1

 

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

                CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

 

 

 

             ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE

 

 

                               Volume II

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                         Wednesday, May 4, 2005

 

                               8:30 a.m.

 

 

 

 

 

 

 

 

                CDER Advisory Committee Conference Room

                           5630 Fishers Lane

                          Rockville, Maryland

                                                                 2

 

                              PARTICIPANTS

 

      Charles Cooney, Ph.D., Chair

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

 

      MEMBERS

 

      Patrick P. DeLuca, Ph.D.

      Paul H. Fackler, Ph.D., Industry Representative

      Michael S. Korczynski, Ph.D.

      Gerald P. Migliaccio (Industry Representative)

      Kenneth R. Morris, Ph.D.

      Marc Swadener, Ed.D. (Consumer Representative)

      Cynthia R.D. Selassie, Ph.D.

      Nozer Singpurwalla, Ph.D.

 

      SPECIAL GOVERNMENT EMPLOYEES

 

      Carol Gloff, Ph.D.

      Arthur Kibbe, Ph.D.

      Thomas P. Layloff, Jr., Ph.D.

      Marvin C. Meyer, Ph.D.

 

      FDA

 

      Gary Buehler, R.Ph.

      Kathleen A. Clouse, Ph.D.

      Jerry Collins, Ph.D.

      Ajaz Hussain, Ph.D.

      Robert Lionberger, Ph.D.

      Robert O'Neill, Ph.D.

      Keith O. Webber, Ph.D.

      Helen Winkle

      Lawrence Yu, Ph.D.

                                                                 3

 

                            C O N T E N T S

 

                                                              PAGE

      Call to Order

                Charles Cooney, Ph.D.                            5

 

      Conflict of Interest Statement

                Hilda Scharen, M.S.                              5

 

      Parametric Tolerance Interval Test for Dose

        Content Uniformity

 

         Current Update on the Working Group

                Robert O'Neill, Ph.D.                            8

 

      Quality-by-Design and Pharmaceutical Equivalence

 

         Topic Introduction

                Ajaz Hussain, Ph.D.                             10

 

         Using Product Development Information to

           Extend Biopharmaceutics Classification

           System-based Biowaivers

                Ajaz Hussain, Ph.D.                             30

 

         Using Product Development Information to Address

           the Challenge of Highly Variable Drugs

                Lawrence Yu, Ph.D.                              79

 

         Using Product Development Information to Support

           Establishing Therapeutic Equivalence of

           Topical Products

                Robert Lionberger, Ph.D.                       140

 

         Summary of Plan

                Ajaz Hussain, Ph.D.                            169

 

      Committee Discussion and Recommendations                 192

 

      Criteria for Establishing a Working Group for

        Review and Assessment of OPS Research Programs

 

         CBER Peer Review Process for

           Researchers/Reviewers

                Kathleen A. Clouse, Ph.D.                      221

 

         CDER Peer Review Research

                Jerry Collins, Ph.D.                           243

                                                                 4

 

                      C O N T E N T S (Continued)

                                                              PAGE

 

      Committee Discussion and Recommendations                 258

 

      Conclusion and Summary Remarks

                Ajaz Hussain, Ph.D.                            273

                Helen Winkle                                   280

 

                                                                 5

 

                         P R O C E E D I N G S

 

                             Call to Order

 

                DR. COONEY:  I would like to call the

 

      meeting to order this morning.

 

                     Conflict of Interest Statement

 

                MS. SCHAREN:  Good morning.  I am going to

 

      be going through the Conflict of Interest

 

      Statement.

 

                The Food and Drug Administration has

 

      prepared general matters waivers for the following

 

      Special Government Employees:  Drs. Charles Cooney,

 

      Patrick DeLuca, Carol Gloff, Arthur Kibbe, Michael

 

      Korczynski, Thomas Layloff, Marvin Meyer, Kenneth

 

      Morris, Nozer Singpurwalla, who are attending

 

      today's meeting of the Pharmaceutical Science

 

      Advisory Committee, to:

 

                1.  Receive an update on current

 

      activities of the Parametric Tolerance Interval

 

      Level PTIT Work Group;

 

                2.  Discuss and provide comments on the

 

      general topic of considerations for assessment of

 

      pharmaceutical equivalence and product design;

 

                3.  Discuss criteria for establishing a

 

      working group for review and assessment of Office

 

      of Pharmaceutical Science Research Programs.

 

                                                                 6

 

                The meeting is being held by the Center

 

      for Drug Evaluation and Research.  Unlike issues

 

      before a committee in which a particular product is

 

      discussed, issues of broader applicability, such as

 

      the topic of today's meeting, involve many

 

      industrial sponsors and academic institutions.

 

                The committee members have been screened

 

      for their financial interests as they may apply to

 

      the general topic at hand.  Because general topics

 

      impact so many institutions, it is not practical to

 

      recite all potential conflicts of interest as they

 

      apply to each member.

 

                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 Dr. Gerald Migliaccio are

 

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      participating in this meeting as non-voting

 

      industry representatives acting on behalf of

 

      regulated industry.  Dr. Fackler's and Dr.

 

      Migliaccio's role on this committee is to represent

 

      industry interests in general, and not any other

 

      one particular company.  Dr. Fackler is employed by

 

      Teva Pharmaceuticals, Dr. Migliaccio is employed by

 

      Pfizer.

 

                In the event that the discussions involve

 

      any other products or firms not already on the

 

      agenda for which FDA participants have a financial

 

      interest, the participants' involvement and their

 

      exclusion will be noted for the record.

 

                With respect to all other participants, we

 

      ask in the interest of fairness that they address

 

      any current or previous financial involvement with

 

      any firm whose product they may wish to comment

 

      upon.

 

                Thank you.

 

                DR. COONEY:  Thank you, Hilda.

 

                I am Charles Cooney, the chairman of the

 

      committee, and will preside over the schedule

 

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      today.  We have several topics on the schedule.

 

      The first of these is a current update of the

 

      working group Parametric Tolerance Interval Test

 

      for Dose Content Uniformity by Robert O'Neill, who

 

      I believe has just come in.

 

                 Parametric Tolerance Interval Test for

 

                        Dose Content Uniformity

 

                  Current Update on the Working Group

 

                DR. O'NEILL:  I am here to just update you

 

      on what we promised you from the last meeting on

 

      October 19th.  As you know, there is a technical

 

      working group that has been put together with folks

 

      from FDA and folks from the IPAC group.

 

                We have been working diligently since

 

      then.  We thought we would have some

 

      recommendations for you today.  We do not, but we

 

      have had approximately eight get-togethers, five

 

      telecons and three face-to-face meetings, the last

 

      of which was about a week, week and a half ago.

 

                What those discussions have been about is

 

      the agreement of the statistical formulations of

 

      the problem. There were a number of discussions

 

                                                                 9

 

      regarding the coverage probability and symmetry of

 

      coverage, off-target operating characteristic curve

 

      agreements, and things of that nature.

 

                There has been some computer programs that

 

      have been shared back and forth, validation of each

 

      other's methods, and I believe there is now

 

      agreement on that aspect of it and that the working

 

      group is turning towards the agreement on where the

 

      operating characteristic curve ought to be placed

 

      and how it might handle certain particular

 

      situations, particularly off-target means.

 

                That is essentially where we are.  I think

 

      everyone is optimistic that probably the next time

 

      we report to you, that there will be actual

 

      recommendations for you to respond to, but that is

 

      essentially where we are right now.

 

                I would be willing to take any questions

 

      if you have any.

 

                DR. COONEY:  Any comments or questions

 

      from the Committee?  If not, thank you very much

 

      and we look forward to the next step.

 

                DR. O'NEILL:  Thank you.

 

                DR. COONEY:  We will immediately begin

 

      with the second topic this morning, which is

 

      Quality-by-Design and Pharmaceutical Equivalence,

 

                                                                10

 

      to be introduced by Ajaz Hussain.

 

            Quality-by-Design and Pharmaceutical Equivalence

 

                           Topic Introduction

 

                DR. HUSSAIN:  Good morning.  I would like

 

      to introduce to you the Topic No. 2,

 

      Quality-by-Design and Pharmaceutical Equivalence.

 

      We believe we have an opportunity here to explore

 

      and what we plan to do with you is to share some of

 

      our initial thoughts and hopefully, engage the

 

      Advisory Committee in discussion to help us make

 

      sure we are on the right track.

 

                In many ways, the discussions continue

 

      from yesterday where, in essence, we are looking at

 

      opportunities that have been created and

 

      re-examining some of our current policies and to

 

      see how we can realize opportunities to move

 

      towards a desired state.

 

                I would like to put this in the context of

 

      moving from a reactive to a proactive decision

 

                                                                11

 

      system for pharmaceutical quality, and recognizing

 

      that this is only a journey, not a destination.  I

 

      think in the world of continuous learning and

 

      continuous improvement, really, continuous learning

 

      is your destination in some ways.

 

                I think over the last four years, we have

 

      focused on discussing some of the opportunities in

 

      general, but if I look at some of the reactive

 

      examples on this chart, yesterday, in some way, we

 

      talked about testing to document quality, repeating

 

      deviations in our specification investigations, and

 

      in some ways we will start focusing on the other

 

      aspects of prior approval supplement for process

 

      optimization and continuous improvement, multiple

 

      CMC review cycles, but more importantly, I think,

 

      how can we leverage the opportunity of quality by

 

      design for demonstrating therapeutic equivalence of

 

      generic products.

 

                I think we struggle often in this arena,

 

      and we have struggled and unable to sort of find

 

      ways of approving generic products and the degree

 

      of complexity has increased such as topical

 

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      products and inhalation products, and so forth, so

 

      how can we leverage the pharmaceutical development

 

      information to seek out ways to find mechanisms for

 

      approving complex generic products, I think is a

 

      topic.

 

                I think the proactive examples I think is

 

      quality by design and real time release, right

 

      first time, process optimization and continuous

 

      improvement within the facilities quality system.

 

                But I think in some ways, today, we will

 

      focus on single CMC review cycle, less so, but I

 

      think quality-by- design approach for demonstrating

 

      therapeutic equivalence of generic products would

 

      be a focus.

 

                Therapeutic equivalence.  The definition

 

      from the Orange Book is as follows.  Drug products

 

      are considered to be therapeutic equivalents only

 

      if they are pharmaceutical equivalents and if they

 

      can be expected to have the same clinical effect

 

      and safety profile when administered to patients

 

      under conditions specified in the labeling.

