine?\" That was

2 a pretty eye-opening account of one

3 novelists view of how drugs get

4 developed and misapproved. She then

5 asked me to read Miracle Cure, which was

6 another very interesting one. And then

7 she asked me if I saw a particular

8 episode of Quincy, and at the time that

9 Tourette\'s syndrome was being raised to

10 the level of interest and it was \--

11 actually, it went to the drug

12 regulations. So, I think we need a good

13 movie and some very good television

14 documentaries that are in a high level

15 of visibility to put the reality into

16 some perspective because I think the

17 public has a really generally

18 misunderstood perspective that

19 everything is absolutely safe and

20 absolutely is going to work on

21 everybody, but that\'s just not the

22 reality and I think high visibility

23 approaches, media directed may be not

24 within the FDA\'s budget but, may be

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1 what\'s necessary.

2 NANCY SMITH: We\'ve been

3 thinking about a lot of these issues.

4 And back to your first question about

5 polling people, one of the things we\'ve

6 been thinking about lately is trying to

7 do a survey to really determine where

8 people get their medical information.

9 Do they get it, as physicians hope, I

10 guess, from talking with their health

11 care providers and their physicians, or

12 do they get it from TV shows and books

13 that they read? And I think, again, in

14 doing any sort of \-- I\'m a statistician

15 in my background \-- in doing any sort of

16 logical, correct sampling procedure is

17 going to be quite expensive. And I

18 think, if we\'re going to do this, we

19 need to do it right so that we can be

20 confident in the results. But I think,

21 in this day of managed care when

22 physicians\' time is limited to such a

23 short period that they can spend on the

24 patient, they don\'t have time to go into

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1 the details that maybe the family

2 physician did 50 years ago. And we have

3 to figure out where people are getting

4 their information and the areas where we

5 could make a difference, where we could

6 get unbiased information. I think many

7 physicians get their information about

8 the products from the detailed people

9 that come around from the pharmaceutical

10 companies. And while I certainly would

11 never say that that\'s misleading, it\'s

12 certainly not completely unbiased, I

13 think we can all see. And physicians

14 that are so very busy don\'t have time to

15 weigh the differences between several

16 products that they might prescribe for a

17 particular individual, so they often

18 take the last one they\'ve heard \-- you

19 know, prescribe the last one they heard

20 about or something of this nature. So,

21 we need to really find out, not just for

22 the consumers about how they get their

23 information but also from all the health

24 care providers so that we can do a

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1 better job of educating all of them.

2 LINDA BROPHY: Any other

3 questions?

4 TOM KIRSCH: My name is Tom

5 Kirsch. I\'m from Johnson & Johnson. I

6 have a comment and then perhaps a

7 question.

8 We heard earlier one of the

9 presenters challenge the FDA try to live

10 up to a perhaps more intense inspection

11 regimen, and I really have to comment

12 about that because, over the last eight

13 or nine years, FDA introduced a process

14 called a Preapproval Inspection Process.

15 And within my own company, over that

16 eight-year period, we would have had

17 perhaps four FDA inspections, if we look

18 at a usual every-two-year kind of

19 surveillance program. In actuality,

20 we\'ve had over 50 preapproval

21 inspections, and I wanted to make sure

22 that the record reflected that. And

23 this has probably consumed maybe a

24 hundred fifty to two hundred days of

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1 inspection time which heretofore would

2 have been \-- if you would have thought

3 of a GNP or surveillance inspection of

4 being approximately five days or perhaps

5 even ten days, it would have been 20 to

6 40 days of inspection. So, I think that

7 certainly, on behalf of my own

8 experience with my own company \-- and

9 we\'re only one company out of 180

10 companies at Johnson and Johnson \-- we

11 certainly feel that the inspections have

12 been very rigorous. Of course, we\'re

13 dealing with two district offices that

14 are known to be very rigorous, namely in

15 Philadelphia and the Newark district

16 office.

17 The other comment that I wanted

18 to ask, and perhaps someone like Doug

19 Ellsworth would maybe want to comment,

20 I\'m wondering if the agency has any

21 ideas or any thoughts about why the

22 first-party audit concept has really not

23 caught on, to my knowledge, I mean this

24 is not really continuing to be acted

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1 upon by industry.

