FOOD AND DRUG ADMINISTRATION


































                      Wednesday, October 20, 2004


                               8:30 a.m.










                CDER Advisory Committee Conference Room

                           5630 Fishers Lane

                          Rockville, Maryland





      Arthur H. Kibbe, Ph.D., Chair

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



      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


      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.



      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.



                            C O N T E N T S



      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



                      C O N T E N T S (Continued)




      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




                         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




      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.




      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




                Thank you.


                DR. KIBBE:  Thank you.




                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.




                    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




                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.




                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




                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




      measure something, you cannot improve it.  So,


      measurement and metrics would be a key factor of




                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




                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




      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




                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




      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




                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




      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




      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




      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




                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




      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




                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




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




      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




      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




                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,




      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




                DR. KIBBE:  Anybody else would like to


      make a comment?


                DR. SINGPURWALLA:  Yes.  I repeatedly hear




      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






                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




                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




                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




      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




      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.




                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




      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




      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




                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




      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




      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




      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




      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




                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




                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




                The second point is it look from a




      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




      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






                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.




                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




                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




                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




      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




                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




      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.




                DR. SINGPURWALLA:  Mr. Chairman, I have a


      few thoughts.  Ajaz, back.




                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




      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




      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




      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




                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




      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




                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




      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.




                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




                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




      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




      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




      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,




      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




      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




                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




      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




      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




      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,




      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.




                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




                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




      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




      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




                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




      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




                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




      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




      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




      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




                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.




                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




      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




                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




      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.




                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




      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




                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




                So, we need to go in the direction of what


      is truly a harmonized or internationalized


      regulation of quality.  We need to somehow control




      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






                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.




                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.




                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.




                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




                How many of us would be willing at the


      ends of our days to become virtual us in a virtual




                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




      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




      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?




                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




                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




      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






                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




      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




                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,




                Does anybody want to throw a few cents'


      worth in while we are prognosticating?




                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




      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




                   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




      scientific gaps, and Jon will identify some of the


      policy gaps and how we intend to sort of fill those




                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




                DR. KIBBE:  That means you are passing the


      ball to Helen.


                DR. HUSSAIN:  Yes.


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




                      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






                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




                DR. KIBBE:  There appears to be a gap in


      the computational problem, too.




                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.




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


      about the organizational gaps and reaching the




      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




                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.




                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




      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




                There is a difference in products and


      regulatory requirements and review processes.  We




      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




                Actually, we have chemists in 18 different




      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




                Part of what is adding to that workload


      and to the backlog is that we get too many




      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




      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. 




      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




      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




                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




      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




      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






                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 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




      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




      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.




                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




                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






                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




                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




      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




                The last thing I have on here--and




      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




      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




      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




      the Review folks in those inspections, and also a


      better way of getting the findings from those




                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




                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




      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




                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




                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




      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.




                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




      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




      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,






                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.




                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




                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.




      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




                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.




                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




      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




      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




                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




      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.




                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




                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




                Product specifications based on




      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




                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




      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




      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




                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




      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




                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




      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




      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




      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.




                So, initial conditions for screening


      experiments and then experimental conditions are


      then dependent on this prior knowledge and risk




                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




      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




                What is a robust design?  A robust design


      is not removing the source of variability, but


      designing a process or product to reduce the




                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




      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




                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




      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




      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




      should be why, why do you need that dissolution




                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




      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




                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




      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




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




                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




      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




                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




      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




                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




      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




                So, say what you do to FDA, is your


      pharmaceutical development information that you




      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




      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,




      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




                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




      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




                We have gone to the molecular level in




      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




                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.




                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




      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




                In the GMPs for the 21st Century, some CMC


      guidance documents are out of synchronization with




      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.




                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




      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




      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






                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