 

                Pharmaceutical equivalent products are

 

                                                                13

 

      drug products are considered to be pharmaceutical

 

      equivalents if they contain the same active

 

      ingredients, are of the same dosage form, route of

 

      administration, and are identical in strength or

 

      concentration.

 

                Pharmaceutically equivalent drug products

 

      are formulated to contain the same amount of active

 

      ingredient in the same dosage form  and to meet the

 

      same or compendial or other applicable standards of

 

      strength, quality, purity, and identity, but they

 

      may differ in characteristics such as shape,

 

      scoring configuration, release mechanisms,

 

      packaging, excipients, expiration time, and within

 

      certain limits, labeling.

 

                So, I think we have certain flexibility

 

      built into the issue of pharmaceutical equivalence,

 

      and one of the desired states is to leverage that

 

      and to say that we want to set specification based

 

      on mechanistic understanding, so if you have a

 

      different mechanism, that is perfectly fine, but

 

      then you set your specification on that.

 

                The discussion yesterday was not to force

 

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      the generic to a particular specification, but

 

      recognize that as part of that.

 

                Today, I think I would like to put this in

 

      the context of risk, uncertainty, and variability,

 

      and I think that framework will help us think more

 

      clearly about the issues.

 

                FDA classifies as therapeutically

 

      equivalent those products:  That are approved safe

 

      and effective, so you have to have a reference

 

      product which is safe and effective, and has an

 

      approved pharmaceutical equivalents against the

 

      repetition of that, and are bioequivalent, that

 

      they do not present a known or potential

 

      bioequivalence problem, and they meet an acceptable

 

      in vitro standard, or if they do present such a

 

      known or potential problem, they are shown to meet

 

      an appropriate bioequivalence standard.

 

                In absence of pharmaceutical development

 

      information and quality-by-design aspect, we have

 

      to assume that they present a bioproblem, so we

 

      often go to the second bullet in most cases; are

 

      adequately labeled, and are manufactured in

 

                                                                15

 

      compliance to Current Good Manufacturing Practice

 

      regulations.

 

                In a sense, the last four years, our

 

      initiative goals have been to focus on

 

      science-based, risk-based approaches, and there are

 

      certain challenges I think in our articulation of

 

      the problem today.

 

                I want to sort of share with you what the

 

      challenges might be.

 

                Risk-based scientific decisions on

 

      pharmaceutical quality is clearly our goal.  Risk

 

      is a combination of the probability of occurrence

 

      of harm and the severity of that harm.  The reason

 

      for focusing on that is an aspect that I feel that

 

      we often get entangled in and unable to really

 

      articulate the problem carefully.

 

                Uncertainty with respect to severity of

 

      harm and/or probability of its occurrence and their

 

      modulating factors is that challenge that we face,

 

      what are the critical quality attributes, and what

 

      is an acceptable variability.

 

                I have argued, and I think I will ask the

 

                                                                16

 

      Committee to think about this, is my argument sort

 

      of correct, in some ways, in the current decision

 

      system which tends to be reactive, one contributing

 

      factor for the reactive decision system is we

 

      confound uncertainty, variability, and risk.

 

                This is, by nature, how we develop our

 

      products to a large degree.  The current paradigm

 

      for product and process development tends to do

 

      this, because our entire effort in new drug

 

      development, for example, is focus on safety and

 

      efficacy of a molecule, but we use a product to

 

      achieve that.

 

                The connection between product quality and

 

      the clinical is generally focused on the molecules

 

      rather than the product.  So, that is a part of

 

      this discussion.

 

                Often intrinsic safety and efficacy of a

 

      new molecular entity is confounded with its product

 

      and manufacturing process just by the nature of our

 

      product development and process itself.

 

                We have multifactorial aspects of

 

      pharmaceutical products and manufacturing

 

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      processes, and there is increasing complexity, and

 

      if we can find a way to articulate our problem more

 

      carefully, this may help moving forward more

 

      quickly.

 

                Establishing constraints based on prior

 

      knowledge and limited development experiments that

 

      are done in the development cycle.

 

                What I have argued is there is a need to

 

      entangle or, as I call it, de-convolute

 

      uncertainty, variability, and risk, and then to

 

      achieve truly a scientific integration of these for

 

      quality decisions, how we set specification.

 

                Yesterday, for example, what we proposed

 

      was an assessment of variability, example, begins R

 

      and R.  That is an attempt to start characterizing

 

      the variability and attempt to start teasing out

 

      what comes from what.

 

                This may appear to be paradoxical, and it

 

      probably is without the concept of quality by

 

      design, and that sort of links to Dr. Woodcock's

 

      paper that we talked about.

 

                Let me illustrate that.  When we approve a

 

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      new drug application, we bring assessment of all

 

      the disciplines to bear on a decision which says

 

      the risk to benefit ratio of this proposed drug

 

      product is acceptable when used in accordance to

 

      the label.  That is the pivotal decision criteria.

 

                Now, that is based on the pivotal clinical

 

      trials along with the toxicology, and along with

 

      all the studies that go along with that, but the

 

      pivotal clinical trials play the major role there.

 

                What do we use for the pivotal clinical

 

      trials?  We use a product, and we often do not have

 

      the opportunity or do not have the intent to gauge

 

      whether the product is modulating the safety and

 

      efficacy of the molecule beyond that of exposure

 

      less the bioavailability.

 

                So, from that aspect, the quality of the

 

      product has to be built in before you get into the

 

      clinical trials, otherwise you confound the

 

      clinical trials with quality problems, and

 

      actually, I will illustrate one example in my

 

      second presentation of that.

 

                As that happens, then, the product is

 

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      approved and then manufacturing is transferred to

 

      production and you have seven production lots, but

 

      that goes to the patient population.

 

                So, you see the disconnect between

 

      pharmaceutical quality or product quality.  I am

 

      not talking about the safety and efficacy of a

 

      molecule, I am talking about how a product

 

      modulates that.

 

                So, in many ways, if I look at drug

 

      development program, and here is an illustration of

 

      that, this is actually a real case study.  The only

 

      difference I have here is I have a line that made

 

      it more linear.  That is the only change I did, but

 

      here is a development program.

 

                The initial formulation was a capsule.

 

      Then, they went to a table, wet granulation tablet,

 

      and each star is a bioequivalent study.  So, they

 

      qualified that change from capsule to tablet using

 

      a bioequivalent study.  Then, they add a film coat,

 

      then, change the site of manufacture of the drug

 

      substance, and so forth.

 

                You see the changes that were occurring in

 

                                                                20

 

      this drug development program, some before clinical

 

      trials were initiated, some during the clinical

 

      trials, site changes, and so forth.

 

                But this company actually qualified, what

 

      they call bridging studies using a bioequivalence

 

      trial.  Towards the end of the review time, to

 

      qualify and bridge the clinical trial, pivotal

 

      clinical trial material with the to-be-marketed

 

      product, they opted to use multiple-dose studies of

 

      the traditional thing, and that failed at the last

 

      minute.  Actually, it didn't fail, it just failed

 

      to establish bioequivalence, so they went back and

 

      actually repeated the study with a larger number of

 

      subjects, but it delayed them.

 

                The point here is all these changes are

 

      being qualified on the basis of their traditional

 

      bioequivalence trial.  In new NDAs, we generally

 

      see from 3 to 6 clinical bioequivalence studies,

 

      and that was our number.

 

                Here is a number that was shared with us

 

      by Jack Cook sometime, this is the year 2000, about

 

      7 per approved compound.  In a sense, if I look

 

                                                                21

 

      at--this is Gary Buehler's slide--I think in many

 

      ways, the difference between the generic drug

 

      approval and the new drug approval is minimal when

 

      it comes to bioequivalence trial.

 

                In many ways, we use bioequivalence to

 

      gauge information which we don't have in the NDA,

 

      but in reality, in some cases, it is simply the two

 

      are comparable.  So, from that aspect, I think when

 

      I look at oral products, immediate release

 

      products, and here is my demarcation in an attempt

 

      to sort of categorize what is uncertainty, what is

 

      variability, and what is risk.

 

                The goal of our generic drug approval

 

      process is to approve a generic product.  An

 

      approved product is expected to have the same

 

      clinical effect and safety profile when

 

      administered to patients under conditions specified

 

      in the labeling.

 

                Based on the previous slide, I have shown

 

      the characteristics of this decision system is,

 

      one, the first one, the product must be

 

      pharmaceutically equivalent, and here the questions

 

                                                                22

 

      are has the applicant demonstrated that it's the

 

      same active, identical amount, same dosage form,

 

      route of administration, and so forth, identity,

 

      strength, quality, purity.

 

                So, that is an assessment process of how

 

      good the identical methods are and how good they

 

      have qualified, so it's a knowledge-based decision,

 

      there is an uncertainty aspect associated with

 

      that.

 

                Then, we have to define acceptable

 

      variability for that product, and we rely on the

 

      compendial or other standards to do that.

 

                The risk in this case, I am talking about

 

      risk from a clinical perspective, is the prior

 

      knowledge that come from NDA.

 

                Need for bioequivalence assessment for

 

      oral products is that next question, and again the

 

      same words from the Orange Book is if you do not

 

      present a known or potential bioequivalence

 

      problem, acceptable in vitro standard is fine.  But

 

      you saw the debate with dissolution, we often don't

 

      go there, we often go to a bioequivalence study.

 

                If you go to in vitro standard compendial

 

      dissolution test method, if you go to a

 

      bioequivalence standard, then, the acceptable

 

                                                                23

 

      variability is our bioequivalence standard, 90

 

      percent confidence interval for test or reference

 

      ratio for rate and extent of absorption is within

 

      80 to 125 percent.

 

                It has to be adequately labeled and

 

      manufactured in conformance to cGMPs, and in that

 

      case, acceptable variability is what we tolerate in

 

      terms of deviation or specifications, and so forth.

 

                So, that is one way of looking at trying

 

      to partition uncertainty, variability, and risk, so

 

      that we can formulate the right questions.

 

                Clearly, I think the quality-by-design

 

      thinking is intended to focus on the intended use,

 

      and design is about doing things consciously.  I

 

      showed this slide to you before.

