1

 

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

                CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

 

 

 

 

 

 

 

             ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                      Wednesday, October 20, 2004

 

                               8:30 a.m.

 

 

 

 

 

 

 

 

 

                CDER Advisory Committee Conference Room

                           5630 Fishers Lane

                          Rockville, Maryland

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                              PARTICIPANTS

 

      Arthur H. Kibbe, Ph.D., Chair

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

 

      MEMBERS

      Patrick P. DeLuca, Ph.D.

      Paul H. Fackler, Ph.D.

      Meryl H. Karol, Ph.D.

      Melvin V. Koch, Ph.D.

      Michael S. Korczynski, Ph.D.

      Marvin C. Meyer, Ph.D.

      Gerald P. Migliaccio, Ph.D. (Industry

      Representative)

      Kenneth R. Morris, Ph.D.

      Cynthia R.D. Selassie, Ph.D.

      Nozer Singpurwalla, Ph.D.

      Marc Swadener, Ed.D. (Consumer Representative)

      Jurgen Venitz, M.D., Ph.D.

 

      SPECIAL GOVERNMENT EMPLOYEES SPEAKERS

      Judy Boehlert, Ph.D.

      Gordon Amidon, Ph.D., M.A.

      FDA Staff

      Gary Buehler, R.Ph.

      Lucinda Buhse, Ph.D.

      Jon Clark, M.S.

      Jerry Collins, Ph.D.

      Joseph Contrera, Ph.D.

      Ajaz Hussain, Ph.D.

      Monsoor Khan, R.Ph., Ph.D.

      Steven Kozlowski, M.D.

      Vincent Lee, Ph.D.

      Qian Li, Ph.D.

      Robert Lionberger, Ph.D.

      Robert O'Neill, Ph.D.

      Amy Rosenberg, M.D.

      John Simmons, Ph.D.

      Keith Webber, Ph.D.

      Helen Winkle

      Lawrence Yu, Ph.D.

                                                                 3

 

                            C O N T E N T S

                                                              PAGE

 

      Call to Order

        Arthur Kibbe, Ph.D.                                      5

 

      Conflict of Interest Statement:

        Hilda Scharen, M.S.                                      5

 

      Committee Discussion (Continued)                           8

 

      Science in Regulation - Visionary Overview

        Arthur Kibbe, Ph.D.                                     43

 

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

        Regulatory Policies

          Ajaz Hussain, Ph.D.                                   74

 

        Organization Gap Analysis

          Helen Winkle                                          75

 

        Scientific Gap Analysis

          Ajaz Hussain, Ph.D.                                  103

 

        Policy Gap Analysis

          Jon Clark, M.S.                                      135

 

      Generic Pharmaceutical Association Perspective

        Shahid Ahmed, M.S.                                     152

 

      Pharmaceutical Research and Manufacturers

      of America Perspective

        Gerry Migliaccio, Ph.D.                                164

 

      Committee Discussion and Recommendations                 182

 

      Pharmaceutical Equivalence and Bioequivalence

      of Generic Drugs

 

        The Concept and Criteria of BioINequivalence

        Concept of BioINequivalence

          Lawrence Yu, Ph.D.                                   205

 

        Criteria of BioINequivalence

          Qian Li, Sc.D.                                       222

                                                                 4

 

                      C O N T E N T S (Continued)

 

                                                              PAGE

 

      Committee Discussion and Recommendations                 234

 

      Bioequivalence Testing for Locally Acting

      Gastrointestinal Drugs

 

        Topic Introduction

          Lawrence Yu, Ph.D.                                   273

 

        Scientific Principles

          Gordon Amidon, Ph.D.                                 275

 

        Regulatory Implications and Case Studies

          Robert Lionberger, Ph.D.                             308

 

      Committee Discussion and Recommendations                 324

 

      Conclusion and Summary Remarks

        Ajaz Hussain, Ph.D.                                    341

        Helen Winkle                                           349

 

                                                                 5

 

                         P R O C E E D I N G S

 

                             Call to Order

 

                DR. KIBBE:  Ladies and gentlemen, I would

 

      like to call the meeting to order.  The first item

 

      of business is the reading of the Conflict of

 

      Interest Statement.

 

                     Conflict of Interest Statement

 

                MS. SCHAREN:  Good morning.  The following

 

      announcement addresses the issue of conflict of

 

      interest with respect to this meeting and is made a

 

      part of the record to preclude even the appearance

 

      of such.

 

                Based on the agenda, it has been

 

      determined that the topics of today's meeting are

 

      issues of broad applicability and there are no

 

      products being approved.  Unlike issues before a

 

      committee in which a particular product is

 

      discussed, issues of broader applicability involve

 

      many industrial sponsors and academic institutions.

 

                All Special Government Employees have been

 

      screened for their financial interests as they may

 

      apply to the general topics at hand.  To determine

 

                                                                 6

 

      if any conflict of interest existed, the Agency has

 

      reviewed the agenda and all relevant financial

 

      interests reported by the meeting participants.

 

                The Food and Drug Administration has

 

      granted general matters waivers to the Special

 

      Government Employees participating in this meeting

 

      who require a waiver under Title 18, United States

 

      Code, Section 208.

 

                A copy of the waiver statements may be

 

      obtained by submitting a written request to the

 

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

 

      of the Parklawn Building.

 

                Because general topics impact so many

 

      entities, it is not practical to recite all

 

      potential conflicts of interest as they apply to

 

      each member, consultant, and guest speaker.

 

                FDA acknowledges that there may be

 

      potential conflicts of interest, but because of the

 

      general nature of the discussions before the

 

      committee, these potential conflicts are mitigated.

 

                With respect to FDA's invited industry

 

      representative, we would like to disclose that Dr.

 

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      Paul Fackler and Mr. Gerald Migliaccio are

 

      participating in this meeting as non-voting

 

      industry representatives acting on behalf of

 

      regulated industry.  Dr. Fackler's and Mr.

 

      Migliaccio's role on this committee is to represent

 

      industry interests in general, and not any other

 

      particular company.

 

                Dr. Fackler is employed by Teva

 

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

 

      employed by Pfizer, Inc.

 

                In the event that the discussions involve

 

      any other products or firms not already on the

 

      agenda for which FDA participants have a financial

 

      interest, the participants' involvement and their

 

      exclusion will be noted for the record.

 

                With respect to all other participants, we

 

      ask in the interest of fairness that they address

 

      any current or previous financial involvement with

 

      any firm whose product they may wish to comment

 

      upon.

 

                Thank you.

 

                DR. KIBBE:  Thank you.

 

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                Yesterday, we concluded with a suggestion

 

      that we might want to continue our discussion about

 

      the questions that the Agency has raised, and I

 

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

 

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

 

      we should go there first and then go back to the

 

      scheduled agenda.

 

                Ajaz.

 

                    Committee Discussion (Continued)

 

                DR. HUSSAIN:  Good morning.  I think the

 

      discussions towards the end of yesterday started

 

      honing down on some of the key challenges we face

 

      in the designing of a Critical Path Initiative in

 

      OPS.

 

                I think, reflecting back on the discussion

 

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

 

      research capabilities and programs already in

 

      place, and the challenge would be to sort of direct

 

      these in a very focused way to help the Critical

 

      Path Initiative, keeping in mind that all of our

 

      research will not be focused on critical path,

 

      there are other aspects that we have to focus on.

 

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                I will sort of reflect back on the PAT

 

      Initiative and how that sort of evolved.  Clearly,

 

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

 

      and there is a whole sequence of initiatives that

 

      have occurred.  The PAT Initiative was a model and

 

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

 

                I will sort of summarize my thoughts here

 

      with a hypothesis statement that Jerry proposed

 

      yesterday, that Critical Path Initiative will

 

      improve the efficiency and effectiveness of drug

 

      development process.  That is the hypothesis that

 

      sort of really we are engaged in trying to fulfill

 

      or trying to confirm.

 

                The challenge would be then how do we

 

      measure efficiency and effectiveness of drug

 

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

 

      measure drug development in terms of the failure

 

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

 

      development.

 

                All of these are relevant metrics, but for

 

      the purposes of a hypothesis, what and how should

 

      we approach and define that, because unless you can

 

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      measure something, you cannot improve it.  So,

 

      measurement and metrics would be a key factor of

 

      that.

 

                The second aspect then would be what are

 

      the root causes of low efficiency and effectiveness

 

      in all the three dimensions.  A number of factors

 

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

 

      forth.

 

                They were indicators of what may be

 

      happening, but you have to keep in mind that is

 

      partial information, information available to FDA

 

      and available in public is just limited because the

 

      companies have far more information about the root

 

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

 

      factor that into our decisionmaking.

 

                The next question is who is in the best

 

      position to address these root cause factors that

 

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

 

      FDA do and what should some industry, academia, and

 

      other agencies should be doing is the key there.

 

                I think based on information and based on

 

      experience at FDA, clearly, we are in a good

 

                                                                11

 

      position to identify many of the problems, not all

 

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

 

      has the responsibility to communicate these

 

      findings in some way or form.

 

                If you look at John Simmons' presentation,

 

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

 

      strategic meeting points during the drug

 

      development process.  That is one aspect,

 

      communication between sponsors of applications and

 

      our review scientists, if that is timely and in a

 

      coordinated manner, that is one effective means of

 

      that.

 

                So, communication through meetings for

 

      specific drug applications, broader communications

 

      with workshops, and then eventually guidance

 

      documents outlining FDA's current thinking on a

 

      given topic are the communication mechanisms that

 

      we have.

 

                For that, clearly, I think you have to

 

      think about resources and how do you facilitate

 

      that process.  If you want to sort of move towards

 

      more meetings and more interactions between

 

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      reviewers and sponsors, then, you have to build the

 

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

 

      considered, too.

 

                Workshops and guidances also take a

 

      significant amount of effort, and so forth, so as

 

      we improve our communication channels, where will

 

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

 

      that is also a management aspect that has to be

 

      discussed.

 

                FDA's knowledge base, I think was clearly

 

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

 

      If we are able to create a knowledge base that can

 

      be useful, not only for identifying problems that

 

      we see, but also for improving of a predictive

 

      ability in all three dimensions, safety, efficacy,

 

      and industrializations, what are the practices that

 

      lead to success, what are the practices that may

 

      not be as efficient, and so forth.

 

                So, this knowledge base would be useful

 

      for that purpose, but again I will remind in the

 

      sense we have to be cautious, there are limitations

 

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

 

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      the information, so you have to factor that in.

 

                But based on our knowledge base and based

 

      on communication, and so forth, I think the

 

      laboratory and the research functions clearly have

 

      to focus on improving methodologies.  There are

 

      many aspects of laboratory work that only FDA is in

 

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

 

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

 

      address some of the challenges.

 

                For example, in the case of regulatory

 

      decisionmaking, risk-based decisionmaking, the

 

      decision process itself often needs support of

 

      science, and so forth, so that is where the

 

      research really could focus on.

 

                Also for development and validation of new

 

      methodologies, standards development, methodology,

 

      validation, say, from biomarker to any new

 

      technology, unless FDA has a role in achieving

 

      that, it may not be fully appreciated within the

 

      Agency, and some of the Agency concerns would not

 

      be addressed if it is done totally outside, so

 

      there has to be some means of linking our

 

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      laboratory work to standards development,

 

      validation of new methods, and so forth.

 

                Our postmarketing experience again is

 

      unique because that is where I think we have a lot

 

      of information, how do we capture that as lessons

 

      learned and how do we use that.  You saw some

 

      examples of how we were learning from that and

 

      going retrospectively and said how could we have

 

      improved the process.  Those experiments would be

 

      very valuable.

 

                One aspect is in terms of innovation, in

 

      terms of new technologies, what is an important

 

      aspect of standard setting?  Standard setting and

 

      guidances are slightly different in my opinion.

 

      For example, in the PAT Initiative, we opted to

 

      move towards ASTM International as the body for

 

      standard setting.

 

                What that does is allows industry,

 

      academia, every stakeholder to be part of that, and

 

      actually identify what standards are needed, and

 

      actually develop those as quickly as possible.

 

                That relieves the burden on FDA, and FDA

 

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      simply adapt or adopt those standards after

 

      evaluation, so that might be an option that seems

 

      to be moving forward in the PAT Initiative for new

 

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

 

      could be considered at the same time.

 

                But at the same time, I think as we look

 

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

 

      what is the role of other agencies and academia

 

      really have to sort of come together.

 

                The role of industry I think is knowledge

 

      sharing. Clearly, it has far more information, and

 

      reluctance to share knowledge will inhibit the

 

      progress, and how do you do that is a key

 

      challenge.

 

                At the same time, I think in order to

 

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

 

      we really I think have to define clearly the

 

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

 

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

 

      these activities.

 

                In some ways, FDA could play that role of

 

      coordination, as Viad declared yesterday, not only

 

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      from the prospective of we are not competing in

 

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

 

      coordination function for FDA would be an important

 

      function for all these activities.

 

                If we have a clear understanding of what

 

      are the issues and what are we trying to achieve,

 

      then, the coordination and synergy would sort of

 

      evolve naturally.

 

                So, those are the sort of thought process

 

      that I could capture.

 

                DR. KIBBE:  Anybody?  Marvin?  You asked

 

      for the straw, you got the straw man.

 

                DR. MEYER:  The virus, are you talking

 

      about that later?

 

                DR. HUSSAIN:  No, that is a very specific

 

      example.

 

                DR. MEYER:  I thought I had more time to

 

      think then, since I was waiting for the virus.

 

                DR. KIBBE:  Does somebody else want to--

 

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

 

      say.

 

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

 

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      think I need a point of clarification because some

 

      of what came out yesterday was the desire to have

 

      either shorter development time, more compounds

 

      coming out that could be effective, new

 

      pharmaceuticals, and it seems to be a push towards

 

      industry to try to become more effective, et

 

      cetera, but I saw a couple times yesterday where

 

      things developed within the Agency to improve the

 

      ability to go after materials through some of the

 

      databases and things were certainly ways to help

 

      that process.