2 DOUGLAS ELLSWORTH: Well, I

3 think, with respect to the first-party

4 audit program, I think the industry

5 didn\'t really see any advantage to

6 entering into that program, but let me

7 just say one thing. You mentioned the

8 number of preapprovals and how many GNP

9 inspections you already had. We\'re

10 looking at that whole issue of

11 inspections, the field and seat are you

12 will inspect in looking at how we can do

13 it more effectively and efficiently and

14 drawing an appropriate balance between

15 product specific preapproval type

16 inspections, in general, GNP system

17 inspections. How to do those in the most

18 effective way and incorporate both so

19 we\'re maybe not in your firm 150 times

20 in one year and that we can rely more on

21 some of the general GNP findings that we

22 have. So, we\'re working on that. And I

23 think that is probably, for us, in terms

24 of risk-based using our resources

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1 appropriately, the things that we need

2 to do first to get our act you will

3 inspect and make sure we\'re doing the

4 best we can and then see what we can do

5 with some of these other types of

6 pilots. That\'s my personal feeling.

7 PAUL G. KING: Since we\'ve

8 opened Pandora\'s box, this is Dr. King

9 and I\'d like to ask a simple question.

10 Do you count the PAI

11 inspections as part of the number of

12 inspections you do towards your

13 compliance goals?

14 DOUGLAS ELLSWORTH: You mean

15 the statutory compliance goals?

16 PAUL G. KING: Yes.

17 DOUGLAS ELLSWORTH: Not that I\'m aware

18 of, no.

19 PAUL G. KING: So, again, so

20 what you\'ve said \-- you\'re essentially

21 saying to the public is, if people pay

22 for the inspections which is what the

23 preapprovals are paid by the companies,

24 essentially, as part of the PDUFA

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1 program, you\'ll inspect them as much as

2 you want. Similarly, if somebody is

3 under a consent decree, you will inspect

4 them like crazy. The rest of the

5 industry, you\'d inspect, what, 23

6 percent this year, and 27 percent last

7 year?

8 First of all, I only raised the

9 issue of inspection as one of the areas

10 where the agency deliberately doesn\'t

11 comply with the law. The point I tried

12 to make was not that you do more

13 inspections or whatever, that you do

14 good science, good regulatory

15 compliance. And I don\'t mean just in

16 the inspection, I mean in the approval

17 process. I can cite many instances by

18 name, if necessary, but just in general,

19 where the agency has approved

20 applications where false tests were

21 submitted or where the product was

22 submitted, where it was only formulated

23 to provide 98 percent of the \"label

24 claim\" and yet those were approved. So,

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1 I want the good science, I want the

2 people to understand the regulations.

3 That\'s the key message I\'ve attempted to

4 bring to the agency.

5 And ,as not a real

6 statistician, but as one who certainly

7 understands statistics, I would hope,

8 that your risk-basing assessment, that

9 you start having people that do, because

10 I see people making decisions on risks

11 that don\'t really understand statistics

12 and I see statisticians working for the

13 industry deliberately skewing those same

14 statistics to help the agency make the

15 \"right\" decision. I do mean

16 deliberately. I\'ve been involved in a

17 case where somebody, to get you people

18 to approve a certain weight-filling

19 range for a product, grouped the data

20 until the final dispersion was monomodal

21 and then exhibited that data to you. Of

22 course, you did approve the

23 weight-filling range as part of that new

24 drug application but that resulted in

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1 the patients all getting less product

2 than they thought they were getting

3 based on the label claim. You know

4 that\'s very interesting when you have

5 agencies driven by quality initiatives.

6 I see the medical people

7 talking about QSR, I hear the agency

8 starting to talk about quality systems,

9 but I don\'t see them doing much about it

10 and I see them doing the wrong things.

11 Yes, I think it\'s great to have \-- you

12 need better science. People need to

13 apply better science. They need to

14 understand the science that they\'re

15 applying and the regulations. So, do it

16 right. And Dr. Woodcock, I want to

17 thank you for not appreciating my

18 comments. At least you heard them.

19 LINDA BROPHY: Well, at this

20 point, I think we\'re ready to close our

21 session. I think we\'ve exhausted all of

22 the questions from the audience here.

23 Thank you for your attention.

24

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