 

                I think what we would like to consider is

 

      in the context of pre- and post-approval changes,

 

      generic drugs, and even extending that to the

 

      concept of follow-on protein pharmaceuticals, the

 

                                                                24

 

      primary goal of a scientific decision framework--I

 

      am not talking with a regulatory process--the

 

      decision criteria that we bring, need to understand

 

      the complexity and uncertainty, but the decision

 

      process should be consistent.

 

                I think that is the fundamental basis that

 

      we work under.  Furthermore, I think our goal is

 

      also to identify and eliminate unnecessary human

 

      and animal testing for this decision framework,

 

      keeping in mind that most bioequivalent studies are

 

      done in normal healthy subject volunteers, new

 

      drugs and so forth.

 

                If we can avoid exposing normal healthy

 

      subject human volunteers, it is desirable, and that

 

      is part of the regulation.  I will share that

 

      regulation with you.

 

                So, Topic 2 today, the premise that we had

 

      in mind was that a quality-by-design approach via

 

      pharmaceutical development information can

 

      potentially provide an excellent means to address a

 

      number of challenges previously discussed at ACPS

 

      meetings without complete or satisfactory

 

                                                                25

 

      resolution, for example, bioequivalence of highly

 

      variable drugs, bio-in-equivalence criteria,

 

      pharmaceutical and therapeutic equipment of locally

 

      acting drug products, such as topical products.

 

                Today, Lawrence will bring his thoughts to

 

      you, and these are our preliminary thoughts, and I

 

      think we just wanted to put our preliminary

 

      thoughts on the table to engage you and engage the

 

      community to help us think about this, so that as

 

      we spend our time thinking about this, we already

 

      have some feedback and we are also on the right

 

      track.

 

                Rob Lionberger will come back.  He

 

      presented a decision tree to you before, but he

 

      will recast that decision tree for topical products

 

      in the context of quality-by-design.

 

                Yesterday, we focused on dissolution

 

      testing, and as the past chair of the BCS Working

 

      Group, I took it upon myself to sort of go back and

 

      re-examine what were my personal thoughts and what

 

      held me back to make the recommendations that you

 

      see in the guidance and see how we can recast that

 

                                                                26

 

      discussion into the quality-by-design thinking, so

 

      that I can take this discussion and give that as a

 

      recommendation to the current Technical Committee

 

      on Biopharmaceutical Classification System.

 

                Again, as I said, these are initial

 

      thoughts, and our goal is to engage you in a debate

 

      and discussion to hopefully give us some

 

      perspective are we on the right track.  The three

 

      topics today are:

 

                How can pharmaceutical development

 

      information help to extend the applications of

 

      BCS-based waivers of in-vivo studies for immediate

 

      release products?

 

                How can pharmaceutical development

 

      information be utilized to address the challenges

 

      of highly variable drugs?

 

                How do we use this to establish

 

      therapeutic equivalence of topical products?

 

                Those are the three topics that we would

 

      like to present, and the general question is are we

 

      on the right track, but then more detailed

 

      recommendations on how we should proceed with these

 

                                                                27

 

      three topics or other topics that we should have

 

      considered instead of this.

 

                So, that is the Topic 2.

 

                DR. COONEY:  Thank you, Ajaz.

 

                We might pause for a moment for any

 

      questions particularly around clarification of

 

      these opening comments from the committee.  Art?

 

                DR. KIBBE:  The question I always struggle

 

      with is how do we define highly variable drugs.

 

      Are we defining them in clinical outcomes, because

 

      then the dosage form might not be involved in it at

 

      all.

 

                DR. HUSSAIN:  The definition hinges on the

 

      bioequivalence drug, the variability that we

 

      estimate from the bioequivalence drug.

 

                DR. KIBBE:  But that could be a function

 

      of intersubject variability, subject population

 

      selection, and have nothing at all to do or

 

      minimally to do with the actual product that you

 

      are making.

 

                DR. HUSSAIN:  That is the discussion

 

      Lawrence will bring to you, so if you hold that

 

                                                                28

 

      question for Lawrence.

 

                DR. KIBBE:  Thank you.

 

                DR. COONEY:  Ken?

 

                DR. MORRIS:  The two comments is that the

 

      Topic 2 premise, the other part of that premise is

 

      that the proper development information is being

 

      generated at the companies which, of course, you

 

      have limited control over, and that is being

 

      shared, just as a caveat.

 

                DR. COONEY:  Nozer?

 

                DR. SINGPURWALLA:  Two comments.  Slide

 

      No. 7.

 

                DR. HUSSAIN:  I am sorry, I don't have

 

      numbers.

 

                DR. SINGPURWALLA:  I know.  Components of

 

      the Challenge.  The second bullet.  That second

 

      bullet is wrongly worded, it has to be changed, and

 

      I will tell you why.

 

                The more important reason is you, on your

 

      eight bullet, are talking about confounding of

 

      uncertainty, variability, and risk.  They should

 

      not be confounded.  Who is confounding them and

 

                                                                29

 

      why?

 

                DR. HUSSAIN:  The current system has a

 

      tendency to do that.  That is what I mean.

 

                DR. SINGPURWALLA:  But that simply means

 

      that the system is not educated enough, because

 

      variability is the cause of uncertainty, is one of

 

      the causes of uncertainty, and risk is a measure,

 

      is a way to measure uncertainty and its

 

      consequence.

 

                So, why is there so much confusion about

 

      these very elementary ideas in the industry and

 

      perhaps in the pharmaceutical community?

 

                DR. HUSSAIN:  I don't know how to answer

 

      that.

 

                DR. SINGPURWALLA:  Well, they need to be

 

      trained, educated.

 

                DR. HUSSAIN:  But let me propose this in

 

      the sense, uncertainty is not risk.

 

                DR. SINGPURWALLA:  I agree with you.  I

 

      agree with what you are saying completely.  What I

 

      am asking is, what is the cause of this confusion,

 

      and it is so easy to remove this confusion?

 

                DR. HUSSAIN:  I understand the concern you

 

      are expressing, and my premise is for years we have

 

      not utilized the pharmaceutical development, and we

 

                                                                30

 

      have treated that as an art rather than a science,

 

      and that is the way to get away from that

 

      confusion.  So, that is the premise.

 

                DR. COONEY:  Any other comments at this

 

      point?  We will have ample opportunity for further

 

      discussion.

 

                Using Product Development Information to

 

                Extend Biopharmaceutics Classification

 

                        System-Based Biowaivers

 

                DR. HUSSAIN:  Let me go on to the

 

      Biopharmaceutics Classification System.  In

 

      preparing for this presentation, I actually went

 

      back and reviewed all the publications that have

 

      occurred in this arena in this discipline, in this

 

      topic area for the last five years, and there has

 

      been a tremendous number of progress in this area.

 

                For example, more recently, Professor Les

 

      Benet's article was published on how you can

 

      actually start predicting metabolism, and so forth,

 

                                                                31

 

      and how you can sort of add that additional

 

      dimension.

 

                There has been a paper published in Pharm

 

      Research on quantitative instead of, you know,

 

      rigid boundaries, and so forth.

 

                But instead of sort of trying to summarize

 

      the progression signs, what I wanted to do was to

 

      go back and re-examine my own thoughts that were

 

      expressed to the Advisory Committee in the year

 

      2000, so I am actually going to repeat an old

 

      presentation, but in light of what we have learned

 

      in the last four years.

 

                My goal here is to share with you some of

 

      the concerns we had when we proposed the BCS-based

 

      waiver guidance in the year 2000, and to what

 

      extent those concerns remain, and to what extent

 

      quality-by-design may be able to alleviate some of

 

      this concern, and the discussion with you, I intend

 

      to use that as recommendation to the current

 

      Technical Committee on BCS.  So, that is the game

 

      plan.

 

                This is an old presentation with some

 

                                                                32

 

      minor modification.  When I had made this

 

      presentation, I was completely focused on risk, and

 

      the title was "Biopharmaceutics Classification

 

      System: A Risk Management Tool."

 

                In light of the learning that I at least

 

      personally had, I want to sort of bring in the

 

      uncertainty and variability components to this.

 

                Since this is a presentation, probably my

 

      last presentation on the BCS topic before I handed

 

      over the reins of responsibility to Lawrence and

 

      Mehul, the new BCS Technical Committee was formed,

 

      when Helen asked me to move to OPS and the PAT

 

      process got started, so my focus went to PAT for a

 

      reason which connects back to this one.

 

                So, this BCS Technical Committee has been

 

      in place under the leadership of Lawrence and

 

      Mehul, and they have been diligently addressing a

 

      number of implementation issues trying to

 

      coordinate all the submissions, and so forth, and

 

      there has been significant activity on this

 

      guidance on the new drug side, very little, if any,

 

      on the generic side.

 

                You also heard from Mehul the database is

 

      now almost ready, is being audited, database and

 

      prospective research for extensions, links to PQRI

 

                                                                33

 

      and FIP, but the PQRI program really didn't take

 

      off, and our thoughts were we wanted to explore

 

      extension of BCS-based biowaivers to Class III and

 

      Class II drugs.

 

                Further research at the FDA, which we

 

      completed, and we did extend the BCS-based

 

      biowaivers to "fed" bioequivalence studies, and

 

      that was part of the thing, and that work was done

 

      with collaboration with Tennessee.

 

                Continuing education initiatives and

 

      practitioners and public, and the group has been

 

      busy.  International harmonization was an aspect,

 

      but to the extent the definition of high solubility

 

      and rapid dissolution, we got into ICH Q6A, the

 

      European Guideline also adopted much of the BCS

 

      recommendation to some extent.  There are certain

 

      differences, though, it is not fully harmonized.

 

                With that as a background, let me trace

 

      for you the evolution of the recommendations in the

 

                                                                34

 

      BCS guidance that we released in the year 2000.

 

                Regulatory Bioequivalence: An Overview,

 

      from my perspective, this is a graphical

 

      representation of our regulation.

 

                If you look at the dosage form that we

 

      deal with, solutions, suspensions, chewable

 

      tablets, conventional tablets, and modified release

 

      products, for solutions, we consider bioequivalence

 

      essentially is self-evident, bioavailability is

 

      self-evident, and biowaivers are granted, condition

 

      being excipients do not alter absorption, and that

 

      is an assessment based on historical data.

 

                For any product that contains drug in a

 

      solid form, we have a concern, and for pre-1962

 

      drugs, we call DESI drugs, in vivo evaluation for

 

      bio-problem, that was the original biopharm

 

      classification system, if you really look at it,

 

      that had many of the elements of therapeutic index,

 

      PK, the solubility, and so forth.