 

                The other thing, though, is that when you

 

      looked at that chart that showed an increase in

 

      cost of materials and a few other things, toxicity,

 

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

 

      think something a little bit insidious over time

 

      has been with improved technologies and increased

 

      concerns over pharmaceuticals, there are new tests

 

      that come in that prolong the evaluation, that

 

      anything the Agency can do to pull things together

 

      to make those things, immunogenicity or other

 

      things that have, you know, you go back two

 

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      generations ago and if you come up with a new

 

      material, would you put it through all of the same

 

      tests, so anything that can be done to simplify and

 

      do more predictive studies in that regard, I think

 

      would help.

 

                DR. HUSSAIN:  Definitely, that is an

 

      important point.  For example, I think as we move

 

      towards more complex materials, the material cost

 

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

 

      forth.

 

                Introduction of new excipients or new

 

      adjuvants, and so forth, is a significant

 

      challenge, and as we go towards nanomaterials,

 

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

 

      on the traditional pharmaceutical excipients, it

 

      would be a very limiting aspect, so I think that

 

      that is clearly on our agenda.

 

                One aspect that I do want to mention, as

 

      we think about this, the patient has to be foremost

 

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

 

      sort of develop this, I think clearly, the patient

 

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

 

                                                                19

 

      because there are many diseases, many aspects where

 

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

 

      shouldn't forget that aspect.

 

                DR. KIBBE:  Marvin, are you ready now?

 

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

 

      simple example where the Agency I think played a

 

      major role and really expedited drug approval, and

 

      that was back when we were battling over assay

 

      method validation.

 

                The hypothesis was if we had a better way

 

      of validating assays or a uniform way of validating

 

      assays, things would get approved without recycling

 

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

 

      others, convened several workshops, had white

 

      papers, ultimately put out a guidance, and I

 

      suspect that hypothesis has been tested, that there

 

      are much fewer problems in the local methodology,

 

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

 

      that.

 

                DR. KIBBE:  Anybody else would like to

 

      make a comment?

 

                DR. SINGPURWALLA:  Yes.  I repeatedly hear

 

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      from individuals like yourself asking industry to

 

      share more information with you.  What is the

 

      incentive to the industry to do so, because there

 

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

 

      read the Washington Post can see the number of

 

      pages devoted to the Merck and also to Pfizer

 

      having a similar drug going to be tested, and

 

      things like that.

 

                So, unless the legal pressures that are on

 

      industry are defused or removed, industry is going

 

      to be foolish to share all the information with

 

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

 

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

 

      It doesn't make sense, does it?

 

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

 

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

 

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

 

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

 

      knowledge exists.  Clearly, that is the aspect, and

 

      it is complicated by the fact that the way it gets

 

      entrenched into the legal and political scenarios,

 

      those are significance challenges, no doubt about

 

                                                                21

 

      that.

 

                DR. SINGPURWALLA:  What is the industry's

 

      response to this?

 

                DR. MIGLIACCIO:  Well, it is complicated

 

      by obviously, intellectual property rights, which

 

      is the life blood of a commercial business, but it

 

      is also complicated by--you just used the word

 

      "trust."

 

                I will give an anecdote here.  I went to

 

      an internal FDA meeting to provide training, and

 

      during that training, provided knowledge about

 

      products, which normally, would not have been made

 

      available.

 

                The reaction was the traditional

 

      predictable reaction, not the forward thinking

 

      reaction, by certain elements of the audience.  So,

 

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

 

      risk on my part.

 

                We have to reduce the risk associated with

 

      sharing knowledge.  That is the fundamental issue

 

      is if we share knowledge and expose ourselves to

 

      compliance action where that knowledge is

 

                                                                22

 

      essentially reflecting what is the scientific

 

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

 

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

 

      that knowledge and risk compliance action versus

 

      scientific discussion, then, the knowledge will not

 

      be transferred.

 

                DR. KIBBE:  Ajaz, anything?

 

                DR. HUSSAIN:  No.

 

                DR. KIBBE:  Anybody else?  Let me just put

 

      three things on the table and perhaps you can think

 

      about them as how they respond to the questions we

 

      were left with yesterday.

 

                One is that I think I heard from around

 

      the room that the Agency has a limited resource

 

      base, and it truly should focus on those aspects of

 

      the critical path that only the Agency can do, that

 

      no one else has the wherewithal or the capability

 

      or the information to do that.

 

                Secondly, that we try to get others who

 

      are even more capable of responding to certain

 

      aspects of the critical path to take on that

 

      burden.  I am thinking primarily of industry and

 

                                                                23

 

      perhaps industry/academia together looking at those

 

      aspects of it.

 

                But the third thing that I think that the

 

      Agency and both the industry will have to look

 

      forward to is that the rate of technological

 

      advance is such that 10 years from now, the

 

      questions that you are trying to answer now will be

 

      ancient history, and the questions that you are

 

      running into are going to be dramatic and clearly

 

      different, and I really look forward to a paradigm

 

      shift in the way we approach therapy, and I would

 

      recommend to the industry that they change their

 

      name from drug companies to companies that provide

 

      therapeutic agents and processes, because they

 

      could be caught up in the same system that the

 

      railroads did.  They were railroad companies, and

 

      not transportation companies.

 

                I don't know how the Agency can respond

 

      effectively without having some type of internal

 

      committee that is constantly looking at four or

 

      five years out and the technology that they are

 

      going to have to deal with then.

 

                                                                24

 

                So, that is where I think the critical

 

      path kind of initiative ought to be looking.

 

                DR. DeLUCA:  Let me just comment.  I made

 

      some notes here from yesterday, and I think that

 

      this is based on collaboration, I think I am going

 

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

 

      think trust.  Certainly, trust is essential in

 

      collaboration, and as we get into talking about the

 

      science-based approach here and research, research

 

      is a search for the truth.

 

                I would like also to commend the Agency in

 

      their research efforts.  I mean yesterday was, I

 

      think, I would say overwhelming to learn the type

 

      of research that is going on and the collaboration

 

      with NIH, so I really have to commend the Agency

 

      for this.

 

                I would like to also talk about the

 

      presentation by Monsoor Khan where he talked about

 

      critical path research and some of their efforts,

 

      and I think Gerry Migliaccio had responded that

 

      industry takes this approach.

 

                I have to say that that is true from my

 

                                                                25

 

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

 

      the novel drug delivery area and the research in

 

      that area, and working with a company that was

 

      scaling up or transferring some technology, that

 

      that approach was taken, the critical path approach

 

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

 

      the problem at hand, but there were other things

 

      that still needed to be done to define some of the

 

      process variables, that once the problem was

 

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

 

      further with that.

 

                So, I think there is a limit to where they

 

      go and I think this is where collaboration is

 

      important, and I think there is a need to continue

 

      on and to search those things out, and probably the

 

      place for that is in academe.

 

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

 

      he talked about the science-based approach to

 

      critical path issues and the research, that it is

 

      probably essential that the research that is going

 

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

 

      think this is something that many times the

 

                                                                26

 

      research that takes place, and if it is in an

 

      industrial setting, may lack the hypothesis driven

 

      type of research, and that probably I think is

 

      important.

 

                I guess my feeling is in hearing all the

 

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

 

      really overreach, I mean there is a limit

 

      resourcewise, but I think more importantly is the

 

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

 

      collaboration is important.

 

                The FDA has been collaborating more with

 

      NIH, and I think translational research issues,

 

      taking the drug product development, that portion

 

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

 

      the critical path, in the formulation and taking it

 

      and the manufacturing science, and I guess I think

 

      that the collaboration has to be there between

 

      academe, industry, and FDA, and FDA could really

 

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

 

      important role.

 

                Just to bring out my experience with the

 

      journal, the APS on-line Pharmaceutical Science

 

                                                                27

 

      Technology Journal, that the submissions, we get

 

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

 

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

 

      in the Pharmaceutical Technology Journal, and you

 

      would really think that you would get more from

 

      industry--but about 90 percent of the submissions

 

      come from academe.

 

                I have to acknowledge that probably in

 

      about 40 percent of those, there is a collaboration

 

      between academe and industry, so that there is a

 

      tie-in and that it is all those being submitted

 

      from the academic institution, the industry is

 

      involved in it.

 

                But I think that this kind of sends a

 

      message, and I have tried to encourage more, more

 

      submissions from industry, and there is

 

      intellectual property situations involved in that,

 

      but I think there is a need.

 

                I know, being in academe and graduating

 

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

 

      industry, few of them publish after they are in

 

      industry.  Before they left, they had eight or nine

 

                                                                28

 

      publications, and then they went in and stopped

 

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

 

                What I wanted to emphasize here is that

 

      there is an essential need for collaboration.  I

 

      think the whole science-based approach to the

 

      regulatory arena is great, and I have to commend

 

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

 

      alone, and I think there is an essential need that

 

      this collaboration occur.

 

                It may be that with that type of

 

      collaboration, you know, for a long time in

 

      academe, we have talked about the NIH and trying to

 

      get them involved with supporting drug product

 

      research and development to little avail, so maybe

 

      now is the time.

 

                Certainly, I think it is essential that

 

      this type of approach be taken in the manufacturing

 

      sciences, because it certainly will benefit, I

 

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

 

      interests of the country, so that hopefully, the

 

      NIH will look a little bit more favorably on

 

      supporting this type of research.  I think the

 

                                                                29

 

      collaboration between FDA and NIH may help in doing

 

      just this.

 

                DR. KIBBE:  Thank you.

 

                Ken, go ahead.

 

                DR. MORRIS:  Thanks, Art.  Welcome to your

 

      last day.

 

                A couple of things I wanted to say first

 

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

 

      think Merck generated or was generated and then

 

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

 

      Agency to tell them that they needed to pull the

 

      drug or to modify it.  They are really very

 

      responsible about that sort of thing.  I understand

 

      your point.

 

                DR. SINGPURWALLA:  The lawyers made them

 

      do it.

 

                DR. MORRIS:  Well, the lawyers made them

 

      do it, but the drug companies in general, the

 

      innovators of generics, when they see problems like

 

      that, are still I think honor bound and have

 

      historically done a good job of monitoring

 

      themselves with respect to public health when there

 

                                                                30

 

      is a clear and present public health injury issue.

 

                But beyond that, let me just comment, if I

 

      can, I have just five points here, relatively

 

      short.

 

                The first is, is that the unique

 

      opportunity afforded by the FDA massive database, I

 

      think is absolutely invaluable and needs to be

 

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

 

      is perhaps the number one initiative in terms of

 

      getting down the critical pathway with all due

 

      deference to proprietary data, of course, as we saw

 

      yesterday.

 

                There are some issues I think, for

 

      instance, tox, where the database would probably

 

      not be nearly as good as even the sampling of the

 

      Big Pharma companies' databases on tox, because you

 

      don't have the tox information on compounds that

 

      never made it to filing, so they may actually have

 

      a bigger database there, which would really help in

 

      the really interesting work we saw yesterday on

 

      modeling.

 

                The second point is it look from a

 

                                                                31

 

      nonbiological and obviously blue collar tablet

 

      smasher, that there is a fairly large disparity

 

      between the amount of internal biological research

 

      versus product development research.  I am not

 

      really in a position to judge what the priorities

 

      in the biologicals should be.  It is all obviously,

 

      very high-caliber research.

 

                I am not in any way commenting on that,

 

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

 

      out the fact that there are developmental research

 

      agendas that probably would be better handled in

 

      part at least, or at least administered through the

 

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

 

      specifics, and have with John and you and others,

 

      of course.

 

                But I think that points out an opportunity

 

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

 

      prioritization that I was asking about yesterday,

 

      is that given the breadth of projects and the

 

      dearth of resources, I think the prioritization,

 

      particularly the internal research projects,

 

      becomes your biggest challenge and one that I think

 

                                                                32

 

      could be helped by the committee, and I think has

 

      been in part, hopefully, in these days.

 

                It also points out, to reinforce Pat's

 

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

 

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

 

      logically done within the Agency, needs to find

 

      federal support in terms of public health

 

      initiatives, as well as the obvious advance of just

 

      basic science.

 

                To address a question that Gerry had

 

      raised with respect to the possible putative

 

      consequences of sharing information, there is a

 

      mechanism that we have been sort of developing,

 

      which is to, through blinded intermediates, to be

 

      able to discuss general topics without filtering.

 

                I am not talking about filtering data or

 

      hiding data, but to bring data to light to the

 

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

 

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

 

      this the sort of data that would give you cause to

 

      think that there was no particular reason to review

 

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

 

                                                                33

 

      time.

 

                So, I think there are mechanisms to do

 

      that.  They are not formal mechanisms, but through

 

      consultants and whatnot, I think you have already

 

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

 

      specific, of course, because once you are too

 

      specific, then, you have already revealed what it

 

      is you are asking about.

 

                Finally, with a question of metrics, I

 

      think the suggestions you made yesterday, the

 

      multiple review cycles I think is a great metric.

 

      That was what the Manufacturing Subcommittee, at

 

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

 

      in the new or the desired state, instead of having

 

      minimal data that the reviewers have to try to

 

      piece together into some sort of Frankenstein

 

      rationale, if you get the rationale in a piece from

 

      the companies with summarized supporting data to

 

      make it a compelling argument, then, the reviewers

 

      just have to assess the sufficiency of the

 

      rationale as opposed to trying to piece together

 

      one on their own.

 

                                                                34

 

                So, I think the review cycles are an

 

      excellent metric.  The time to approval, of course,

 

      is a low hanging fruit there in terms of a metric

 

      although it is not independent, and for generics,

 

      of course, that is compounded by the workload

 

      itself.

 

                Maybe you could normalize it by

 

      normalizing the time to approval to the number of

 

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

 

      meetings that John talked about yesterday, John

 

      Simmons talked about yesterday.

 

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

 

      talked about this before--is to track FDA personnel

 

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

 

      at retention of the FDA reviewers themselves.  I

 

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

 

      that celebrated a position, but obviously of key

 

      importance.

 

                I think that does two things.  One is it

 

      gives us a metric of how effectively the program

 

      works, and the other is that it gives an internal

 

      metric for the personnel management, so you don't

 

                                                                35

 

      burn out your best and brightest.

 

                DR. HUSSAIN:  Ken, the whole aspect of the

 

      critical path was in a sense that review cycles

 

      have really come down, so that review cycle is not

 

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

 

      there are different metrics for that purpose.