 

                For post-1962 drugs, generally, in vivo,

 

      some exceptions with IVIVC.  Then, we introduced a

 

      SUPAC-IR guideline in '95, and we introduced the

 

                                                                35

 

      elements of BCS guidance, BCS system in that to

 

      give a waiver for minor changes and moderate

 

      changes that Mehul talked to you about yesterday.

 

                For modified release, we don't have a

 

      classification system, bioequivalence has to be

 

      demonstrated in vivo with the exception of SUPAC

 

      modified release for within a product.  If you have

 

      in vitro bioequivalence, you can make changes.

 

      Again, Mehul summarized that.

 

                I want to trace back the discussion to a

 

      bioequivalence hearing, which I did not attend.  I

 

      was just graduating in '86, but I was connected to

 

      this because I made the slides of a number of

 

      people who presented here, so I knew what was

 

      happening.

 

                This was a pivotal discussion and I think

 

      set the stage for what evolved as bioequivalence

 

      standard.  There were two comments that I want to

 

      share with you.

 

                One was Dr. Bob Temple.  He said, after

 

      the end of this discussion, it seems sensible to

 

      think that swallowing something that turns into a

 

                                                                36

 

      solution rapidly would be difficult to lead to

 

      differences from one product to another.

 

                So, the clinicians were arguing you don't

 

      need biostudies for everything.  Arnold Beckett had

 

      made that argument years at that time, so he said

 

      you shouldn't go with in vivo for everything, but

 

      we did.

 

                Milo Gibaldi, an eminent pharmacokinetic

 

      professor, "I have learned that there is no support

 

      here for attempting to provide such assurance

 

      solely with in vitro data."  So, that was a pivotal

 

      aspect, I think, and I went back and sort of tried

 

      to examine the thoughts and the concerns that were

 

      expressed at that session.

 

                The other aspect that I do want to put on

 

      the table is need to reduce our reliance on in vivo

 

      bioequivalence studies.  Why?  Ethical reasons.  21

 

      CFR 320.25 says, "No unnecessary human research

 

      should be done." Science continues to provide new

 

      methods to identify and eliminate unnecessary in

 

      vivo bioequivalence studies.

 

                Focus on prevention, "building quality

 

                                                                37

 

      into products - right first time."  So you see the

 

      PAT initiative and how this will connect to that

 

      was in the thought process and why we aggressively

 

      moved in that direction, "right first time," I used

 

      before Pfizer.

 

                Time and cost of drug development and

 

      review is a key, because if you see that we have

 

      three to six bioequivalent studies in our NDAs.  We

 

      actually at some point said we don't even review

 

      some of those because they are redundant, so why

 

      expose normal healthy subjects to a new drug which

 

      is under development with all the risks associated

 

      with that.

 

                So, prior to SUPAC-IR/BCS, in vivo

 

      bioequivalence assessments to justify a majority of

 

      manufacturing changes.  So, this was a significant

 

      hurdle, and that changed.  In the SUPAC-IR guidance

 

      in '95, we brought in the classification system and

 

      provided a tiered approach for changes based on in

 

      vitro.

 

                For example, highly soluble, highly

 

      permeable drug, the critical processes for gastric

 

                                                                38

 

      emptying, dissolution is not likely, and

 

      dissolution is not likely to be rate limiting, but

 

      we said 0.1 single point, 85 percent, and so forth.

 

                So, you can see that for each class, we

 

      recommended a tiered approach for waiver of

 

      biostudies for minor changes, and so forth.  We

 

      excluded the Narrow Therapeutic Index drugs from

 

      waiver consideration, but we never defined what

 

      narrow therapeutic index was, and we still haven't.

 

                The guidance in 2000 really extended that

 

      and put that as a waiver for first time approval,

 

      and also provided the methods to classify your

 

      drug, and so forth.  The pivotal recommendation in

 

      that was waiver for in vivo bioequivalence studies.

 

                I do want to stop here and say the title

 

      of this guidance was debated to the nth degree

 

      before we agreed on this internally.  The word

 

      "waiver" was to signify that we want an in vivo

 

      study for everything that is in solid, so the title

 

      was very carefully chosen to reflect that.

 

                Anyway, it's waiver for in vivo

 

      bioequivalence studies is recommended for a solid

 

                                                                39

 

      oral test product that exhibit rapid and similar in

 

      vitro dissolution under specified conditions to an

 

      approved reference product when the following

 

      conditions are satisfied:  products are

 

      pharmaceutically equivalent, drug substance is

 

      highly soluble and highly permeable and is not

 

      considered to have a narrow therapeutic range and

 

      excipients used are not likely to affect drug

 

      absorption.

 

                The class membership, the boundaries that

 

      you see, which are rigid, high solubility, the

 

      highest dose strength is soluble in less than or

 

      equal to 250 ml of aqueous buffers over the pH

 

      range that we had 1 to 6.5 or so, whatever that

 

      thing is I forgot.

 

                The reason for 250 ml is the glass of

 

      water that we take when we do a bioequivalence

 

      study.  High permeability, the extent of absorption

 

      in humans is determined to be greater than 90

 

      percent.

 

                Rapid dissolution is 85 percent dissolves

 

      within 30 minutes in three different conditions,

 

                                                                40

 

      HCL, pH 4.5 and 6.8 buffers using traditional

 

      settings of dissolution apparatus.

 

                Now, clearly, I had approached this as a

 

      risk to bio-in-equivalence because since we started

 

      with the premise that you needed bioequivalence

 

      trials for approval of changes, and so forth, so

 

      the risk factor for me was the proposal the

 

      recommendations should not result in

 

      bio-in-equivalence.

 

                The risk factors that we had in mind were

 

      clearly manufacturing changes, poor process

 

      capability, high between and within batch

 

      variability, but the thing we focused on, reliance

 

      on in vitro dissolution tests and how reliable that

 

      is, single point specification, sampling,

 

      predictability were the issues.

 

                Clearly, the other factors were there,

 

      deficiencies in BE study design, Type II errors,

 

      and so forth.

 

                Now, assessment of risk, what is the risk

 

      of bio-in-equivalence between two pharmaceutically

 

      equivalent products when in vitro dissolution test

 

                                                                41

 

      comparisons are used for regulatory decisions?

 

      That was the question we asked.

 

                What is the likelihood of occurrence and

 

      the severity of the consequences?

 

                Severity was not meeting the

 

      bioequivalence criteria was unacceptable, but what

 

      was the likelihood, so we needed some information

 

      on that.

 

                Regulatory decision, whether or not the

 

      risks are such that the project can be pursued with

 

      or without additional arrangements to mitigate the

 

      risk, and clearly, acceptability of the decision,

 

      is the decision acceptable to society?  This took

 

      four years.

 

                We started working on this in '96, and if

 

      you think I was busy with the PAT presentations

 

      around the globe, that is exactly had to do the

 

      same thing for this one, too, because the mind-set,

 

      the paradigm was so entrenched in the old system.

 

                Professor Gordon Amidon spent some time

 

      with us, he and I.  I had the luxury of having the

 

      biopharm document room right outside my office in

 

                                                                42

 

      the Parklawn Building, so we went through a number

 

      of applications, about 160 applications at that

 

      point, to get a sense of what is happening.

 

                Roughly, what we found was on the new drug

 

      side only, because we have failed studies or we

 

      have all the studies submitted on the generic side,

 

      we couldn't use that database because you just have

 

      the passing studies in there.

 

                So, we looked at the new drug side and

 

      said when does dissolution signal

 

      bio-in-equivalence or does not signal

 

      bio-in-equivalence.  What we found there was

 

      generally, you see big differences in dissolution,

 

      no difference in blood levels.

 

                But, on the other hand, there were signals

 

      that dissolution fails to signal bio-in-equivalence

 

      about 30 percent of the time, and we wanted to ask

 

      why.

 

                So, minimizing risk of bio-in-equivalence,

 

      does in vitro dissolution process emulate in vivo

 

      dissolution process in vitro and in vivo?  Dosage

 

      form disintegration, dissolution, and stability

 

                                                                43

 

      were the concern.

 

                The gastrointestinal fluid volume,

 

      composition, and hydrodynamic conditions were the

 

      concern, and clearly, I think one thing which was

 

      pivotal for the oral discriminating part was the

 

      surface tension, and that could have been picked

 

      up.

 

                Residence time in the stomach and small

 

      intestine were an issue, so we did a lot of

 

      analysis actually of gastric emptying and what

 

      factors affect gastric emptying, and so forth.

 

                Impact of excipient differences on GI

 

      physiology and drug bioavailability were the

 

      questions.

 

                The key question was how well this

 

      emulates in vivo, because this is our standard

 

      dissolution test.

 

                This was a cartoon that I prepared and to

 

      take a look at typical physiologic parameters in a

 

      single dose fasting BE study.  We had fairly good

 

      estimates of the gastric fluid plus the 8 ounces of

 

      water.  We knew what the gastric pH range is

 

                                                                44

 

      generally in the normal subject.

 

                We had the information on the gastric

 

      emptying time, which is highly variable, but

 

      approximately T50 is 15 percent.  The permeability

 

      is low, and that was an advantage in the stomach

 

      compared to small intestine, the surface tension is

 

      lower, and clearly, volumes in the small intestine

 

      were uncertain, and pH, and so forth, and the

 

      permeability was high.  Hydrodynamics was a big

 

      question in our minds.

 

                Lawrence summarized to you the debates

 

      that we have had for dissolution for the last 30

 

      years, and that dissolution tests are over

 

      discriminating, on one hand, and in the USP, the

 

      statement that products that dissolve about 70

 

      percent in 45 minutes have no medically relevant

 

      bioequivalence problems, what was the basis of

 

      that.

 

                Dissolution tests are not sufficient to

 

      assure bioequivalence, and demonstration of IVIVC

 

      is necessary, but when you do that, product

 

      specific, so those are two sides of the debate.

 

                I showed you this slide of the problems

 

      with the dissolution tests of false positives and

 

      false negatives, but then we also looked at things

 

                                                                45

 

      that we made decisions on.

 

                Here is a product.  The generic product

 

      was Product B.  We actually withdrew this product

 

      from the market after approval.  This is a pre-62

 

      drugs, it was approved on the basis of dissolution,

 

      meeting the USP specification criteria.

 

                This was a pre-62 drug, one of the older

 

      drugs, and we had a challenge from the innovator,

 

      which is Product A, that the generic is not

 

      bioequivalent, and that was the basis at which we

 

      had withdrawn this product, Product B, from the

 

      market.

 

                The Cmax, you can see is clearly high, but

 

      in many ways, Product B was more reliable, less

 

      variable, and it was more modern technology, but

 

      the constraints on us is you have to be equal, if

 

      not better.

 

                Here are examples of where there were real

 

      dissolution impacts on in vivo absorption.  Here is

 

                                                                46

 

      a weak acid where the initial formulation for

 

      clinical was capsule.  They went to

 

      wet-granulation, and the to-be-marketed was a

 

      direction compression with dicalcium phosphate, and

 

      the dissolution in this case was Q17 30 minutes in

 

      simulated intestinal fluid.

 

                That's the criss-cross you see if you do

 

      acid in alkaline conditions, you don't distinguish

 

      that, and this had to be reformulated.  But this

 

      was I think in my mind a signal that we probably

 

      are designing our products for dissolution rather

 

      than the intended use.

 

                I wanted to walk through this with you,

 

      and that was one of the reasons for the

 

      quality-by-design thinking.

 

                Here is a Drug X.  This is actually a

 

      clinical study, 100 mg dose, so it's a highly

 

      soluble drug by all definition.  It's a weak base

 

      exhibits a sharp decline in solubility with

 

      increasing pH above 3.

 

                Now, the clinical trial material in this

 

      case was wet granulation, drug particle size of D50

 

                                                                47

 

      of 80 microns, and this was a concern, because our

 

      particle size specification was very crude.  I mean

 

      what does D50 percent give me.  We had lactose,

 

      microcrystalline cellulose, and so forth.  You see

 

      that formulation there.

 

                But the point to focus there is the

 

      dissolution 0.1 normal HCL was 65 percent in 15

 

      minutes and 100 percent in 20 minutes.

 

      Disintegration time was 10 minutes.

 

                The way I had presented this, the

 

      to-be-marketed was the formulation of direct

 

      compression, but actually the wet granulation in

 

      this case was a U.S. formulation, a formulation

 

      using U.S. clinical trials, and the European

 

      clinical trials were done with the to-be-marketed,

 

      and we had to bridge those together.

 

                The to-be-marketed formulation, you can

 

      see what happened here.  Direction compression,

 

      drug particle size of 300 microns, dicalcium

 

      phosphate, and so forth, and the dissolution is

 

      more rapid now, 0.1 normal HCL - 85 percent in 15

 

      minutes, about 95 percent in 20 minutes, so the

 

                                                                48

 

      initial dissolution burst is very rapid,

 

      disintegration time is 1 minute.

 

                Clinical product exhibits poor dissolution

 

      at 7.4. Can you imagine, I mean this is a BCS Class

 

      I drug.  The Cmax or the rate or the exposure of

 

      this in terms of p concentration for the

 

      to-be-marketed formulation in this case was half,

 

      so you see half the blood levels in terms of

 

      height.  So, it simply was signal that if you don't

 

      get the physicochemical properties of drug

 

      understood, you will have these problems.

 

                So, in vitro and in vivo dissolution,

 

      dissolution methods evolved over the last 30 years.

 

      The year 2000, I said there were reproducible test

 

      methods for lot-to-lot quality assurance, so you

 

      can imagine my surprise of the calibration, which I

 

      was not aware of at that time.

 

                The dissolution media volume and

 

      composition selected to maintain "sink" conditions.

 

      In vivo dissolution is a complex process, and you

 

      have to consider pH profile, bile concentration,

 

      motility patterns, and so forth.

 

                In vivo, the "sink" condition is created

 

      due to intestinal permeability, and this was a

 

      contention, which Lawrence and others, we recently

 

                                                                49

 

      published to show how permeability actually impacts

 

      in vivo dissolution, so we have published on this

 

      now already.

 

                I will talk to you about in vitro-in vivo

 

      correlation.  The formulation specificity of IVIVC

 

      has been known since 1997.  This is drug

 

      spironolactone from a publication in J. Pharm

 

      Science in '97.

 

                So, you can see a change in particle size.

 

      You may have a correlation, but a change in

 

      particle size could be outside that.  So, a

 

      correlation itself why this formulation specific

 

      has to be really brought into context.

 

                So, reliance on current dissolution

 

      practice can pose an unacceptable level of risk

 

      from bio-in-equivalence perspective.  Compared to

 

      high solubility drugs, risk is higher for low

 

      solubility drugs.

 

                Products with slow or extended dissolution

 

                                                                50

 

      profiles pose a higher risk.  The dissolution is

 

      rate limiting.

 

                So, in a sense, we wanted to use

 

      dissolution test only to rule out that dissolution

 

      is not rate limiting.  So, that was the basis for

 

      our thought process.  So, we constructed a rapid

 

      dissolution criteria for that purpose.  We did not

 

      want to use dissolution tests for bioavailable

 

      decisions if there was a hint that dissolution is

 

      rate limiting.

 

                Potential for significant differences

 

      between in vivo and in vitro "sink" conditions

 

      higher for low permeability drugs, which we had to

 

      prove later on with a simulation study that

 

      Lawrence did.

 

                Now, to establish a boundary for rapid

 

      dissolution, we simply postulated that since

 

      gastric mucosa does not have high permeability to

 

      drugs, you have a 15-minute time, so you can take

 

      advantage of that.

 

                So, if the dissolution is rapid, then,

 

      much of it is complete before it empties into the

 

                                                                51

 

      small intestine where you have high permeability.

 

      So, in a sense, a very rapidly dissolving drug will

 

      behave essentially like a solution, and it does.

 

                So, here is a snapshot of dissolution

 

      versus AUC and Cmax ratios and the bioequivalence

 

      goalpost of a drug metoprolol.  The reason I did

 

      not take the name off here, because this is already

 

      an ACPS presentation, it is already on the website.

 

                So, you can see a solution versus all the

 

      other formulations that we have approved, generic

 

      and innovator, plus there are research

 

      formulations, which we deliberately made to be very

 

      slowly dissolving.

 

                You see that essentially, for the most

 

      part, the slope is zero.  We then did extensive

 

      simulation work to establish that if in vivo

 

      dissolution is rapid, as a function of different

 

      gastric emptying as a function of mean intestinal

 

      transit time, you are not likely to see a

 

      difference between solution and a tablet, and that

 

      was the basis for our 85 percent and 30 minute in

 

      vitro criteria for rapid dissolution, but we did

 

                                                                52

 

      not apply that to low permeability drugs because of

 

      the risk factors that we felt were coming from

 

      excipients.

 

                The question we asked was is the current

 

      approach for evaluating excipients for decisions

 

      related to biowaiver for oral solutions sufficient.

 

      That is the database I have.

 

                There were hints that the excipient

 

      effects were not fully appreciated.  For example,

 

      there was a study by Ian Wyling's group where you

 

      could show mannitol, 2.3 grams of mannitol clearly

 

      had a big impact on bioavailability of cimetidine,

 

      a low permeability drug, and on the other hand,

 

      Fassihi had shown that a high permeability drug had

 

      minimal impact of sorbitol, even 10 grams of

 

      sorbitol.

 

                So, that was a hint, and we actually

 

      conducted a study at the University of Tennessee,

 

      and we have now completed that study, even getting

 

      to a mechanistic basis for generalizing the

 

      permeability effect to other excipients, is to test

 

      this out.

 

                Metoprolol was our boundary drug for high

 

      permeability, so we did a study with ranitidine and

 

      metoprolol, and we did a crossover study in

 

                                                                53

 

      replicate design to get an estimate of subject, the

 

      formulation interaction also.

 

                So, it is a very simple formulation.  You

 

      have your drug.  You have sucrose or sorbitol, and

 

      you have 15 ml of water.  That is the simplest

 

      study.

 

                What we found--I will just show you a

 

      picture--just a confirmation for a low permeability

 

      drug like ranitidine, a dramatic effect.

 

                Now we have completed the study of the

 

      dose response, the amount of sorbitol that triggers

 

      this is about 1.2 grams.  For metoprolol, the Cmax

 

      was affected, but not to the same extent.  AUC was

 

      not.

 

                In addition, there were a tremendous

 

      amount of information coming out of other excipient

 

      effects on transporters, and so forth.  So, this

 

      was an evolving issue at that time, and it

 

      continues to be evolving issue, and methodologies

 

                                                                54

 

      were being proposed of in vitro evaluation of this.

 

      I won't get into that.

 

                But we also did an extensive evaluation of

 

      excipients and what we found was I think in most

 

      cases, excipients that are used in solid dosage

 

      form really do not have a significant impact, but

 

      the way we had to evaluate that was comparing the

 

      differences in formulation that we have approved,

 

      like, for example, verapamil, and so forth.

 

                But the risk factor was excipients.  Is

 

      the current approach for evaluating excipients for

 

      decisions related to biowaiver of oral solutions

 

      sufficient?  Well, I think we left the question

 

      there.

 

                For BCS-based biowaivers, a higher

 

      standard was adopted by limiting biowaivers to

 

      highly permeable drugs. Excipients used in solid

 

      oral products are less likely to impact drug

 

      absorption compared to liquid oral products,

 

      because it was simply the volume and amount in

 

      there.

 

                For example, we had products on the market

 

                                                                55

 

      that contains 23 grams of sorbitol in one dose, so

 

      you can see cross interaction possibly.

 

                High permeability attribute reduces the

 

      risk of bio-in-equivalence, decreased small

 

      intestinal residence time by osmotic pressure,

 

      because low permeability generally have a tendency

 

      to be absorbed in small segments of the intestine.

 

                Clearly, on the other hand, the boundary

 

      that we chose for high permeability to be 90,

 

      because there are other surfactants, and so forth,

 

      that could increase permeability, so if you set

 

      your boundary at 90, there is no risk of failing.

 

                There were other examples.  There were so

 

      many examples that we had not really paid attention

 

      to.  Here is a submission--not a submission--this

 

      is a graph that a student of mine sent me from a

 

      company, and they have seen such effect.

 

                Here is a drug, a tablet and a solution.

 

      The solution has almost half the bioavailability of

 

      a tablet, so you can see that, with sorbitol or

 

      mannitol for a low permeability drug, it can have

 

      lower bioavailability.