 

                DR. KIBBE:  Marvin, do you have something

 

      else?

 

                DR. MEYER:  A quick comment.  Helen was

 

      saying last night that on the ANDA side, that the

 

      generics are now, or shortly going to be, required

 

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

 

      of 12, the test.

 

                Maybe, and this is terribly naive because

 

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

 

      there is some way down the line of having the NDAs

 

      be accompanied by a synopsis, at least, of what

 

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

 

                We tried doing virus filtration this way,

 

      and it failed because, we think it because, and

 

      this might be attached with the NDA, but reviewed

 

      independent of the NDA. There might be a group at

 

                                                                36

 

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

 

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

 

      impact on the NDA and yet would provide the Agency

 

      with I think some valuable information.

 

                DR. KIBBE:  I am concerned that as much as

 

      we in academia value getting all the information,

 

      industry values having information that their

 

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

 

      failures they corrected, and they know what

 

      mistakes not to make, they generally think they

 

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

 

      really excited about turning that over to someone

 

      else, let them make their own mistakes and figure

 

      it out.

 

                I think the time that we will actually be

 

      able to share all the information about all the

 

      drugs that have ever been approved is when Glaxo

 

      finishes buying everybody or Pfizer has merged with

 

      whoever is left, and there now is International

 

      Therapy Development Company.

 

                DR. KIBBE:  Ajaz, anything to wrap up

 

      with?  Okay.

 

                                                                37

 

                DR. SINGPURWALLA:  Mr. Chairman, I have a

 

      few thoughts.  Ajaz, back.

 

                [Laughter.]

 

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

 

      escape if you would like.

 

                DR. SINGPURWALLA:  Ajaz, you asked three

 

      questions here.  To be quite honest with you,

 

      yesterday, I couldn't focus on these because I

 

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

 

      to and what is happening.

 

                But subsequently, I think I can answer

 

      some of your questions very directly.

 

                I looked at TR Critical Path Initiative

 

      Challenges document, and to be quite honest with

 

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

 

      think you are thinking along the proper lines.

 

                Two, three things come to my mind.  Your

 

      mention or at least the mention of design of

 

      experiments that was discussed is one of the right

 

      ways to go about things.

 

                You also mentioned the use of bayesian

 

      ideas. That  is the best way to reduce time cycles

 

                                                                38

 

      because you are taking advantage of all other

 

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

 

      that only for clinical trials, but you want to use

 

      it throughout the entire process.  Again, you have

 

      highlighted it, so I think again you are on the

 

      right track.

 

                The one thing is you cited examples from

 

      manufacturing.  That is fine, but I seriously

 

      consider you also look at the area of weapons

 

      development.  They face problems very similar to

 

      yours and you may want to see what they are doing

 

      and how they are developing their particular

 

      processes, and the weapon development process has

 

      much in parallel.  The two communities are very

 

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

 

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

 

      are on the right track.  You are focusing on the

 

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

 

      wanted to reaffirm it.

 

                DR. HUSSAIN:  Thank you.

 

                DR. KIBBE:  Paul.

 

                DR. FACKLER:  Let me just offer a couple

 

                                                                39

 

      of thoughts to those questions, you know, are you

 

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

 

      the generic industry, but it is difficult to give

 

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

 

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

 

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

 

      develop new drugs.

 

                So, I think you face a very difficult

 

      challenge trying to assist a process that maybe the

 

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

 

      economics of drug development in 2004 is

 

      significantly different than it was in 1994.

 

                You know, if you have a company selling

 

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

 

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

 

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

 

      billion in revenue out of the new drugs that they

 

      are developing.

 

                So, you know, a product that has some

 

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

 

      benefit society probably just gets put in an

 

      envelope somewhere, and not brought out.  It is a

 

                                                                40

 

      problem with the situation in industry, but I am

 

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

 

      assist that.

 

                Let me speak to the generics because there

 

      was a presentation yesterday, and speaking for the

 

      generic industry, we have communicated with FDA

 

      where we think we need help.  We have asked about

 

      topical products, we have asked about inhaled

 

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

 

      time to approval is a real issue for us.

 

                So, the question was are you on the right

 

      track, and at least from the generic perspective,

 

      the answer is yes.  I think you are trying to

 

      overcome the hurdles that we face, that would

 

      assist us in bringing products to the market

 

      earlier.

 

                I know it is not really the main thrust of

 

      the Critical Path Initiative, but for our portion

 

      of it, the answer is yes.

 

                DR. KIBBE:  Thank you, Paul.

 

                DR. HUSSAIN:  I think just the point

 

      generics are equally important for us, so they are

 

                                                                41

 

      part of the critical path from an OPS perspective.

 

                DR. KIBBE:  Gary.

 

                MR. BUEHLER:  Well, we have had a number

 

      of mentions of our workload.  It is significant.

 

      We did receive 563 applications I believe the last

 

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

 

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

 

                It is a bit scary, but we are dealing with

 

      it, and we are communicating with the industry

 

      significantly on what we can do to make their

 

      applications better and to make our responses to

 

      them more predictable, so that they know what we

 

      want.

 

                As part of the critical path, and we are

 

      trying to work in providing the information that

 

      the industry needs to develop their products, and

 

      this is through the dissolution methods and the

 

      bioequivalence methods that we get tons of letters.

 

                We got over 1,000 correspondence last

 

      year, over half of them requesting what is the

 

      bioequivalence method for a particular drug, what

 

      is the dissolution method for a particular drug, so

 

                                                                42

 

      we can begin to develop our products.

 

                We are trying to get that up as a

 

      web-based program, so that they can actually access

 

      these methods.  We have people working full time in

 

      our office to research this information, so we can

 

      make it available to the firm.

 

                Now, this isn't revolutionary stuff.  This

 

      is stuff that we have always provided them.  We

 

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

 

      make it easier for them to access this information,

 

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

 

      letters that we get obviously take up our resource

 

      time, and we want those resources to be put toward

 

      application review.

 

                We hope to be able to get these up soon.

 

      I know I promised them I think six months ago to

 

      the industry.  Things are never as easy as you

 

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

 

      people have to sign off and make sure that we are

 

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

 

      away the farm, but we do want to give away

 

      information that is needed by the generic industry.

 

                                                                43

 

                The generic industry is a very viable,

 

      very robust industry right now.  A lot of new

 

      players are getting into it, a lot of people want

 

      to put applications in as evidenced by our

 

      workload.  We welcome that workload, we are glad.

 

      This country needs generic products.  A lot of

 

      people out there can't afford prescription drugs

 

      out there.

 

                So, we welcome the work and we welcome the

 

      challenge.

 

                DR. KIBBE:  Anybody else?  Okay.

 

                We have an opportunity now to hear from an

 

      absolute genius.  They asked me to give a talk on

 

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

 

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

 

      all enjoy it.

 

               Science in Regulation - Visionary Overview

 

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

 

      slides.  This is to reduce some of the slide

 

      overload that we are suffering from.  You all have

 

      copies of these slides.  You can tell that the

 

      slides are really informative because they are

 

                                                                44

 

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

 

      hey, there are 22 slides and each one has 180

 

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

 

      up a couple of simple slides.

 

                First, the title was given to me by the

 

      Agency.  I looked at it and I said Visionary

 

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

 

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

 

      about why they think I am a visionary, and I

 

      realized it was because I live in Pennsylvania,

 

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

 

      and renown visionary, the seer or all seers, the

 

      procrastinator for all good things, Punxsutawney

 

      Phil, who comes out and tells you whether you are

 

      going to have winter for another six weeks or not.

 

                I also would like to make a disclaimer, we

 

      do lots of disclaimers.  All the ideas that I

 

      express today are strictly my ideas, and I would

 

      not saddle anyone in the scientific community and

 

      industry over the Agency with any of these

 

      cockamamie ideas.  So, they are all mine and

 

      hopefully, they will stimulate your thinking

 

                                                                45

 

      without putting you completely to sleep.

 

                So, what has the FDA and we been doing for

 

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

 

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

 

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

 

      when you looked through the agenda, you saw the

 

      beginnings of what was I think a wonderful three-

 

      or four-year push in an area that can significantly

 

      impact industry's bottom line, and hopefully, the

 

      industry will be in a mood of generosity and have

 

      that bottom line, some of those savings reflected

 

      in the cost of goods produced.

 

                The effort I think was an opportunity for

 

      me to view the way that scientists from industry,

 

      both the generic and innovator companies,

 

      scientists within the FDA, and scientists from

 

      academia, and those consultants who serve all of

 

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

 

      a reasonable approach to it, something that would

 

      work in the community that we work in, and really

 

      come up with something worthwhile.

 

                I could go on about the successes we have

 

                                                                46

 

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

 

      media always wants failures and disasters to report

 

      on, and so I will move directly into those.

 

                First, is it the Agency's role to apply

 

      science to regulation?  Of course, we all agree it

 

      is.  The application of the scientific method to

 

      goalpost generation for the industry is extremely

 

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

 

      have done and where we are going, and perhaps make

 

      some projections out.

 

                If we are going to regulate a

 

      science-based industry with science, then, we need

 

      to use a scientific approach to where we are going.

 

                We all are familiar with linear

 

      regression, and we know that there is a certain

 

      amount of error associated with it, but in order to

 

      project beyond the data that we already have, we

 

      have to have a significant amount of data going

 

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

 

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

 

                We know that the further out in the future

 

      we can project, the less reliable the answer is,

 

                                                                47

 

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

 

                So, where have we been in terms of

 

      regulating the quality of drug products and

 

      therapies in the United States? Of course, we start

 

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

 

      ought to get the physicians together and say why

 

      can't we have quality products to give to our

 

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

 

      was formed.

 

                So, we started the regulation of the

 

      quality of how we treat our patients by getting the

 

      health care providers who treated patients together

 

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

 

                After the Civil War, the pharmacists got

 

      together and decided that while the USP had

 

      standards for individual ingredients, it really

 

      didn't have standards for how to mix them together

 

      and make them useful, so they decided to publish

 

      the National Formulary, and I was instrumental in

 

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

 

                This is the sum total of how to make

 

      pharmaceuticals in 1888, and compare it with what

 

                                                                48

 

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

 

      how controversial each little, tiny issue is.  Of

 

      course, we also know that you have to learn Latin

 

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

 

      language that it is written in.

 

                At the same time, the industry actually

 

      regulated itself.  There was a comment made here a

 

      little while ago, which said that lawyers make them

 

      do things.  I would argue that in the current

 

      litigious society, companies act slower to remove

 

      drugs from the market when they have worrisome data

 

      than they would if there wasn't a litigious

 

      society.

 

                I think they worry more about what it

 

      means to their future class action suits to

 

      actually admit that there is a problem until they

 

      have all their lawyers lined up, so they know how

 

      to defend themselves, and if they weren't worried

 

      about the fact that the American public has an

 

      exaggerated misconception of what drugs do and

 

      work, they would act quicker.

 

                I think the American public in general

 

                                                                49

 

      expects drugs to be safe and effective, and they

 

      don't recognize that drugs can be safe and

 

      effective if used correctly, but in the wrong way,

 

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

 

      get that.  They just don't get it.

 

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

 

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

 

      leadership that the industry had back in the 19th

 

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

 

      quality ether for anesthesia.  This was an

 

      extremely important drug in those days, and so he

 

      founded a company for the express purposes of

 

      making sure he had high quality ether.

 

                He built it in Brooklyn, and then his

 

      company started making other things and then he

 

      noticed that there were other companies that were

 

      copying his products, calling them the same thing

 

      and putting them out there less expensively, and he

 

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

 

      made correctly.

 

                So, he did something unique which I don't

 

      think any of the companies would do today.  He got

 

                                                                50

 

      all his formulas together, how he made everything,

 

      and he published them in the Journal of the

 

      American Pharmaceutical Association with the

 

      proviso that if anybody wanted to make a product

 

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

 

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

 

      at least the public would have a good quality

 

      product, and if they could make it less expensively

 

      than we could, good luck to them.

 

                Well, I wonder how many companies are

 

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

 

      of course, Eli Lilly was producing well over 100

 

      generic products.  It was the largest generic

 

      manufacturer in the United States.  It produced

 

      everything that could be made that was listed in

 

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

 

      an interesting time.

 

                Now we get into government regulation.

 

      Now, why did the government get into regulation?

 

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

 

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

 

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

 

                                                                51

 

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

 

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

 

      it was.

 

                They said that's terrible, terrible,

 

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

 

      sure that when something was labeled quinine, it

 

      really was indeed quinine.  That was the first shot

 

      out of the cannon.

 

                We finally had the Food and Drug Act of

 

      1906, which really just said that if you are going

 

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

 

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

 

      time we got into the concept of misbranding, which

 

      was putting something in something and calling it

 

      something that it wasn't, and that is basically

 

      what misbranding is.

 

                We have a lot of meetings for misbranding

 

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

 

      is supposed to have been.

 

                The Agency wasn't really founded then, but

 

      the government said that if we wanted to take

 

      action against the company that misbranded a drug,

 

                                                                52

 

      that it was incumbent upon the government to prove

 

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

 

      and that there was intent to defraud.  If you do

 

      that to the government, we can't enforce any

 

      quality on anybody, because we don't have any

 

      information to use for it.

 

                But I want you to remember that concept

 

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

 

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

 

      that brought us right back to that place.

 

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

 

      New York City area with antifreeze as a sweetening

 

      agent in a sulfa drug preparation.  That was the

 

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

 

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

 

      now have a new regulation.  You will notice the

 

      trend here - disaster, new regulation, disaster,

 

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

 

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

 

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

 

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

 

      have to work.

 

                                                                53

 

                Homeopathic remedies are exactly that.

 

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

 

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

 

      they claim contains the essence of the power of

 

      whatever drug was in the first bottle of 1,000

 

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

 

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

 

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

 

      find a molecule because you have diluted more than

 

      Avargordo's number, so we have products on the

 

      market.

 

                By the way, the Food, Drug, and Cosmetic

 

      Act says specifically that drugs are things that

 

      are contained in the homeopathic pharmacopeia,

 

      which means that they are precluded from acting

 

      against products that are in the homeopathic

 

      pharmacopeia even though we know they don't work.

 

                We are still working with things that are

 

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

 

      know.  Nowadays we have people who claim that water

 

      solves medical conditions.  What the heck, you

 

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

 

                                                                54

 

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

 

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

 

      it is better for you than the water you get for

 

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

 

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

 

      like that.  I have a problem my students always

 

      complain about.  I have one of those minds that

 

      kind of wanders, and so I do that.

 

                Let's get back to misspelled words and

 

      regulation. So, in 1951, two pharmacists got

 

      together, a guy named Carl Durham and a guy named

 

      Hubert Horatio Humphrey--I love his name.  They

 

      were pharmacists.  One was in Congress and one was

 

      in the Senate.  Hubert came from Minnesota.  He

 

      ultimately became vice president, ran for

 

      president, didn't make it.

 

                I often wonder what would happen if the

 

      president of the United States was really a

 

      physician or a pharmacist, a health care worker,

 

      what difference that would make in their approach

 

      to the health care problems.

 

                So, they got together and they said, you

 

                                                                55

 

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

 

      pretty dangerous, that the average person really

 

      can't understand, and maybe we ought to have

 

      somebody help them figure out what to take, so they

 

      established two criteria, prescription drugs and

 

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

 

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

 

      forbid, they actually should work.

 

                We are a unique country among the

 

      developed nations of the world.  We only have two

 

      categories of drugs. Most of them have many more

 

      categories of different levels, and, in fact, I

 

      like the Australian system.  They are listed in the

 

      group of things they call poisons, so we clearly

 

      know where they belong, right?  They are the poison

 

      list.

 

                In 1962, we finally got around to hoping

 

      that we could figure out that the drugs were both

 

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

 

      drugs have to be safe and effective.  The Agency

 

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

 

      people that this is an approved drug, because that

 

                                                                56

 

      gives you a marketing advantage over the drugs that

 

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

 

      are effective.  Hmm, that's interesting.

 

                Then, Congress, in its infinite wisdom,

 

      jumped right in there with DSHEA, and DSHEA says

 

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

 

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

 

      1906 regulation which says that it only has to be

 

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

 

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

 

      problems with it, the Agency has to compile the

 

      data before they can make you take it off the

 

      market.  I just love that, you know, retrograde

 

      regulation, I just wonder about the wisdom of that.

 

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

 

      public has for unsubstantiated claimed herbal

 

      remedies.

 

                All right.  Here is where we really get to

 

      where the rubber meets the road, and that is the

 

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

 

      father was a pharmacist, my uncle was a pharmacist,

 

      I became a pharmacist because I didn't know

 

                                                                57

 

      anything else.

 

                I grew up in a drugstore, and when I was

 

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

 

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

 

      gotten over the second half of that.

 

                But in those days, the average cost of

 

      drugs that my father filled--he has a wonderful

 

      ledger, handwritten in ink pen where he wrote down

 

      the name of the patient, the prescription, the

 

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

 

      it, you will find that the average charge to his

 

      patient was $1.75.

 

                I asked him one day, being a nosy

 

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

 

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

 

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

 

      thought that was pretty good.

 

                Of course, nowadays, the average charge of

 

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

 

      the pharmacy gets $3.50.  There has been a shift

 

      here somewhere.

 

                At that time, Tetracycline came out.  It

 

                                                                58

 

      was about 50 cents a capsule.  The price of

 

      Tetracycline has gone down dramatically, but we

 

      keep bringing out new drugs, and I think each time

 

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

 

      that we charged for the last new drug, and we

 

      multiply by 1.5.

 

                You also understand that there is

 

      absolutely no relationship between the charge for

 

      the drug and the cost of actually manufacturing it,

 

      and that they factor in all of the other costs to

 

      maintain the corporate entity that creates new

 

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

 

      money in order to float all of the research and the

 

      marketing, and all the other efforts that go on,

 

      and so that there is some disconnect.

 

                Waxman and Hatch got together.  We

 

      recognized back in the 1980s that the cost of

 

      health care was going up quickly.  Uwe Reinhardt

 

      has a wonderful graph that he puts up, a Princeton

 

      economist, that shows the gross national product

 

      and its rate of increase and the cost of health

 

      care and its rate of increase, and then he predicts

 

                                                                59

 

      some date in the future where the two will meet.

 

                Then, he has a cartoon where he has two

 

      physicians lying in beds in the hospital together,

 

      prescribing for each other, and he said that is

 

      going to be the entire productivity of the United

 

      States is going to be this.

 

                So, we know that there is a disaster in

 

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

 

      and we have a culture in the United States where we

 

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

 

      unique.  Very few developed countries have that

 

      compunction.  So, we try to regulate it through

 

      competition.

 

                So, the Waxman-Hatch Act or the

 

      Hatch-Waxman Act, depending on whether you are a

 

      Republican or a Democrat, came into being, and it

 

      was a compromise that was supposed to benefit the

 

      innovator companies by ensuring them a reasonable

 

      patent extension or exclusivity time frame in order

 

      to recoup the investment to bring the new drug to

 

      the market, and established rules and regulations

 

      for the development of generic drugs.

 

                                                                60

 

                It seems to work in some areas and we hope

 

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

 

      end of the issue, and if we start to make

 

      projections out in the future, we are going to have

 

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

 

      the first time that the FDA was an active

 

      participant in controlling costs.

 

                I think I see that as something going

 

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

 

      issues associated with cost, and, of course, here

 

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

 

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

 

      dead horse.

 

                My wife is Canadian and my inlaws are in

 

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

 

      says that Canadian drugs are bad for American

 

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

 

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

 

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

 

      to say anything about it, because there is nothing

 

      wrong with Canadian drugs.  So, that makes an

 

      interesting argument.  I think we can go down that

 

                                                                61

 

      road as long as we want.

 

                I think the next level of regulation is

 

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

 

      want information that shows that the next new drug

 

      is not only safe and effective, but better.  I

 

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

 

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

 

                We have a history of producing lots of

 

      drugs that might be different, but not necessarily

 

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

 

      think both the industry and the Agency should be

 

      prepared to think about how they would handle that

 

      situation.

 

                Remember that we are trying to regulate

 

      according to best science, and sometimes we lose

 

      track of best science.  There are some classic

 

      equations that we use that we depend upon to help

 

      us decide what is good science.  One is the

 

      Noyes-Whitney expression.  The Noyes-Whitney

 

      expression describes dissolution profile, and it

 

      was developed by these gentlemen using a very

 

      interesting standard material.  It was a fused

 

                                                                62

 

      cylinder of material.

 

                So, their apparatus and how they did it

 

      were standardized based on one solid hunk of an

 

      individual chemical in the cylindrical form, so

 

      they could accurately determine the area exposed to

 

      the fluid and therefore, from it, determine all of

 

      the equations.  Nowadays we use a standardized

 

      compressed tablet.  I would argue that the

 

      dissolution apparatus is probably less variable

 

      than an individual tablet coming off a tablet run.

 

                If you wanted to standardize an apparatus,

 

      you ought to standardize it with something which is

 

      less variable than the apparatus you are

 

      standardizing.  I wonder about that.  I guess we

 

      could ask our colleagues down the street what they

 

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

 

      science and figure out what is going on.

 

                The other one I like to talk about

 

      occasionally is Arrhenius.  Arrhenius developed a

 

      relationship between temperature and rate of

 

      reaction that was developed for reactions that

 

      happened in dilute solutions.

 

                                                                63

 

                We apply them, same rules, too, tablets,

 

      ointments, creams, and lotions.  We put things

 

      aside for three months at elevated temperature, and

 

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

 

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

 

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

 

      went through the data that the Agency has, that we

 

      would be hard pressed to get a correlation

 

      coefficient much over 0.3 for that data.

 

                The other thing is what is the rule and

 

      regulation.  When a rule or regulation gets out

 

      there and purports to be doing something, and it

 

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

 

      that says you have to do accelerated stability at

 

      40 degrees and 75 percent relative humidity, but

 

      you can take the humidity and temperature chamber

 

      and you can put in it a tablet container that is

 

      sealed with a descant in it and do the study.

 

                That is kind of like saying let's see how

 

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

 

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

 

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

 

                                                                64

 

      about those kinds of things.  You sit around in an

 

      academic office, you are a tenured full professor,

 

      what are they going to do.  You wonder about those

 

      things.

 

                I think that there is going to be a lot of

 

      international regulation.  I think that we are at

 

      the stage where the companies are truly

 

      international.  The largest provider of generic

 

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

 

      the big developmental innovator companies are

 

      really housed everywhere.

 

                In fact, the numbers of workers at

 

      pharmaceutical plants in the world has shifted from

 

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

 

      really have to have cooperative control on quality.

 

      I am sure that England and Germany and France want

 

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

 

      Canadian Health Protection Branch insists that they

 

      do.

 

                So, we need to go in the direction of what

 

      is truly a harmonized or internationalized

 

      regulation of quality.  We need to somehow control

 

                                                                65

 

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

 

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

 

                One of the problems I have with all of

 

      this is that drug costs to consumer seems to make

 

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

 

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

 

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

 

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

 

      bottle of Viagra--oh, excuse me.

 

                DR. SINGPURWALLA:  I don't.

 

                DR. KIBBE:  Oh, there is a man with

 

      confidence.

 

                [Laughter.]

 

                DR. KIBBE:  The reason is that most of us

 

      in the public are covered by some insurance plan

 

      that covers the cost of the hospital bed, but we

 

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

 

      10 percent of the total cost of health care in the

 

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

 

      cheaper to give reasonably expensive drugs to

 

      patients than to put them in a hospital.  But the

 

      patients don't pay for it out of pocket.

 

                                                                66

 

                I wonder why the huge lobbying efforts of

 

      the pharmaceutical company isn't applied to getting

 

      drugs covered by Medicare and Medicaid instead of

 

      anything else. If they could ever do that, they

 

      could forget about the arguments in the newspaper

 

      about the cost of drugs.

 

                I am sure there is lots of economic issues

 

      associated with that.

 

                The last three things I have are

 

      continuous quality improvement, PAT, and

 

      federally-funded efficacy testing.  I don't know

 

      whether we are going to get the right to demand

 

      that you do an efficacy test against seven or eight

 

      of your competitors in order to get approval, but I

 

      think that the world deserves a chance to look at

 

      what is those relative efficacies in an abstract or

 

      at least impartial way.

 

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

 

      wonderful initiative, it has its own journal now,

 

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

 

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

 

      some beautiful pictures in here.

 

                                                                67

 

                I went through it immediately and wanted

 

      to see if I knew anybody that actually was involved

 

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

 

      pictures of all sorts of people that were actually

 

      on the committee with it, if anybody is interested

 

      in it.  I thought that was pretty neat.

 

                I think that there are things in the

 

      horizon that really threaten the way we do business

 

      both at the industrial level and at the regulatory

 

      level.  One of them is the development of

 

      nanotechnology and computational power.

 

                We are looking forward to a singularity in

 

      computational power, a point beyond which we cannot

 

      predict or even understand the future.  In

 

      approximately 2014 or 15, the computer on your desk

 

      will have not only digital computational power, but

 

      parallel processing, and will be able to think

 

      better than you can.  We will be able to process

 

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

 

      point in time, it will be the most intelligent

 

      being on the planet, and we humans will relegate

 

      ourselves to second place.

 

                                                                68

 

                When that happens, what do we do about

 

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

 

      they can do.  If aging is truly a degradation of

 

      the DNA strand within people, if we can inject

 

      nanobots who know how to count DNA strands and

 

      repair them, how are we going to age?

 

                If we have the capacity to scan individual

 

      molecules and relationship in the neural net, can

 

      we then scan down a person's entire knowledge base

 

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

 

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

 

      facility?

 

                How many of us would be willing at the

 

      ends of our days to become virtual us in a virtual

 

      environment?

 

                Where are we going?  Challenges to the

 

      FDA.  In our experience over the last several

 

      millennium, an ever- increasing rate of new

 

      technological development.  It was 20,000 years

 

      from the time we developed hand-held rock until we

 

      actually made a bow and arrow with a processed

 

      rock, and the rate at which we develop things now

 

                                                                69

 

      is astronomical.

 

                We need to have improved productivity in

 

      the industry, but that needs to be related to an

 

      improvement in the cost of goods sold to the

 

      American public, and the Agency needs to maintain

 

      public confidence.  It needs to not say things that

 

      are clearly difficult to defend in the public

 

      environment.  It needs to be responsive to the

 

      public needs and realistic, so that the public

 

      understands the expectations of drugs.

 

                If there was any advertising that the

 

      Agency could do, that I think would help in the

 

      long run, it is to get the American public to

 

      understand that drugs are not safe, that they can

 

      be used safely.

 

                The American public has an unrealistic

 

      expectation for their medications and an

 

      unrealistic expectation of how they should feel as

 

      they go through life, and they expect that these

 

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

 

      we need to get them to stop thinking that way.

 

                We need to maintain and improve

 

                                                                70

 

      international cooperation in both regulation and

 

      harmonization, and we need to, in the final

 

      analysis, decriminalize Grandma.  When she crosses

 

      the border to pick up drugs, she needs to

 

      understand that we don't think that she is

 

      committing a heinous crime against society, that we

 

      understand that the economics are driving her to

 

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

 

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

 

      the price she can afford.

 

                Does anybody have any questions?

 

                [Applause.]

 

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

 

      exhilarating presentation.  I am sorry, I just love

 

      those kinds of things.

 

                Now, we are going to get into some serious

 

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

 

      podium.

 

                DR. HUSSAIN:  Could we just take a break

 

      now and then start after the break?

 

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

 

      whatever you want to do.  You know the energy level

 

                                                                71

 

      after making a presentation.  I really want to

 

      complain about the lack of a soapbox.  I asked for

 

      a soapbox up there because I knew I was going to

 

      get on my soapbox.

 

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

 

      get back and get back to work at two minutes to

 

      10:00.

 

                [Recess.]

 

                DR. KIBBE:  We have comments on my talk

 

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

 

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

 

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

 

                As is the tradition with this year's

 

      committee, Nozer has a comment.

 

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

 

      I have a question for you.  The question is what

 

      would your reaction be to the idea of nationalizing

 

      the drug industry?