 

                So, that was the basis that we came up

 

      with the recommendations and the boundaries for the

 

      BCS classification system that gave the basis for

 

                                                                56

 

      waiver for new drug applications.

 

                So, Class I drug, you have jejunal

 

      permeability. This was our research that we

 

      classified the number of drugs, and the volume of

 

      water required to dissolve the dose on the x axis.

 

      Class I dissolution in vivo is not likely to be

 

      rate limiting, and well characterized excipients.

 

      So, dissolution itself is likely to be rapid

 

      inherently, and then we can rely on in vitro

 

      dissolution for that purpose.

 

                Class II dissolution is likely to be rate

 

      determining and complex in vivo dissolution, and

 

      solubilization process, so no, not going there.

 

                Class III was where the debate was.  Some

 

      hesitation with the use of current dissolution

 

      test, because the site specific absorption was a

 

      concern, and excipients.

 

                Class IV was generally problem drugs with

 

      in vitro dissolution may not be reliable.

 

                So, that was the basis for our

 

      recommendations.

 

                So, wrapping up, in terms of quality

 

      design thinking, what can we do now?  If I

 

      summarize my concerns, one major concern was if we

 

      went towards a dissolution-based method, people

 

                                                                57

 

      will design products for dissolution rather than

 

      the intended use was a concern, and that example

 

      sort of illustrates that, the one to-be-marketed

 

      difference, that was a concern.

 

                So, I wanted to feel comfortable having

 

      some formulation assessment as part of this

 

      extension.  Clearly, I think excipients and the

 

      transporters, all were evolving issues at that

 

      time.  There is a lot more information available

 

      now than we had.

 

                So, in quality-by-design thinking, you

 

      really have focus on what are the critical

 

      variables that affect dissolution, and these are

 

      easily identifiable especially for immediate

 

      release dosage form.

 

                You easily can start thinking about

 

                                                                58

 

      excipients and what their impact might be on

 

      solubilization, and so forth, and Lawrence himself

 

      has done some work in this area, and so forth.

 

                So, with that in mind, what my thoughts

 

      are, in addition to thinking about evaluating the

 

      boundaries themselves, I would like to recommend to

 

      the group that, first of all, BCS should be, and

 

      probably will be, a key, too, in quality-by-design

 

      decision trees that we talked about.

 

                I mean solubility, permeability

 

      characterization has to be a starting point for the

 

      formulation, so clearly, I think we need to build

 

      these concepts in the decision trees we talked to

 

      you about yesterday, but also quality-by-design and

 

      design space with respect to pre- and post-approval

 

      by bridging studies.  Waivers for in vivo studies

 

      based on design space concept, sort of is that

 

      connection to extension concept.

 

                The challenge I think is from a generic

 

      industry perspective, there is a lot of hesitation

 

      to seek for approval, the first time approval, a

 

      biowaiver based on that, concerned with

 

                                                                59

 

      permeability assessment, and so forth.

 

      That concern probably will remain.

 

                It is not a scientific concern, it is a

 

      perceptional concern, it's a regulatory concern,

 

      and so forth, but that doesn't say that you cannot

 

      classify a drug for a generic product after

 

      approval.  The rest of the post-approval changes,

 

      they could be based on that, and that could be

 

      quality by design.

 

                I think those are the key connections that

 

      if the Technical Committee sort of starts building

 

      in, their efforts really get connected to the PAT

 

      and the quality-by-design thinking, so you see the

 

      connections sort of evolved.

 

                Clearly, they have already started

 

      developing in FDA's knowledge base, a knowledge

 

      base.  Drug-excipient interaction, I think is an

 

      increasing issue from chemistry and clinical

 

      pharmacology aspect, and I think you need to start

 

      connecting those dots.

 

                At the same time, drug substance and

 

      formulation variables and clinical performance that

 

                                                                60

 

      Mehul alluded to the variability, but with what is

 

      happening on the clinical side now, with focus on

 

      biomarkers, focus on surrogate markers, and so

 

      forth, I think we need to proactively keep an eye

 

      on that.

 

                I mean this is an evolving issue, but seek

 

      out some connectivity between quality and clinical,

 

      and be available to what is happening at least, and

 

      that is the point I made also to Jurgen yesterday

 

      when he gave his report.

 

                So, with that, let me stop and open it for

 

      discussion.

 

                DR. COONEY:  Thank you, Ajaz.

 

                Comments and questions from the Committee?

 

                DR. MEYER:  While I am formulating my

 

      question, I will ask another one, so I will give

 

      you some time to think.

 

                How confident are you that our knowledge

 

      base on excipients allows a reviewer to sit back

 

      and say, well, it has X, Y, and Z, and therefore,

 

      there is no problem?

 

                DR. HUSSAIN:  Well, I think the

 

                                                                61

 

      traditional excipients for immediate release dosage

 

      forms that we use as formulation aids for process

 

      ability, and so forth, I am fairly confident that

 

      there are very little concern there.

 

                There are other excipients that are

 

      necessary to aid in the dissolution process, such

 

      as surfactants and other aspect.  I think a close

 

      grouping of those would be necessary.  I think if

 

      we collect this information, it will start making

 

      the case, but if you have properties, such as high

 

      solubility, and so forth, you probably would not

 

      need those anyway.

 

                So, I think you can carve out excipients

 

      that we know are not an issue.

 

                DR. COONEY:  If I can just pick up on

 

      Marvin's point for a moment, your initial question

 

      was about knowledge base of the excipients per se,

 

      but it is really the relationship of the excipients

 

      to the drug substance, to the API, that seems to be

 

      the area of uncertainty, and that knowledge, it

 

      seems to me, is much less clear.

 

                DR. HUSSAIN:  If I amy sort of put that in

 

                                                                62

 

      the context, traditional screening experiments that

 

      are done for drug excipient compatibility, may

 

      provide not only information that will be useful

 

      for stability, failure modes of the product, but

 

      also hints about the interactions among excipients

 

      and drugs, how they might have a bearing on

 

      dissolution.

 

                DR. COONEY:  Ken.

 

                DR. MORRIS:  The point you just raised is

 

      the source of my question, as well, since

 

      drug-excipient interactions are typically for

 

      chemical stability.

 

                Is it like particularly for something like

 

      BCS Class III, is it more of the concern that the

 

      interaction with the drug is changing absorption,

 

      or that the interaction of the excipient with the

 

      mucosa or the sites of absorption?

 

                DR. HUSSAIN:  I think they are both

 

      concerns in the sense, but the concerns we had when

 

      we were working on this were more on the impact on

 

      the GI membrane, transporters, and so forth, the

 

      concerns with excipient-drug interactions that

 

                                                                63

 

      might be physicochemical were less of a concern,

 

      because we did not really focus on that aspect.

 

                DR. MORRIS:  That is sort of where I would

 

      assume it, but I just don't know enough biopharm.

 

                DR. HUSSAIN:  The aspect I think is this.

 

      I think the draft guidance that we have issued on

 

      polymorphism, for example, I think is a

 

      concentration there, in the sense what we have said

 

      is you could have a different polymorph, but if you

 

      can design your product well and if it meets the

 

      criteria, it's fine.

 

                So, I think that is the flexibility that

 

      already sort of comes through that, is that ability

 

      to demonstrate that, you can be different, but yet

 

      meet the intended use.

 

                DR. COONEY:  Art, then Marvin.

 

                DR. KIBBE:  This is more complex than we

 

      can handle in one or two days.  The number of

 

      excipients you use exponentially increases the

 

      possibility that one excipient is reacting with

 

      another excipient, that is reacting with the API.

 

                On top of that, the processing of the

 

                                                                64

 

      product changes things.  I mean we know all sorts

 

      of problems with mag. stearate and overblending,

 

      but we know certain issues. The question that

 

      always sits in the back of my mind is we have been

 

      discovering these issues on a regular basis over

 

      the last 20 years, have we discovered them all, and

 

      how can I be naive enough to think I have

 

      discovered them all, and I don't think I have.

 

                So, that gives me a basic uncomfort level

 

      with just waiving stuff when I really want a part

 

      that works in my patients.  So, I am uncomfortable

 

      with that.

 

                I have a question, a substantive question.

 

      If I make a soft gelatin capsule which contains a

 

      solution, is it a solution or is it a capsule?

 

                DR. HUSSAIN:  Capsule.  That's the way it

 

      is.

 

                DR. KIBBE:  On your basic I guess third

 

      slide, I could argue it's solution.

 

                DR. HUSSAIN:  Yes.  That's the aspect, I

 

      think now we can start thinking about those aspects

 

      if you have not done so in the past.

 

                But let me go back to the concern you

 

      raised in the sense, impact of magnesium stearate,

 

      and on dissolution, it is clearly documented.

 

                                                                65

 

      Impact of magnesium stearate on in vivo absorption

 

      has not been done yet.

 

                All the studies we have done, we had no

 

      impact of magnesium stearate on immediate release,

 

      and so forth, on in vivo absorption.  I could not

 

      find a single paper that conclusively tells me that

 

      what we see in vitro, the big difference is

 

      translating in vivo differences.

 

                There are two reasons for that.  One, is

 

      that old study that was published in 1967, J. Pharm

 

      Science, by Professor Newton from the University of

 

      London, where he demonstrated for lithium carbonate

 

      that if you include a very, very small amount, 0.01

 

      percent or 0.001 percent of sodium sulfate in your

 

      formulation, you negate the effect of magnesium

 

      stearate that you see in the solution.

 

                So, that was a hint to me that suggested

 

      that the surface tension differences that we see

 

      between in vivo fluids and in vitro fluids probably

 

                                                                66

 

      are the reason, because all the studies we did at

 

      the University of Maryland, we actually probed this

 

      for a low solubility drug--I am forgetting the name

 

      of the drug--we didn't see in vivo relevance of

 

      that.

 

                So, now that is the reason we have to

 

      start thinking about is risk-based decision to

 

      really understand the behavior of things in vitro,

 

      because one of the concerns that we had earlier was

 

      you see big differences in vitro, how do you know

 

      this will or will not translate.

 

                If quality-by-design, we are thinking, why

 

      is this assessment, then, that provides a basis to

 

      think about it.

 

                DR. KIBBE:  But that argument, I think

 

      would logically lead us to the conclusion that we

 

      have to go to a bioavailability study, we have to

 

      go to a clinical trial.  We can't rely on any of

 

      the standard tests that we do that are surrogates,

 

      because they don't work out, because they either

 

      show a problem that isn't real, or they ignore a

 

      problem that is real.