 

                DR. KIBBE:  That is a wonderful question

 

      and I think the answer to it resides with our

 

      colleagues over there.  I know that if they ever

 

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

 

                                                                72

 

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

 

      thing.  One of them is direct-to-consumer

 

      advertising.  I think the issue of why the public

 

      has the misconception that drugs are not safe can

 

      be tied directly to direct-to-consumer advertising.

 

                Many years ago, in my one opportunity to

 

      appear on the Today Show, I was interviewed by

 

      Debra Norville on the topic, and I was debating an

 

      industry representative, and I said that it would

 

      completely change the dynamics of prescribing and

 

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

 

      has.

 

                Two days ago, I was sitting at home

 

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

 

      single ad on TV, every single ad was for a

 

      prescription drug, and it just has to have a

 

      dramatic effect on the way patients interact with

 

      their physician and how they get health care.  I

 

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

 

      too.

 

                Does anybody want to throw a few cents'

 

      worth in while we are prognosticating?

 

                                                                73

 

                MR. CLARK:  You mentioned something about

 

      E.R. Squibb challenging the world to meet his

 

      efficiency in his products that he manufactured.  I

 

      was just trying to point out that while he

 

      challenged the world, that challenge could prove

 

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

 

      Squibb would be required to freeze his

 

      manufacturing technique, whatever it may have been,

 

      and that while his challengers came in with new

 

      techniques, he would be burdened with an approval

 

      process that would slow down his ability to

 

      compete, and we should be able to create a

 

      regulatory environment that protects the public as

 

      it still encourages innovation, and not just

 

      encourages the innovation for innovation's sake,

 

      but encourages applying it to the products and to

 

      improve the entire environment.

 

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

 

      he did then now, because the Federal Government is

 

      in his business now.

 

                MR. CLARK:  Exactly.

 

                DR. KIBBE:  And that has happened after

 

                                                                74

 

      World War II.  Before World War II, the Federal

 

      Government stayed out of everybody's business, and

 

      that is a dramatic change in the way we do business

 

      in the United States.

 

                We need to get to the desired state--I

 

      recommend Pennsylvania, far less hurricanes--the

 

      desired state, however, is going to be defined by

 

      Ajaz.

 

                   The "Desired State" of Science and

 

                     Risk-based Regulatory Policies

 

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

 

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

 

      Manufacturing Committee discussion that was

 

      reported quite elaborately by Judy Boehlert, the

 

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

 

      gap analysis, what we see as gaps between the

 

      current state and the desired state from an

 

      internal FDA perspective, what are the challenges

 

      we face internally, and get your feedback on that.

 

                So, what we have are three presentations,

 

      one, Helen will sort of look at the organizational

 

      issues, I will try to identify some of the

 

                                                                75

 

      scientific gaps, and Jon will identify some of the

 

      policy gaps and how we intend to sort of fill those

 

      gaps.

 

                If you could sort of give us feedback on

 

      are we missing in our gap analysis, it is a

 

      preliminary gap analysis right now, and then how we

 

      proceed, and then this will be followed by

 

      discussions and presentations by PhRMA and GPhA

 

      perspective on how they see the progress we have

 

      made and some of the challenges that remain.

 

                So, that is the discussion for this

 

      morning.

 

                DR. KIBBE:  That means you are passing the

 

      ball to Helen.

 

                DR. HUSSAIN:  Yes.

 

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

 

      act.

 

                      Organizational Gap Analysis

 

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

 

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

 

      know where to begin, and my topic is so boring

 

      anyway.

 

                                                                76

 

                I am going to talk about organizational

 

      gap in the Agency right now as far as the desired

 

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

 

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

 

      about at the Manufacturing Subcommittee, and I

 

      think it is really important that we look at these

 

      gaps and talk more about them, and sort of discuss

 

      how we can possibly fill some of them.

 

                I have some ideas on filling on some of

 

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

 

      need.

 

                DR. KIBBE:  There appears to be a gap in

 

      the computational problem, too.

 

                [Pause.]

 

                DR. KIBBE:  We are passing around a

 

      transportation note for people who need help to get

 

      to the airport.

 

                MS. WINKLE:  Is everybody leaving now?

 

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

 

                [Laughter.]

 

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

 

      about the organizational gaps and reaching the

 

                                                                77

 

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

 

      a second, showing you the organizational chart of

 

      OPS, because I think as I talk about organizational

 

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

 

      organization looks like, and I think you have a

 

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

 

      have four offices.

 

                You actually heard from all four of those

 

      offices yesterday, but you say, in yellow, where

 

      the CMC is done in all four offices, so almost

 

      every part of the organization in some way is

 

      affected by the changes that are being made by the

 

      new paradigm and what we are trying to accomplish

 

      with the desired gap, which complicates the issues

 

      somewhat.

 

                It is very important as we look at the

 

      organizational gaps that it is multi-dimensional,

 

      it goes across all of the organization.  It is

 

      between organizations and it is within

 

      organizations.  There is lots of gaps here and we

 

      need to look at all of these gaps and figure out

 

      how we are going to handle them.

 

                                                                78

 

                It is outside of OPS and other parts of

 

      CDER.  We really do a lot of work with products

 

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

 

      those gaps are closed as we move forward in trying

 

      to accomplish the desired state.

 

                So, basically, what I am going to be

 

      talking about here is what we need to consider and

 

      resolve in our process or processes before we can

 

      adequately implement regulatory direction and

 

      support through applications process and review of

 

      what we are calling the desired state.

 

                I also want to point out as I talk, and

 

      you will see this a lot, that the organizational

 

      gaps that I am going to point out really intersect

 

      with the science gaps that Ajaz is going to talk

 

      about and the policy gaps that Jon is going to talk

 

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

 

      these separately although that is what we are

 

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

 

      through the organizational gaps, you will see a lot

 

      of the intersections.

 

                What constitutes the gap in OPS and what

 

                                                                79

 

      are actually the process issues for implementing

 

      the desired state, and how we will review at

 

      different levels?  This is really some of what we

 

      need to talk about.

 

                One of the big problems here is the

 

      appropriate utilization and focus of available

 

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

 

      am having problems.  It is the resources.  We have

 

      a lot of human resources.  You have already heard

 

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

 

      our best resources and how to focus those resources

 

      on those issues that are most important.  So, that

 

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

 

      the gap.

 

                We are not always focused on those issues

 

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

 

      have the science expertise available to focus on

 

      the gaps or focus on the issues correctly.  So,

 

      this is a big gap that we have across the entire

 

      organization.

 

                There is a difference in products and

 

      regulatory requirements and review processes.  We

 

                                                                80

 

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

 

      fall under a different act than the ANDAs and the

 

      NDAs.  So, there are some complications and some

 

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

 

      determine how best to handle.

 

                The organizational structure, the way it

 

      is set up really creates a really large gap in how

 

      we are going to move forward.

 

                I think we have made it clear in the past

 

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

 

      different times, Dr. Nasr has talked about this at

 

      different times, that we have chemists from the

 

      Office of New Drug Chemistry that are located in

 

      the different clinical divisions, so that we lack

 

      consistency in how they make decisions often,

 

      because it is done outside of the whole chemistry

 

      structure, so to speak.  It is done within the

 

      Clinical Division, and we also lack the flexibility

 

      of being able to use our staff and to utilize the

 

      science and the staff because of these

 

      collocations.

 

                Actually, we have chemists in 18 different

 

                                                                81

 

      teams across the Clinical Divisions, and they very

 

      rarely interact with each other, so it really

 

      causes a lot of complications in how we do our

 

      work, and it will cause even more complications

 

      when we get into the new paradigm.

 

                I think one of the main gaps is that we

 

      are very process driven, not science driven.  This

 

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

 

      are regulating a science industry.  It is a science

 

      industry that we are regulating through process.

 

                Some of the things that contribute to this

 

      is PDUFA in generic drugs, first in, first

 

      reviewed.  We have a tiered approach to our

 

      reviews.  We have heavy backlogs.  I think that

 

      Gary has made that point several times to this

 

      committee.  The workloads are big, the backlogs are

 

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

 

      more on process than science.  So, this is causing

 

      us to really have to rethink how we want to do

 

      things.

 

                Part of what is adding to that workload

 

      and to the backlog is that we get too many

 

                                                                82

 

      supplements.  We require supplements on little

 

      changes that really have no significance in the

 

      manufacturing process.

 

                Also, part of the gap is the interaction

 

      with inspection.  We have a lack of appropriate

 

      reviewer involvement, and we get no feedback.  We

 

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

 

      to the industry with the observations, we don't

 

      even have any correspondence in most cases with the

 

      inspection people on things that they find when

 

      they go out on inspections.

 

                So, how you are supposed to really have

 

      knowledge about the products that you are reviewing

 

      in the future or where you can use that knowledge

 

      that has been gathered and incorporate that into

 

      your thinking about reviews and products, you can't

 

      do, so that really creates a lot of gaps.

 

                One of the things that is going to create

 

      a gap in the future is the possibility of having a

 

      two-tiered system. As we talk about the desired

 

      state, as we talk about the things that are

 

      required under the desired state, we don't have

 

                                                                83

 

      regulations that are going to require manufacturers

 

      to submit pharmaceutical development information.

 

      We don't have regulations that are going to require

 

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

 

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

 

      encourage them to do that.

 

                So, you are going to have some companies

 

      that are naturally going to submit this stuff, or

 

      naturally going to move toward PAT and toward other

 

      aspects of improving on their manufacture, but you

 

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

 

      are looking at is the possibility of having a

 

      two-tiered system which is going to create a gap

 

      even within one reviewer.

 

                He is going to have to be able to look at

 

      both tiers and make decisions, and this is going to

 

      complicate issues a lot when we move ahead.

 

                We use guidances to accomplish

 

      consistency, and those guidances are sometimes very

 

      prescriptive, and this adds to the whole gap, and

 

      also not only are we using guidances for

 

      consistency, they are also up for interpretation. 

 

                                                                84

 

      Unless they are prescriptive, they are interpreted

 

      differently by different people, so obviously, we

 

      have some concerns about this.

 

                Organizational components are too

 

      reactive, and not proactive.  Now, this is caused

 

      by workload, and the workload continues to

 

      perpetuate the problem.

 

                You have to be reactive because you have

 

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

 

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

 

      be creative and innovative and think about those

 

      issues and problems that you are going to have down

 

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

 

      new therapeutics that are coming along or new novel

 

      delivery systems or different things like that, too

 

      busy moving the freight from day to day.

 

                Use of available scientific expertise and

 

      scientific collaboration.  Often within especially

 

      in ONDC, because they are broken up according to

 

      the clinical divisions, you may not have the

 

      necessary scientific expertise to look at an issue,

 

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

 

                                                                85

 

      direction is for making a decision on a product.

 

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

 

      scientific collaboration.  I mean we have a lot of

 

      SGEs, we have several in this room that are helping

 

      us on different scientific issues of a broader

 

      nature, but we could be taking advantage of some of

 

      those and calling and getting more information in

 

      the future.

 

                There is a challenge in focusing on the

 

      appropriate questions or what are the right

 

      questions.  Reviewers have a tendency--and this is

 

      not any kind of negative against reviewers--but

 

      they do have a tendency to look at all the data

 

      that is provided, and we have not focused down on

 

      what the appropriate data is, and, therefore, the

 

      appropriate questions that we need to have

 

      answered.

 

                We have a lack of utilization of

 

      appropriate tools.  We could be using statistics

 

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

 

      the questions that we have around review.  There

 

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

 

                                                                86

 

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

 

      causes a gap is the lack of communication between

 

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

 

      also a lack of communication between organizations

 

      or components of the organization, and this is one

 

      of the things that we need to focus on to help

 

      close the gap.

 

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

 

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

 

      important to emphasize some of the stuff, because

 

      we do realize that we have some big gaps here.

 

                I do want to upfront say, though, that

 

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

 

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

 

      going to come along, and I am really looking for

 

      advice from the Advisory Committee as to some of

 

      the things that we need to be thinking more

 

      carefully about, or make suggestions for some of

 

      the things that we could be doing to help close

 

      this organizational gap.

 

                One of the things we have been doing is

 

      making some structural changes in the organization

 

                                                                87

 

      In the Office of New Drug Chemistry, which Judy

 

      talked about yesterday for the Manufacturing

 

      Subcommittee, we are reorganizing the Office of New

 

      Drug Chemistry.  We are actually doing away with

 

      the collocation and making one Office of Chemistry

 

      when we move to White Oak.

 

                We feel that this is going to give us a

 

      lot of consistency or at least more consistency,

 

      and give us the opportunity to have more

 

      flexibility as to how we look at the review

 

      process.  We feel that this is going to have some

 

      real advantages to us.

 

                We are also, in our Office of Generic

 

      Drugs, we have set up a third division for doing

 

      chemistry.  The workload is so heavy in the office

 

      that we felt like if we had more divisions where we

 

      could spend more time and focus more on some of the

 

      issues, that we could help in some of the gap

 

      problems, having reviewers on inspections or as

 

      consultants to inspection, so have complete

 

      knowledge on products and the results of

 

      inspections.

 

                                                                88

 

                This is something that we have been

 

      working on.  We have been working with our Office

 

      of Compliance and with our field component.  We

 

      feel like we would like to have reviewers on

 

      inspection.  We think it is very important for them

 

      to go out and provide some of the scientific

 

      knowledge to the inspectors as the inspections are

 

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

 

      question even came up yesterday on resources to do

 

      this.

 

                This is a resource issue.  You are taking

 

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

 

      already talked about the workload being

 

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

 

      inspections and spend time away from their desks,

 

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

 

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

 

      this in every inspection.

 

                But I do think it is important that before

 

      the inspections are done, even though the reviewers

 

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

 

      inspectors and talk about some of the issues that

 

                                                                89

 

      they have seen in the reviews of these particular

 

      companies and give them some advice on what they

 

      may want to focus on more in the inspections.

 

                One of the big things that is really

 

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

 

      again this sort of goes across the whole concept of

 

      the science gap and the guidance gap, and our

 

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

 

      questions we still need to answer and address.

 

                This is only a few of them, but I think

 

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

 

      grips with on manufacturing science and how that is

 

      going to affect our review and what our review

 

      process is going to be to handle these things in

 

      the future - things like quality overall summaries.

 

                Dr. Nasr talks about incorporating this

 

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

 

      conclusions on this.  We are still in the proposal

 

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

 

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

 

      the industry, and what we really need to see in

 

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

 

                                                                90

 

      look at.

 

                What we need in the way of pharmaceutical

 

      development information.  There is a lot of

 

      information that these companies have in the

 

      pharmaceutical development arena, and do we want

 

      all of that information.  If we get that

 

      information, what are we supposed to look at, what

 

      would we focus on.  We need to answer those

 

      questions, it is very important, before we start

 

      asking for this information.

 

                We have to have addressed that before, I

 

      think, companies are going to feel comfortable in

 

      providing it.  I think many companies see this as

 

      just more information they are sending us to look

 

      at and more questions they are going to get from

 

      us, so we really have to develop our processes.

 

                We also need to look at things like how

 

      industry will determine critical attributes, so as

 

      we look toward the desired state, that we are able

 

      to regulate that and include those in our process,

 

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

 

      do as far as reviewing these.

 

                                                                91

 

                This is just a small part of the

 

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

 

                Also, as far as closing the gap, we need

 

      to have a better understanding of what constitutes

 

      the design space across all products, and once we

 

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

 

      need to know when notification to FDA is necessary

 

      for change in manufacturing.

 

                We have not reached these conclusions yet,

 

      and we need to have working groups, whatever it

 

      takes, to really develop our own internal thinking

 

      on this and work with industry to make sure that

 

      the direction we are going is going to be useful to

 

      them.

 

                We need to have a better understanding of

 

      what risk for a product is and develop a systematic

 

      risk approach to review processes.  I keep seeing

 

      time and time again, people talk about risk

 

      management or risk processes, and stuff like that.

 

      I think when you talk about risk management, you

 

      are talking about something different for every

 

      person.

 

                                                                92

 

                I mean what is in my mind, what is in

 

      everybody else's mind in this room could be

 

      entirely different, and we at the Agency need to

 

      narrow down as far as review is concerned, decide

 

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

 

      have a very, very concise program for ensuring that

 

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

 

                Guidances.  Again, Jon is going to talk

 

      about guidances, but it is really necessary for us

 

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

 

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

 

      many guidances out there that are outdated, many

 

      guidances that are overly prescriptive, many

 

      guidances that don't fit into the new paradigm at

 

      all.

 

                Jon is in the process, he and his staff,

 

      of going through the guidances, removing some,

 

      redoing some, and looking at what guidances we will

 

      need for the future in order to incorporate some of

 

      the changes.

 

                Training.  This goes to the question Mel

 

      asked, training, training, training is necessary

 

                                                                93

 

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

 

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

 

      think it is really important and part of what we

 

      need to do to close the gap, is determine what

 

      really training our reviewers need and what

 

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

 

      think we have come to those conclusions yet.

 

                We need to determine how we are going to

 

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

 

      the direction that we go, and we need to have

 

      developed the processes for doing that.  We need to

 

      develop an internal system for handling differences

 

      in Review Divisions.

 

                I met a couple of months ago with PhRMA on

 

      a RAC Committee on a dialogue session, and this was

 

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

 

      dispute resolution process, some kind of mechanism

 

      where, when there are differences in review, that

 

      we are able to handle those decisions and get

 

      information out as to how these issues are

 

      resolved.

 

                The last thing I have on here--and

 

                                                                94

 

      actually, I wrote this slide before we even had

 

      some of the conversations yesterday--was what is

 

      really important is we need to have appropriate

 

      metrics for measuring things.

 

                Today, in the review, we measure by what

 

      we accomplish, how many supplements we get.  Well,

 

      let me tell you when you are measuring supplements,

 

      and that is an indication of how good you are doing

 

      your job, you are going to want more supplements.

 

                We have got to really back off of the

 

      metrics that we currently have and look for those

 

      appropriate metrics to help close these gaps.

 

                So, some of the current steps we have

 

      across OPS, we mentioned before that we are setting

 

      up a working group under the Manufacturing

 

      Subcommittee of the Advisory Committee to begin to

 

      address many of these questions that we have.  We

 

      are also setting up some CRADAs to get some case

 

      studies to help us, too, in getting a better

 

      understanding of these issues and how we are going

 

      to handle them in our processes.

 

                ICH, too, is going to be an important part

 

                                                                95

 

      of helping us handle some of our organizational

 

      decisions especially Q8 as it looks at the desired

 

      state and implement some guidelines on it.

 

                We are doing some workshops.  We have a

 

      Workshop of Specification Setting and looking at

 

      how we need to have a mechanistic understanding of

 

      setting specifications in line with the direction

 

      that we are going.

 

                That particular workshop is set up in

 

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

 

      think there is still going to be issues that come

 

      out of that workshop where we are going to have to

 

      look more specifically at some of the specification

 

      areas and really dig deeper into them, so I really

 

      anticipate more workshops than this just in the

 

      area of specifications, but I think a number of

 

      workshops are on the horizon in order for us to be

 

      able to address many of these questions.

 

                I actually think, too, one of the things

 

      that we are probably looking at having a workshop

 

      on is quality overall summaries.  If that is the

 

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

 

                                                                96

 

      the industry and others, so that we have a better

 

      understanding of what we need for using that type

 

      of process and what it means to us in the industry

 

      when we do.

 

                We already have some collaboration with

 

      academics. As I said, we are involved in several

 

      CRADAs or in the development of several CRADAs.  I

 

      think these are going to be very helpful for us in

 

      getting a better understanding of some of the areas

 

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

 

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

 

      and we have been doing some work with the Product

 

      Quality Research Institute.

 

                As I already said, we have an internal

 

      review of our current guidances, which is very

 

      important to helping us have the appropriate

 

      guidances out there.  We are developing a program

 

      for team interactions for inspections.

 

                We are sort of basing this on how we have

 

      handled PAT and the team approach, and we are

 

      working with Compliance in the field to develop a

 

      better way of handling inspections and including

 

                                                                97

 

      the Review folks in those inspections, and also a

 

      better way of getting the findings from those

 

      inspections.

 

                Training for reviewers.  We have already

 

      had a number of scientific seminars.  We have

 

      started that, especially, OGD has one every six

 

      months or so, and those seminars have been very

 

      beneficial to our staff in helping us have a better

 

      understanding of where we need to go, but we need

 

      more seminars and we need, again, really a set

 

      training program for all of our reviewers.

 

                We did form an OPS Coordinating Committee

 

      within the immediate office, and actually, Keith

 

      Webber and Gary Buehler are the chairs of that

 

      committee, and we will be looking at all the issues

 

      that come into OPS to try to ensure that we have

 

      consistency throughout all of OPS on handling

 

      these.

 

                One of the other things that we are in the

 

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

 

      finalizing the guidance on comparability protocol.

 

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

 

                                                                98

 

      changing the organizational structure, but much

 

      more than changing the organizational structure, we

 

      are changing from a review program to an assessment

 

      program, and that assessment program will focus on

 

      quality attributes of the manufacturing including

 

      chemistry, pharmaceutical formulation, and the

 

      manufacturing process.

 

                So, the significant thing here is that we

 

      will be looking at much more the chemistry, the

 

      CMC, and that is where the assessment program is

 

      focused.

 

                We have the proposed QOS.  We have also

 

      implemented a team approach.  We are establishing a

 

      peer review process.  We have already done this on

 

      a limited basis to provide more scientific input to

 

      our scientists in their review processes, and

 

      helping everyone have a better understanding and

 

      sharing the knowledge that they learn from the

 

      reviews.

 

                We are implementing a Quality Systems

 

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

 

      doing, is they are developing a mock NDA under the

 

                                                                99

 

      new paradigm, under the desired state paradigm, so

 

      that they will have a better feel for some of the

 

      questions and issues that can come up, and they are

 

      looking at reducing supplement requirements.

 

                OGD has reorganized, as well.  As I

 

      mentioned, they have an additional Chemistry

 

      Division.  They are looking at changes in the

 

      supplement review and evaluation to determine if

 

      some of the supplements can be eliminated.

 

                They have also taken on the team approach

 

      on some applications, so that they have better

 

      utilization of scientific expertise and ensure

 

      consistency across similar product areas, and they

 

      are also looking at efficiencies in review to

 

      eliminate redundant or non-essential review

 

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

 

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

 

      in order to eliminate the gap.

 

                OBP, which is, of course, our newest

 

      review organization, is looking at supplement

 

      requirements to determine where we can eliminate or

 

      reduce supplements.

 

                                                               100

 

                Some additional steps.  I think we need to

 

      involve stakeholders in the review of guidances.

 

      Maybe under the Manufacturing Subcommittee we need

 

      a group that looks at some of the guidances.  I

 

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

 

      is a step we need to do.

 

                We need to determine how to handle the

 

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

 

      mentioned this before, and I think it is going to

 

      be important to involve industry and others in

 

      doing that.

 

                We need to have external workshops,

 

      develop a dispute resolution process.  One of the

 

      things, too, besides looking at regular GMP

 

      inspections, we really need to look at better ways

 

      to handle pre-approval inspection process.

 

                I would really like to see reviewers more

 

      involved in making some of the decisions on whether

 

      to do pre-approval inspections and to set better

 

      criteria for getting those done plus participate on

 

      the inspections if we feel they are necessary, and

 

      develop appropriate metrics.  These are things we

 

                                                               101

 

      haven't started on, but are obviously necessary,

 

      and I am sure there is others.

 

                Just to finish up, observations and

 

      conclusions.  I think we need to continue to

 

      address and analyze the organizational gap issues.

 

      I think they are going to be really important to

 

      us, to have determined what they are and to resolve

 

      how we are going to handle them in the future in

 

      order to move in the direction that we need to do

 

      to be able to regulate under the desired state.

 

                One of the things I think that is very

 

      important that we need to think about is culture.

 

      When I talk about culture, I am talking about the

 

      culture within FDA, and I am talking about the

 

      culture outside of FDA.

 

                There are a lot of changes that need to be

 

      here.  I realize that the culture is always a

 

      different area of thing to handle.  I thought

 

      Jerry's example was an excellent example of how the

 

      culture is a problem in some of the things that we

 

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

 

      that we have got to manage and figure out how best

 

                                                               102

 

      to handle.

 

                All of this, all of this, the changes in

 

      the organizational gap will take time, and we need

 

      to be dedicating the time to make it happen.

 

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

 

      resolving some of the science gaps that we have.

 

      We need to include stakeholders in making some of

 

      the decisions and developing some of the

 

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

 

      the stakeholders or we are really not going to have

 

      the answers that we need.

 

                The training of reviewers is important,

 

      and the thing I think that is going to be something

 

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

 

      forward, we are going to see other gaps that we

 

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

 

      ready to fill those.

 

                That is all I have.  Thank you.

 

                DR. KIBBE:  Thank you, Helen.

 

                Should we take questions or you want to

 

      move to the--

 

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

 

                                                               103

 

      yes.

 

                DR. KIBBE:  I will hold my really tough

 

      and incisive questions until later.

 

                        Scientific Gap Analysis

 

                DR. HUSSAIN:  Last night I had a phone

 

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

 

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

 

      which recently got an approval for an inhalation

 

      product, and they were ecstatic. They had submitted

 

      a complete development pharmaceutics report, and

 

      that process went extremely well.  This was a

 

      one-cycle review approval for an important product

 

      including all the development report.

 

                So, I think that is a wonderful example

 

      that shows ONDC has already moved and things are

 

      moving in this direction already.  We probably will

 

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

 

                Anyway, I would like to sort of focus on

 

      the scientific gaps.  I will use some background

 

      information.  I know a number of members on this

 

      committee who are new, so I thought I will spend

 

      some starting with the basics.

 

                                                               104

 

                I think, as Dr. Woodcock had come to the

 

      Manufacturing Committee, her articulation of what

 

      is quality has really come to almost fruition, and

 

      she is publishing this article soon.  The

 

      definition of quality is fundamental as we move

 

      forward, and there are some challenges as we move

 

      forward.

 

                Good pharmaceutical quality essentially

 

      means an acceptably low risk of failing to achieve

 

      the desired clinical attributes.  That is the goal

 

      of achieving quality.

 

                The challenge has always been, and you

 

      heard many of the discussions yesterday, saying the

 

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

 

      to strengthen and address--how do we link

 

      measurements and risk?

 

                I think what we believe quality by design

 

      approach that we are developing under ICH Q8 is a

 

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

 

      is characterized during development.  You have to

 

      think about, when you think about quality by

 

      design, the clinical is a confirmation of that.

 

                                                               105

 

      That is the fundamental aspect that I think is

 

      going to be a significant challenge in how we

 

      achieve that.

 

                At the same time, you have to remember

 

      that development is only one part of it.  You

 

      essentially have to make sure you have a quality

 

      system.

 

                The final link between product and

 

      customer-driven quality attributes really means you

 

      have a good quality system for manufacture that

 

      brought us consistently also, that requires

 

      integrated product and process knowledge on an

 

      ongoing basis, because you don't stop learning at

 

      the time of approval.  In fact, you learn quite

 

      significantly after manufacturing status.

 

                You have to assure ongoing control, and

 

      you have to enable continuous improvement.

 

                In summary, I think Dr. Woodcock

 

      articulated this at our ONDC scientific rounds on

 

      October 6th.  The future definition of quality

 

      should be probabilistic in nature. That is the

 

      fundamental aspect, and we are not there yet.

 

                                                               106

 

                Science management, risk management, and

 

      quality management are critical aspects, and I

 

      think we really would like to be leaders in this,

 

      and I personally believe that we are.

 

                But let me take a look backwards from

 

      beginning with the end in mind.  Since we started

 

      the PAT Initiative, the cGMP Initiative, our focus

 

      has been on looking at the entire system, and we

 

      have been looking backwards from a manufacturing

 

      end to the entire discovery development product,

 

      and it is what do we learn from that.

 

                But before you look, before you measure,

 

      it is always good to make sure your measurement

 

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

 

      is the symbol there.