 

                DR. HUSSAIN:  Right.  That second bullet,

 

      that is what I am really thinking about.  If you

 

      have to qualify your design space, your

 

                                                                67

 

      bioavailability studies, if you are a new drug

 

      applicant, that becomes your test of hypothesis is

 

      to say that we have looked at these are the big

 

      differences we see that has an impact.

 

                So, one category of BCS-based biowaivers

 

      would be SUPAC related where you have demonstrated

 

      this in vivo, and that becomes the basis for that,

 

      and not just rely on in vitro testing and lack of

 

      that information.

 

                So, waiver is an extension of SUPAC in

 

      terms of design space is a bigger opportunity

 

      probably in the quality-by-design thinking.

 

                DR. COONEY:  Marvin.

 

                DR. MEYER:  Ajaz, I think I asked this

 

      question yesterday, and I think you said you were

 

      going to address it and maybe you did and I missed

 

      it, the rigid fixing of the--

 

                DR. HUSSAIN:  Boundaries.

 

                DR. MEYER:  --boundaries.  I really don't

 

                                                                68

 

      have any problem with the rigid definition of high

 

      solubility, high permeability, I mean we have

 

      pretty well nailed that down, but then you have, of

 

      course, if it's soluble in greater or less than or

 

      equal to 250, well, if it's only soluble in 300, is

 

      that really poor solubility, and if it's only 89

 

      percent absorbed, is that really low permeability,

 

      and, if so, does it fall in that 30 percent

 

      probability of failing a product?

 

                How do you deal with--you have to draw the

 

      line, but on the other hand, you draw the line, it

 

      becomes somewhat arbitrary and capricious.

 

                DR. HUSSAIN:  Very good point.  This is I

 

      think an important point because the objective of

 

      this guidance was to make the decision.  This is

 

      the decision.  You meet this, there is no issue.

 

      If you don't meet, you always have an option to

 

      explain, but nobody uses that option.

 

                So, this, in my opinion, is an approach

 

      that we had before.  In the new paradigm, the

 

      decision trees that we developed opens the door in

 

      a sense.  Here, the decision is pre-made, but

 

                                                                69

 

      instead of premaking that decision, how can you

 

      allow your science to drive a decision process that

 

      can justify the recommendations that come, but that

 

      then becomes specific to a company.  It is not a

 

      general guidance.  It is a decision tree to arrive

 

      at a proper decision.

 

                So, that would be an extension concept for

 

      BCS, not a general decision recommendation, which

 

      is what we have been trying to achieve.  It has

 

      changed the boundaries, and so forth.  But to

 

      incorporate that as a decision process, it becomes

 

      demonstrate this, and the decision can be yours

 

      sort of a thing.

 

                DR. MEYER:  So, it's sort of a work in

 

      progress, so to speak.

 

                DR. HUSSAIN:  It's not.  I mean I think

 

      the group has been busy with a number of things,

 

      but this isn't a thing that they could start

 

      thinking about, we have not done so.

 

                DR. COONEY:  Ajaz, if I can get clarity on

 

      that point.  I think the point you just made is

 

      that the decisions on class membership will be

 

                                                                70

 

      integrated into the thinking about the decision

 

      trees.

 

                DR. HUSSAIN:  Yes.

 

                DR. COONEY:  Is that correct?

 

                DR. HUSSAIN:  Definitely.  If you are a

 

      Class I drug and you exhibit the rapid dissolution

 

      with the conditions we have outlined, the decision

 

      is okay.  Anything else, the guidance does not

 

      recommend a waiver.  That's how it is.

 

                Based on what Marvin just suggested, and

 

      what I am formulating that as, this is a decision

 

      for every sponsor right now.  Their design and

 

      process understanding would vary from one end to

 

      the other end, but one way of extending this

 

      concept is not a general decision that this is

 

      where you get the waiver, but to define a decision

 

      tree and how you demonstrate to the degree of

 

      confidence that we need, that waiver would be you

 

      have demonstrated an understanding that the waiver

 

      will be granted.

 

                That will be Class I, that will be Class

 

      II, that will be Class III, so you have different

 

                                                                71

 

      levels of complexity in those, but the signs and

 

      the level of understanding could drive you to that,

 

      but that probably will become a post-approval as

 

      part of the design space.

 

                DR. COONEY:  Tom.

 

                DR. LAYLOFF:  I think I am not confused,

 

      but I don't understand some things like when a drug

 

      goes into the intestinal space, it is bound, not by

 

      water, but probably proteins and various other

 

      things that are present in the medium, and then it

 

      is absorbed through different sites depending on

 

      how it is wrapped in with the rest of the medium,

 

      and that is a drug-specific property, which then

 

      can be affected by an excipient, which might change

 

      the transport site, it may change the structure of

 

      the solution characteristics, is that correct?

 

                DR. HUSSAIN:  No, I think the basic

 

      premise is this, yes, you can have binding, you can

 

      have a number of other complexation reactions, and

 

      so forth, that occur.  Many of those are ionic and

 

      loose, so you establish equilibrium.

 

                For some drugs, you have complexation that

 

                                                                72

 

      really are almost very tight like with calcium and

 

      tetracycline, and so forth, there are a few such

 

      examples, but in this scenario, what we are talking

 

      about are equivalent behavior of the same drug

 

      molecule in two different formulations.

 

                So, if there are intrinsic properties of

 

      the drug molecule itself that will contribute, but

 

      that molecule is the same, that we are dealing with

 

      two formulations.  Now, how do formulations act

 

      with that behavior is a concern.

 

                I will sort of extend that concern to a

 

      paper that we had, a poster that we had, is that of

 

      precipitation.  A weak basis will dissolve very

 

      rapidly in acid conditions, but when they get

 

      emptied, there is a potential for precipitation,

 

      and so forth, and that could be a very complex

 

      process, and the size of the particles, not

 

      precipitation, crystallization may differ based on

 

      the excipients you have and the conditions you

 

      have.

 

                There is a potential that excipients could

 

      impact that.  So, that is generally Class II drugs,

 

                                                                73

 

      that's the boundary for Class I for high solubility

 

      was intended to prevent some of those things from

 

      occurring, too.

 

                DR. LAYLOFF:  Do you think the

 

      complexation and coordination around the drug

 

      substance would actually affect the transport site,

 

      change the site of transport, would change the

 

      properties of the system?

 

                DR. HUSSAIN:  Yes, it is clearly possible,

 

      but unlikely for an immediate release dosage form

 

      with the type of excipients we use.

 

                DR. MORRIS:  You know when I think about,

 

      it sort of makes my head hurt, but when I think

 

      about--

 

                DR. HUSSAIN:  It's complex.

 

                DR. MORRIS:  --the amount of time we spent

 

      working on developing design spaces for the

 

      processing end of things, which as Jerry says, may

 

      be a way off, but still in comparison relatively

 

      simple to the larger problem, is there an

 

      opportunity in the context of using development

 

      data to somehow leverage tox studies to be able to

 

                                                                74

 

      get early reads on, not the tox itself, but in

 

      terms of some of the dynamics that are going on

 

      with the dosage forms?

 

                DR. HUSSAIN:  I have a decision tree,

 

      which I did not present yesterday, but it was part

 

      of the handout.  That decision tree came out of our

 

      AAPS workshop on how to leverage that.  The paper

 

      is published, Diane Burgess [ph], Eric Duffy from

 

      FDA is on it, so it is there in your handout.  I

 

      don't have it in this one.  Take a look at it.

 

                That leverage is every bit of information

 

      coming from Pharm Tox, and so forth, to start

 

      building that case for that.

 

                DR. MORRIS:  For the design of the dosage

 

      form?

 

                DR. HUSSAIN:  Yes, for particle size

 

      dissolution and bioavailability concentration.

 

                DR. COONEY:  Marvin.

 

                DR. MEYER:  Ajaz, when a generic company

 

      sends in their ANDA, it was my understanding that

 

      the generic group does not go back to the NDA to

 

      review the contents of the NDA, so they don't look

 

                                                                75

 

      at the excipients and see which excipients are now

 

      different in the ANDA than were in the NDA product?

 

                DR. HUSSAIN:  I will let Lawrence answer

 

      that, but we do have a process of inactive

 

      ingredient guide that we consult, and so forth.  I

 

      put him on the spot here.

 

                DR. YU:  I guess this morning we talk

 

      about excipients, which emphasize how complex the

 

      process is.  Yes, with advances in molecular

 

      biology, we discovered I even don't know how many

 

      transporters going on.  As far as the PGP, at least

 

      32 and 64 is transporters, however, I want to

 

      emphasize that how those transporters impact

 

      absorption we rarely see in clinical settings.

 

                In other words, we very see excipients

 

      impact on absorption of Drug A, B, C, D, but in

 

      vivo setting, we have very, very few, two or three

 

      publications out there compared to tens of

 

      thousands of publications to show that excipients

 

      impact in vitro.

 

                So, I have to say that we still want to

 

      see more evidence to show the impact of excipients

 

                                                                76

 

      on absorption of drugs in general.

 

                Secondly, while we see the impact exceeds

 

      absorption, we very open to see the unique of some

 

      of the products out there.  The reality for, say,

 

      70 or 60 percent of immediate release products,

 

      people espouse the intensity, use very limited

 

      number of excipients, I would say 10, within 10.

 

      For example, Avacel almost uses the majority of

 

      products.  All those excipients impact, and have

 

      not seen in vitro, as well as in vivo.

 

                Certain, because of those common used

 

      excipients, since we have a sufficient knowledge to

 

      judge whether they are going to impact absorption

 

      or not, will generate and not see the formulations,

 

      however, in very few cases, some cases, we suspect

 

      potential impact of excipients absorption, we will

 

      look into it further before we make any scientific

 

      decisions about approvability of any NDAs.

 

                I hope that answers his question.

 

                DR. HUSSAIN:  The other aspect, just to

 

      build on what Lawrence said, traditionally, the

 

      composition, especially for immediate release, it

 

                                                                77

 

      is hardly any different than the quality.

 

                DR. MEYER:  My real question was do you go

 

      back and look at the NDA to see if Pfizer used

 

      Avacel, and Teva used who knows what, do you make

 

      that comparison, say, well, wait a minute, they are

 

      putting in two things instead of Pfizer's one

 

      thing.