 

                The reason I was so sensitive to that is I

 

      think the dissolution variability from a

 

      manufacturing end, we really fully appreciate it

 

      when we are putting that white paper together, that

 

      today, companies don't have the ability to document

 

      lower variability than that of the calibrated

 

      tablet, and which is made with the conventional

 

                                                               107

 

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

 

      reality that a lot of us fully understood during

 

      this process.  Art mentioned that, and so forth.

 

                So, what are the challenges here in the

 

      sense the challenge is organizational

 

      communication, and knowledge sharing and

 

      information sharing.  If you work in silos, the

 

      boundaries between organization, which I call

 

      interface, the quality of the interface between

 

      functional unit, that means the effectiveness and

 

      efficiency of the process, the interface can be

 

      handoffs between functions, and often is in need

 

      for better coordination, and that is what we

 

      learned through our GMP Initiative.

 

                The rapid and broad movement of

 

      information and knowledge sharing is necessary for

 

      process optimization between organizations, within

 

      any organization itself, so we have to move from

 

      technology transfer to knowledge transfer.

 

                But just toward the stage, reliability is

 

      a phrase that we often don't use in

 

      pharmaceuticals, but reliability has a very

 

                                                               108

 

      distinct body of information, body of knowledge

 

      associated with that.

 

                So, if you look at this figure, you have

 

      performance, you have life, shelf life, and you

 

      have a desired specification on both sides, on the

 

      performance.

 

                The first, Figure A is good performance,

 

      but poor reliability because the performance

 

      changes significantly over time, and the

 

      variability of the spec changes, too.

 

                The second one is good performance and

 

      good reliability over the life.

 

                The third is poor performance below spec.

 

                So, I think the key is when we think about

 

      performance, we are thinking about performance of

 

      the shelf life, the bioavailability, and so forth,

 

      remaining unchanged throughout the shelf life.

 

      Just to keep that in mind.

 

                In the current state, today, chemistry,

 

      manufacturing, controls, design information

 

      available in applications is limited and varied.

 

      Our reviewers have a high degree of uncertainty

 

                                                               109

 

      with respect to what is critical and what sort of

 

      process controls are necessary.

 

                Our reviewers have significant doubt on

 

      the level of process validation and process

 

      understanding.  So, they have no option but to

 

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

 

      the pharmaceutical manufacturing from an

 

      engineering sense, testing is control, but in an

 

      engineering sense, control is very different.  It

 

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

 

                Risk coverage post-approval is a

 

      challenge, and supplements are a means for risk

 

      mitigation.  That is the way we have approached it.

 

                Traditional use of market standards--these

 

      are the pharmacopeial standards--as release tests

 

      are not effective for process understanding and

 

      continuous improvement.  In fact, by definition, if

 

      you have attribute data or so-called zero

 

      tolerance, continuous improvement is impossible by

 

      definition.  That is the definition in QS 9000,

 

      because we can only have continuous improvement

 

      when the product is already in spec.

 

                                                               110

 

                If you have zero tolerance criteria, by

 

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

 

      is the fundamental thing.  Also, we understood and

 

      wrote about that in our Manufacturing Science white

 

      paper.

 

                We have variable test methods for physical

 

      characteristics, less than optimal systems

 

      perspective and approach, low efficiency and high

 

      cost of drug development and manufacturing, and

 

      continuous improvement is difficult, I would dare

 

      to say not possible.

 

                So, the success of the cGMP Initiative was

 

      to get a consensus desired state statement, so I am

 

      not using the exact words that we developed.  They

 

      are modified and the desired state statements

 

      adopted by ICH, these are the ones. Product quality

 

      and performance are achieved and assured by design

 

      of effective and efficient manufacturing processes.

 

                Since we are looking back from the

 

      manufacturing side, manufacturing goals are kept

 

      first.

 

                Product specifications based on

 

                                                               111

 

      mechanistic understanding of how formulation and

 

      process factors impact product performance, and an

 

      ability to effect continuous improvement and

 

      continuous "real time" assurance of quality.

 

                Now, let's start looking at this in the

 

      sense what are the gaps and how do you fill those

 

      gaps.

 

                Information and knowledge for regulatory

 

      assessment and decision process based on the

 

      desired state is information related to quality and

 

      performance and how the design impacts that.  So,

 

      we need to know impact of formulation and process

 

      factors on performance.

 

                We need information to judge and develop

 

      specifications based on mechanistic understanding.

 

      We need information to evaluate and facilitate

 

      continuous improvement, and continuous "real time"

 

      assurance of quality.

 

                The focus is on design, and if you are a

 

      formulator, especially one trained a few years ago,

 

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

 

      simply logical extension, so this is nothing new

 

                                                               112

 

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

 

      think differently the design process.

 

                Design is about doing things consciously,

 

      and not because they have always been done in a

 

      certain way.  It is about comparing alternatives to

 

      select the best possible solution.  It is about

 

      exploring and experimenting in a structured way.

 

      So, that is what design vocabulary brings to us.

 

                So, in the context of drug product

 

      development, design is about doing things

 

      consciously, so you start with the intended use.

 

      That is the fundamental issue.  You cannot forget

 

      the clinical use of the product that you are

 

      designing.  That includes route of administration,

 

      patient population, and all other things that

 

      impact on the intended use.

 

                That intended use defines for you what the

 

      product design should be.  You have options to

 

      select, and you select a product design.  That

 

      design leads you to design specifications, and

 

      those design specifications define the

 

      manufacturing process and its control necessary to

 

                                                               113

 

      develop those design specifications back to deliver

 

      the intended use.

 

                So, you have product performance, design

 

      specification that reliably and consistently

 

      deliver the therapeutic objective, and you have

 

      manufacturing capability, ability to reliably and

 

      consistently deliver the target for a design.  This

 

      is straightforward, logical, no rocket science, and

 

      we have been making and doing this for 100 years.

 

                So, that was the basis that we said we

 

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

 

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

 

      that, will essentially bring this type of

 

      information.

 

                It will not deal with the drug substance

 

      manufacturing part of it, but it will start with

 

      drug substance characterization.

 

                So, it will bring in characterization of

 

      components of drug product.  It will bring in

 

      aspects of manufacturing compatibility, and so

 

      forth.  Much of this information is sort of missing

 

      or varied in the current submission, and we are

 

                                                               114

 

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

 

      ideal, we have to live with that because that is

 

      how everything goes in green, we felt that the

 

      sections provide enough room for bringing all the

 

      information to bear on that.

 

                So, we have made significant progress, and

 

      I think the draft 4 we are working on has captured

 

      most of this.

 

                What is the importance of design thinking?

 

      Design thinking makes the user paramount, ensuring

 

      that services we end up will do the job they are

 

      supposed to, as well as delighting the customer.

 

                Design thinking and methods provide new

 

      routes to better public services that meet people's

 

      needs and deliver value for money.  That is the

 

      key.

 

                We have been making tablets for 100 years

 

      or more.  It is a design problem.  We essentially

 

      have not used the vocabulary, we haven't brought

 

      that in.  Tools, such as pre-formulation

 

      characterization, and so forth, literally have

 

      become [inaudible], but that information often is

 

                                                               115

 

      missing in our assessment.

 

                So, if I distinguish between conventional

 

      and novel design for the sake of distinction in

 

      terms of how we use prior knowledge, the key aspect

 

      of this design and quality relationship is utility

 

      of prior knowledge.  For similar drug products, you

 

      have probably more prior knowledge, and for novel

 

      designs, you have to rely more on the experiments

 

      you generate, but prior knowledge is the key.

 

                If you are going to come with a new tablet

 

      formulation, and you have 300 similar tablet

 

      formulations on the market, how much more

 

      information do we need?  If you leverage the prior

 

      knowledge correctly and characterize your drug

 

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

 

      way it is, you can leverage that knowledge.

 

                Level of mechanistic understanding will

 

      depend, will vary.  Pre-formulation programs, many

 

      good pre-formulation programs get to the mechanism

 

      of degradation, get to the mechanism of absorption

 

      including Bioform Classification System,

 

      characterization, that is the fundamental.  That

 

                                                               116

 

      defines literally every aspect of the manufacturing

 

      process and other things.

 

                So, if you have that information, if you

 

      will not be mechanistic completely, but you have

 

      valuable information, that moves forward.

 

                The challenge I think is to think about

 

      design during drug development.  As you develop

 

      your characterization and your development program,

 

      you have to keep in mind the ability to reliably

 

      predict performance, confirm as you progress.

 

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

 

      adding to your knowledge base, is a means to

 

      evaluate the predictability of your prior

 

      knowledge, and so forth.

 

                So, if you think about designing the

 

      entire development project from a design

 

      prospective, and capturing your predictability, you

 

      actually have an opportunity to move forward very

 

      quickly in terms of regulatory aspects, as well.

 

                So, level of understanding increases over

 

      time, and I think we have to recognize that.

 

      Structured empirical approach is often necessary

 

                                                               117

 

      because you often are not mechanistic.

 

                Use of prior knowledge to identify and

 

      select a design space for characterization is

 

      fundamental, and I think Ken Morris mentioned this

 

      yesterday.  People often jump into design of

 

      experiments without knowing what design space they

 

      want to explore.

 

                If you miss the prior knowledge, you

 

      actually increase your workload, you increase your

 

      cost by not being intelligent enough to say what

 

      are the critical variables upfront, and sort of

 

      exploring the design space.  You cannot approach

 

      this in a blinded fashion.

 

                For example, now, if you have multiple

 

      number of variables that you have to study,

 

      obviously, you cannot study all of them.  That is

 

      where risk comes in.  Prior knowledge and risk

 

      assessment is the way to address that, for example,

 

      failure mode effect analysis would be a means to

 

      say all right, these are the critical variables, at

 

      least these are potential critical variables, these

 

      are the ones we will select and move forward.

 

                                                               118

 

                So, initial conditions for screening

 

      experiments and then experimental conditions are

 

      then dependent on this prior knowledge and risk

 

      assessment.

 

                Impact of formulation and process factors

 

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

 

      intelligent about our clinical trial material

 

      itself, and how do we design clinical trials,

 

      because that is where the connection between

 

      quality and clinical comes together, and I will

 

      show you an example as we go.

 

                Similarly, with shelf life.  If you are

 

      getting mechanistic understanding, and so forth,

 

      prior knowledge and shelf life, I think is a

 

      wonderful opportunity which we don't utilize today.

 

                Just to give you an example, these are

 

      standard procedures in industry.  Here, is a work

 

      from Amgen in a sense how do they address the large

 

      number of variables as they go through process

 

      characterization, pre-characterization experiments,

 

      is to bring the prior knowledge to bear on this.

 

                So, process characterization studies start

 

                                                               119

 

      with pre-characterization work, screening

 

      experiments, interactions, and combinations of key

 

      parameters leading to process redundancy.

 

                They sort of covered that with a formal

 

      risk analysis.  So, these are standard procedures,

 

      and in many, many aspects, the formulation

 

      development process has built in robust approaches,

 

      but it is not formalized, it is not well

 

      understood.

 

                What is a robust design?  A robust design

 

      is not removing the source of variability, but

 

      designing a process or product to reduce the

 

      variability.

 

                A very simple example that in

 

      pharmaceuticals we have, is we know magnesium

 

      stearate is a wonderful lubricant, but it has a

 

      drawback of affecting dissolution, we know that.

 

                Half of the formulations that we have in

 

      our submissions actually have a robust design built

 

      in.  They will use a smaller model on sodium lauryl

 

      sulfate.  That negates the negative effect of

 

      magnesium stearate.  We have known that as

 

                                                               120

 

      pharmacists, formulators, and so forth, a long

 

      period of time, but we never captured that as a

 

      knowledge base.

 

                If you are making a tablet, you are

 

      compacting. Compaction has an effect on

 

      dissolution.  If you have right amount of

 

      disintegrating agent, you remove the effect of

 

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

 

      what a robust design principle brings to bear on

 

      that.

 

                What is troubling often is, if you look at

 

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

 

      have regulated, the way we have done experiments

 

      often is to define our input or independent

 

      variables in terms of equipment.  Say, for example,

 

      if you look at the SUPAC guidance, we say equipment

 

      of same design and operating principles, you can do

 

      this, and so forth.

 

                That is not a quantifiable.  It is an

 

      identifier. So, we know that performance of a unit

 

      operation depends on material characteristics,

 

      particle attributes, equipment design, and

 

                                                               121

 

      operating conditions.

 

                Instead of sort of defining of input as

 

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

 

      doing a design experiment, if you are smarter, you

 

      will say all right, what are the forces acting on

 

      the particle irrespective of the equipment design.

 

      That removes that and improves your ability to

 

      generalize.  So these principles have been there

 

      for 60 years.

 

                Let me explain, in a sense, I think the

 

      key aspect here is risk-based specifications.

 

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

 

      through this.

 

                What specific test conditions and

 

      acceptance criteria are appropriate for a

 

      conventional or immediate release dosage form?

 

                Now, Professor Nozer corrected me before,

 

      so I will correct myself again.  He said this is

 

      not a decision tree, this is an event tree.

 

                Question 1 is:  Dissolution significantly

 

      affects bioavailability?  That is the Question 1.

 

                If the answer is yes, develop test

 

                                                               122

 

      conditions and acceptance criteria to distinguish

 

      between unacceptable bioavailability.

 

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

 

      changes in formulation or manufacturing variables

 

      affect dissolution?

 

                If the answer is no, go down.  Adopt

 

      appropriate test conditions and acceptance criteria

 

      without regard to discriminating power, to pass

 

      clinically acceptable batches.

 

                The first question is how do you know

 

      dissolution significantly affects viability.  Most

 

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

 

      is called a "Related bioavailability study."  They

 

      will compare a solution with a solid dosage form,

 

      and often you see they are superimposable.  That

 

      means dissolution is not rate limiting.  So,

 

      dissolution is not likely to affect that.

 

                Do changes in formulation variables affect

 

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

 

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

 

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

 

      but you still put a dissolution test.  The question

 

                                                               123

 

      should be why, why do you need that dissolution

 

      test?

 

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

 

      what really have not been addressed adequately, and

 

      our dissolution specification setting is one, two,

 

      three, these were your three batches, this is your

 

      specification.  Often, it is limited to that.

 

                I want to remind you that variability is

 

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

 

      This was published recently from Cambridge

 

      University and Pfizer.

 

                It said if you don't account for

 

      variability and you assume that meeting

 

      specification means you are bioequivalent, that may

 

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

 

      analysis, if your specifications are not set right,

 

      you have a 50-50 chance whether you are

 

      bioequivalent or not, or whether you meet

 

      specification or not.

 

                So specifications for dissolution are not

 

      likely to be the ones ensuring bioequivalence.  It

 

      is the entire control process that does that, but

 

                                                               124

 

      we focus so much attention on just one test, we

 

      miss the whole point.

 

                Let me come back to this decision tree.  I

 

      think in a quality by design thinking, this is what

 

      are my questions.  So, dissolution significantly

 

      affect bioavailability is a product design issue.

 

      You start with your pre-formulation, your biopharm

 

      classification, the solubility, permeability, and

 

      all that aspect, and you have an anticipation

 

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

 

      your related bioavailability study, you are

 

      conforming your past prior knowledge.

 

                So, postulate-confirmed based on mechanism

 

      or empirically, and that can apply to the question

 

      dissolution significantly affect bioavailability or

 

      do changes in formulation affect dissolution or

 

      not.

 

                But Jurgen points out, the key question is

 

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

 

      number.  Where did that magic number come from?  I

 

      think this is where the clinical relevance comes

 

      in, what is a relevant acceptance criteria to judge

 

                                                               125

 

      whether an acceptable bioavailability is there or

 

      not, and that is a clinical pharmacology question.

 

      That is where we link to the clinic.

 

                If you have a good PK/PD assessment, and

 

      so forth, you have far more information available

 

      to make a more rational judgment, and that is the

 

      question there.

 

                So, design of manufacturing and controls,

 

      and the question is how reliable those are, do

 

      changes in formulation and manufacturing variables

 

      affect dissolution? If the answer is yes, Are these

 

      changes controlled by another procedure and

 

      acceptance criteria?

 

                If the answer is yes, we come back and put

 

      a dissolution test.  My question is why?  If the

 

      dissolution test itself is variable, and so forth,

 

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

 

      series of tests, and so forth, your chances of

 

      failure keeps increasing.

 

                So, the questions that we need to ask are:

 

      How good or how reliable are your design and

 

      controls that you have put in place for particle

 

                                                               126

 

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

 

      conditions?

 

                So, overall risk-based CMC would ask why

 

      for these questions, but also, so what?  If

 

      dissolution is not rate-limiting, the question

 

      should be so what, why do we need a dissolution

 

      test, and so forth.

 

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

 

      So, quality by design thinking brings an overall

 

      CMC systems approach, for example, link to morphic

 

      form, particle size, stability failure mechanisms,

 

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

 

                Continuous improvement is not possible

 

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

 

      direct cut-and-paste from our SUPAC guidance.

 

      Level 1 change, definition of change is this

 

      category includes process changes including changes

 

      such as mixing times and operating speeds within

 

      application/validation ranges.

 

                If you need to have validated those

 

      ranges, any movement within that is a change today.

 

      So, it requires to be reported.  If you change

 

                                                               127

 

      outside those ranges, you not only have to report

 

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

 

      which is a profile comparison, and the supplement,

 

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

 

      not possible.

 

                Our law and our regulations provide

 

      provisions for those approaches, and this is a

 

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

 

      We are required to make decisions based on

 

      potential to have an adverse effect on identity,

 

      strength, quality, purity, or potency of the drug

 

      product.

 

                We have used the phrases "substantial,"

 

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

 

      useful, they are not probabilistic, and I think

 

      that is where we have to work at.

 

                But also, if you look at CFR 314.70, there

 

      is a provision no change means no reporting beyond

 

      the variations already provided in the application,

 

      and that is where the design space comes in.

 

                So, what is this design space?  The design

 

      space is simply a space of knowledge or information

 

                                                               128

 

      where you know you will not affect your

 

      bioavailability, you will not affect your

 

      stability, and you will be in specification, but

 

      you are improving the manufacturing efficiency, you

 

      are improving the manufacturing process through new

 

      equipment, better controls through process

 

      adjustment in response to incoming input variables,

 

      and so forth.

 

                So, that is what continuous improvement

 

      is, and Box defined this years ago as evolutionary

 

      operations.

 

                So, that is how ICH Q8 information that

 

      brings reliability to your deliver design

 

      information, ICH Q9, which will develop the failure

 

      mode effect analysis and risk communication, too,

 

      all of them come together to define a design space

 

      for continuous improvement, and that design space

 

      will depend on the company's information that sort

 

      of comes about.

 

                You will know which area is the change,

 

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

 

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

 

                                                               129

 

      red area.  That's about it.

 

                Yesterday, Steve showed this slide that I

 

      had developed for thinking about the entire system,

 

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

 

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

 

      knowledge space, and the knowledge space in

 

      relation to the clinical knowledge space and in

 

      relation to the manufacturing knowledge space all

 

      have to come together to sort of address this.

 

                A personal learning that I had going

 

      through the GMP process is a better appreciation

 

      for quality system.  I am still an academic at

 

      heart, and when you put me into a documentation

 

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

 

      something I want to avoid.

 

                The quality system that we have worked out

 

      in the GMP Initiative is actually quite nice and

 

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

 

      prove it, and improve it. Those are the fundamental

 

      principles.

 

                So, say what you do to FDA, is your

 

      pharmaceutical development information that you

 

                                                               130

 

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

 

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

 

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

 

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

 

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

 

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

 

      have corrective actions.

 

                If you are unable to ask why, unable to

 

      answer why, then, there is a risk profile that

 

      increases.  And prove it is more optional, there is

 

      continuous improvement in innovation sort of comes

 

      in there.

 

                The challenges, I think in pharmacy, in

 

      pharmaceutical education, we have been doing this

 

      all along. What has been missing is a formal

 

      structure and communication tool.

 

                I draw some similarity here.  If I look at

 

      what has happened in chemical engineering, and now

 

      I think chemical engineering is going through

 

      soul-searching activities to redefine themselves,

 

      but this is how chemical engineering evolved.

 

                It started with industrial chemistry, unit

 

                                                               131

 

      operations, material and energy balance, chemical

 

      engineering thermodynamics and control, applied

 

      kinetics, process design, transport phenomena,

 

      process dynamics, process engineering.  Now, they

 

      are in molecular transformation, multi-scale

 

      analysis, and systems view.

 

                So, they went from industrial chemistry to

 

      unit operations, to chemical engineering science,

 

      to system engineering.

 

                Industrial pharmacy is still industrial

 

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

 

      Europe, it's a pharmaceutical engineering degree

 

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

 

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

 

      those principles.

 

                It is important to do that, it is

 

      important to bring a systems engineering

 

      perspective because not only we have to deal with

 

      the traditional goals of quality, the GMP

 

      Initiative offered new, non-traditional goals, that

 

      is, risk-based, flexibility, robustness,

 

      scalability, continuous improvement, innovation,

 

                                                               132

 

      and efficiency.  These are typically

 

      non-traditional goals.

 

                The characteristics of these goals are

 

      complexity and uncertainty associated with that.  The

 

      relationship between goals and characteristics

 

      that we are seeking is knowledge and information

 

      centric relationships.

 

                There are fundamental issues there,

 

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

 

      system will continue to be a paper chase exercise,

 

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

 

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

 

      one quality system to another.  Unless this process

 

      is in the same sciences there, this will not

 

      happen.

 

                I will skip that and focus on where we

 

      are.  My assessment is this.  This is not rocket

 

      science, this is straightforward and simple for

 

      those who have been in this area for quite some

 

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

 

      education training.

 

                There are signs that I see.  The phone

 

                                                               133

 

      call this morning from a major company, and, in

 

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

 

      or not.  Their positive experience with the

 

      development report already in a four-cycle review

 

      is a good example that our folks can manage this

 

      process well, but consistency and making sure it

 

      happens consistently is a challenge.

 

                So, the immediate education need that I

 

      see going through the PAT training, and so forth.

 

      Now, for a broader training is introduction to

 

      statistical quality control.  That is fundamental.

 

      We are missing that, and I emphasize it is not

 

      biostatistics.  There is a distinction between

 

      statistical quality control and biostatistics,

 

      hypothesis testing, and where we keep missing that.

 

                I meet with the PhRMA Statistics Group,

 

      and so forth.  It comes back we are missing the

 

      quality dimension here.  We have to understand

 

      variability.  We have to focus and put training

 

      programs on molecular pharmaceutics and

 

      biopharmaceutics.

 

                We have gone to the molecular level in

 

                                                               134

 

      most of those areas.  Engineering principles is a

 

      key aspect.  Risk assessment and communication

 

      would be a program.  All of this will come together

 

      quite nicely with the ICH Q8/Q9 training program

 

      itself, but I think we would like to add some

 

      additional training.

 

                I know Ken has been working with us quite

 

      constantly on focusing on what the right questions

 

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

 

      a more formal training program on all of these

 

      aspects.

 

                I would like to say systems approach and

 

      thinking is important.  Unfortunately, most of the

 

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

 

      programs actually takes us away from systems

 

      thinking to focus as narrowly as possible, and so

 

      forth, but in an applied area in the regulatory

 

      setting like this, systems thinking is important.

 

                Unfortunately, I go and talk about Deming,

 

      many people in the industry have never heard of the

 

      name Deming. I think we need to introduce people to

 

      Deming and others.

 

                                                               135

 

                Team building and communication will be

 

      the key.

 

                I will end my talk saying that coming

 

      together is a beginning, keeping together is

 

      progress, working together is success.

 

                The GMP Initiative brought us together.  I

 

      think the PAT Initiative took us further, and a

 

      smaller group is actually making progress.

 

                I am fairly positive.  I went through a

 

      quite depressive cycle in some of the challenges,

 

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

 

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

 

      rather quickly.

 

                          Policy Gap Analysis

 

                MR. CLARK:  I am going to deliver a talk

 

      about something of the policy gap, but what I will

 

      really be talking about is a guidance development

 

      process and some changes that we have done there.

 

      My talk will be quite pedestrian and quite short,

 

      which I hope to be some relief.

 

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

 

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

 

                                                               136

 

      were this agenda an application, we would be found

 

      in violation of an agreement, and if we showed a

 

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

 

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

 

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

 

      the path of righteousness, and such.

 

                I want to point out that somebody

 

      mentioned earlier today about failure, about

 

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

 

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

 

      to point stayed in my mind.

 

                One of the things that we will be talking

 

      about in Yokohama in Q8 is what role that plays in

 

      an application, and to help define a design space,

 

      is there a place for us to use that in an

 

      evaluation of an application, and if you have

 

      determined where your system fails, can that offer

 

      you some relief as to where you operate.  I wanted

 

      to just bring that point up as I start in this

 

      speech.

 

                In the GMPs for the 21st Century, some CMC

 

      guidance documents are out of synchronization with

 

                                                               137

 

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

 

      guidance process that developed these documents has

 

      strong and weak points, and one of the main

 

      strengths of this is the technical input from our

 

      staff, from our review staff.

 

                One of our weaknesses is in the

 

      decisionmaking process for actually moving the

 

      documents from step to step and getting them out,

 

      which causes it to be very slow.

 

                I would like to really dwell on the

 

      strength.  One of the things that we need to take

 

      away from our previous guidance development process

 

      is that these deliberative processes are well

 

      meaning, and these people are highly trained, and

 

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

 

      they are trying to articulate the things that are

 

      on their minds and how to get applications approved

 

      in the best way.

 

                They may have become proscriptive and

 

      prescriptive, but that is not a failure in their

 

      attempts to articulate the best way to get an

 

      application approved.

 

                                                               138

 

                We believe that there may be a better way

 

      to articulate that point, and obviously, with the

 

      rollout, and you compare the rollout to the

 

      documents that we have on our guidance page, there

 

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

 

      familiar with the two sets of documents, so I will

 

      move on from there.

 

                The draft cycling that was the weak point,

 

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

 

      you will see that there was a CMCCC working group

 

      assigned from a CMCCC committee body.  That CMCCC

 

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

 

      the body for now, to develop a document.

 

                They would go ahead and develop a

 

      document, and this might take six months, and it

 

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

 

      but they would develop an articulation of the areas

 

      of interest for that document.

 

                They would then proceed to take that and

 

      go through each review team, through some kind of a

 

      hierarchical structure in the organization.  Those

 

      review teams would then have comments, not unlike

 

                                                               139

 

      the public comment system, and those comments would

 

      go back to that review group, and they would

 

      redraft the document, which might take another year

 

      or two.

 

                Because these people are not dedicated to

 

      that task, they are also reviewing drugs, they are

 

      also involved in a lot of other efforts like ACPS,

 

      and they are also involved in guidance development.

 

                So, they go back to the review teams, goes

 

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

 

      to the working group or back up to the committee

 

      for review, and then from  the committee, it goes

 

      to an OPS editor.

 

                Now, that process, those steps might take

 

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

 

      editors then have a go at making sure that the

 

      legal language is current with the desires of our

 

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

 

      edit if their suggestions are minimal, and so on.

 

                If not, if the suggestions are strong and

 

      get into the body of the document to a large

 

      degree, it might actually go right back up to the

 

                                                               140

 

      body and have to go all through all that stuff I

 

      just mentioned all over again, and were I

 

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

 

      but I won't.

 

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

 

      goes out to public comment.  Then, you have public

 

      comments dockets come back.  You might have 1,000

 

      comments if you are lucky. It might be a couple

 

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

 

      foot high if you are not so lucky.

 

                If that happens, well, it will happen,

 

      then, you have to catalog all those comments,

 

      address each of them somehow, address them by

 

      groups or individually, and then if you have to

 

      make substantial changes to the document in order

 

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

 

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

 

      through this whole thing again.

 

                I think you can understand that that could

 

      be a laborious process, and that is my excuse for

 

      why guidances take so long to get out of the

 

      Agency.

 

                                                               141

 

                When somebody says that a guidance will be

 

      available soon, they may think it is going to be

 

      available soon, because they think they are near

 

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

 

      not understand is that there is an iteration that

 

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

 

      have been dealing with over the years.

 

                This is a slide that puts into words some

 

      of what we just discussed, but it also points out

 

      that there is a rapid change in FDA thinking over