 

                Can that potentially make a difference?

 

      Do you review the NDA product composition?

 

                DR. YU:  Well, certainly, we will review

 

      any scientific literature out there and information

 

      available to us to make the best decisions.

 

                DR. MEYER:  But do you review the NDA?

 

                DR. HUSSAIN:  Marvin, often we don't have

 

      to, because it's in the label.

 

                DR. MEYER:  Well, that's true.  It didn't

 

      used to be.

 

                DR. HUSSAIN:  But definitely, the criteria

 

      there is to look at what has been approved and what

 

      has been used in dosage forms and inactive

 

      ingredient guide, and so forth.

 

                DR. YU:  I guess the answer is as long as

 

                                                                78

 

      are trying to build in the science base or any ANDA

 

      decisions,

 

      we will use any information which is available,

 

      whether scientific literature or not, to us.

 

                DR. COONEY:  Are there any other questions

 

      at the moment?  Thank you, Ajaz.

 

                We are running a bit ahead of schedule.  I

 

      think this would an appropriate time to take a

 

      break for 15 minutes.  We will reconvene at 8 past

 

      10:00 and then begin immediately with Lawrence Yu's

 

      presentation.

 

                [Break.]

 

                DR. COONEY:  I appreciate everyone's

 

      diligence to staying on time.  It has worked very

 

      well.

 

                Lawrence Yu will proceed with a

 

      presentation on Using Product Development

 

      Information to Address the Challenge of Highly

 

      Variable Drugs.

 

                Lawrence.

 

            Using Product Development Information to Address

 

                 the Challenge of Highly Variable Drugs

 

                DR. YU:  The assignment to me today, this

 

      morning, is for me to discuss how to use

 

      pharmaceutical development information to address

 

                                                                79

 

      or potentially address the bioequivalence issues of

 

      highly variable drugs.

 

                Before I go on and talk about how to use

 

      or potentially use the pharmaceutical development

 

      information to highly variable drugs by equivalency

 

      issues, I want to give you a very brief overview or

 

      update what has been happening before.

 

                For highly variable drugs, this is not the

 

      first time, it's the second time we present it to

 

      you.  In the first presentation on April 14th of

 

      2004, we discussed the challenges and the

 

      opportunities for bioequivalence of highly variable

 

      drugs.

 

                At this meeting, the objective was to

 

      explore and define bioequivalence issues of highly

 

      variable drugs, for example, what is called highly

 

      variable drugs and discuss potential solutions to

 

      deal with the bioequivalence of highly variable

 

      drugs.

 

                We invited a number of speakers from

 

      industry, academia to address issues related to

 

      bioequivalence including why the bioequivalence of

 

      highly variable drugs is an issue, highly variable

 

      drugs a source of variability by Gordon Amidon from

 

      the University of Michigan, and the clinical

 

                                                                80

 

      implications of highly variable drugs by Leslie

 

      Benet, and from bioequivalence method include the

 

      skin method by Laszlo, as well as bioequivalence of

 

      highly variable drugs, we had a good discussion at

 

      this meeting.

 

                I want to highlight some of the things

 

      which have been discussed at this meeting,

 

      particularly the slides by Professor Leslie Benet

 

      from the USCSF.  His talk with implications of

 

      highly variable drugs, the argument was why highly

 

      variable drugs are safer.

 

                Specifically, he said for wide therapeutic

 

      index highly variable drugs, we should not have to

 

      study the excessive number of patients to confirm,

 

      to demonstrate that two equivalent products meet

 

      the preset statistical criteria or by equivalent

 

                                                                81

 

      standards.

 

                This is because, by definition, highly

 

      variable approved drugs must have a wide

 

      therapeutic index, otherwise, there have been

 

      significant safety issues and lack of efficacy

 

      during Phase III.

 

                Highly variable narrow therapeutic index

 

      drugs are dropped in Phase II since it is

 

      impossible to prove either efficacy or safety.

 

                Now, for the benefit of some new members

 

      for this committee, I have two slides to briefly

 

      review why this issue, why the one-size-fits-all,

 

      what we are using today.

 

                In order to determine bioequivalence, we

 

      normally define as a rate of bioavailability,

 

      defined as a rate and extent of drug absorption.

 

      Bioequivalence is defined as absence of significant

 

      difference in the rate and extent absorption.

 

                In practice, when we give the drugs

 

      orally, for example, to a healthy volunteer, we

 

      will draw the blood.  We got the plasma

 

      concentration profile.  We are certainly not able

 

                                                                82

 

      to get exactly how much and how fast drug gets

 

      absorbed, therefore, in practice, we use AUC, area

 

      under the curve, to represent extent of absorption.

 

                We use Cmax as a surrogate for the rate of

 

      absorption, certainly in some cases we also look at

 

      Tmax, because indeed, if you look at Tmax and Cmax

 

      here, it represents the rate of absorption.

 

                So, from that, we will define what the

 

      bioequivalence study is passing or not passing.

 

      Basically, the bioequivalence criteria, either

 

      statistical criteria here is 80 to 125 percent.

 

                At this date, that is the

 

      one-size-fits-all regardless drug, drug product,

 

      regardless of therapeutic class, regardless for

 

      anything, that bioequivalence study, you have to

 

      use preset, so-called bioequivalence criteria,

 

      which is 80 to 125 percent.

 

                Now, let's look and explain why the highly

 

      variable drug is an issue.  Let's look at the red

 

      one.  If you use a highly variable or intersubject

 

      variability is high.  Statistical confidence

 

      interval, if you use the same number of subjects,

 

                                                                83

 

      when variability goes higher, the confidence is

 

      going wider.  When confidence gets wider, it

 

      becomes more and more difficult pass the confidence

 

      interval or bioequivalence interval if 80 to 125

 

      percent.

 

                So, that explains when the variability

 

      goes higher, it gets more and more difficult to

 

      pass a study.

 

                On the other side, in order to narrow the

 

      confidence interval, for example, here it is fair

 

      to demonstrate bioequivalence for super red one

 

      here in order to make confidence interval narrower,

 

      you have to use a large number of subjects, because

 

      the higher the variability, the higher the

 

      confidence interval, the higher the number of

 

      subjects in general, the narrower the confidence

 

      interval.

 

                Therefore, for highly variable drugs, you

 

      will have to use higher number of subjects.  Just

 

      to give you example here, for example, normally, we

 

      have a 20 percent or 30 percent intersubject

 

      variability.  You maybe use 18, 24, even sometimes

 

                                                                84

 

      for good product or good drugs, you only need to

 

      use 12, actually, they can pass the bioequivalence

 

      confidence interval.

 

                But this is not always true, because when

 

      the variability goes higher, now, this variability

 

      could be because of a drug, or it could be because

 

      of a product, so think about if variability goes

 

      100 percent--some of you think 100 percent, that is

 

      unrealistic, but we do have a drug, we do have

 

      examples--think about with 100 percent variability,

 

      assume test and the reference, there is 5 percent

 

      difference, you end up it could be 500 or more

 

      subjects, or 300 subjects, so this is certainly a

 

      large number of subjects in order to pass the

 

      bioequivalence study.

 

                So, Leslie argued at the previous meeting,

 

      from the clinical perspective, this is not

 

      necessary.  To give you a real example, these are

 

      slides from Leslie Benet.  Now, you would argue,

 

      you may ask how do we get intersubject variability.

 

                Certainly, you could get this number from

 

      literature or sometimes company conduct a pilot

 

                                                                85

 

      study, get some kind of estimate how many subjects

 

      need to be used to pass the bioequivalence study.

 

                Of course, in this case, based on

 

      intersubject variability, you need to use 300, now

 

      this is the drug.

 

                So, at the previous meeting, when we

 

      present the issue to you, and also we present some

 

      of the possible potential solutions including

 

      widening the confidence interval.  Now, that is

 

      very straightforward.  You said by confidence 80 to

 

      125 is too narrow for highly variable drugs, and

 

      your intuitive thinking is just widening the

 

      confidence interval, that is one of the potential

 

      solutions.

 

                Another solution is a scaling approach, in

 

      other words, based on the variability of reference

 

      list product, reference list drugs, and calculate,

 

      use statistical approaches to calculate the

 

      confidence interval, then, to determine whether the

 

      study is passing or not.

 

                Obviously, I have to say this.  The active

 

      approach because the confidence interval too wide

 

                                                                86

 

      in order for the study to pass, so let's widening

 

      the standards.

 

                You came in and asked to do that, that

 

      certainly the scaling approach, we ought to

 

      carefully look into, the Committee suggested--a

 

      quote here--"the need to understanding where the

 

      variability originated.  The members added that

 

      prior knowledge of all biostudies may help set more

 

      appropriate specifications or criteria to make

 

      decisions.

 

                So, you suggest that we have to understand

 

      the origin of the variability.  Now, to look at the

 

      mechanistic understanding of variability for drug

 

      substance obviously is the same, reference list

 

      product and the generic product, or any other

 

      product, but the potential difference could be

 

      formulation.  Certainly, the generic products could

 

      be narrower or could be wider, the variability.

 

                We believe at this point, in order to

 

      understand the origin of the variability, that

 

      pharmaceutical development report, or

 

      pharmaceutical development information can help us

 

                                                                87

 

      understand the source of variability, can help us

 

      make rigid scientific evaluation.

 

                Now, in order to see the utility of

 

      pharmaceutical development report to evaluation or

 

      reviews of NDAs, let me go back and review some of

 

      the basic fundamentals or the premises for ANDA

 

      approvals.

 

                Ajaz has mentioned about therapeutic

 

      equivalence. Basically, the products are considered

 

      to be therapeutic equivalents only if they are

 

      approved as safe and effective, they are

 

      pharmaceutically equivalent, they are

 

      bioequivalent, adequately labeled, and manufactured

 

      according to cGMP.

 

                Now, here, I want to emphasize the

 

      pharmaceutical equivalence.  When we define

 

      pharmaceutical equivalence, we basically have the

 

      same active ingredients, obvious.  I know we are

 

      managing about pharmaceutical solid polymorphism,

 

      which was presented to you two years ago, has a

 

      drugs guidance out there and published by FDA in

 

      December of 2004.

 

                You have to be same dosage form, same

 

      route of administration, and identical in strength

 

      and concentration, and may differ the other

 

                                                                88

 

      characteristics, such as shape, excipients,

 

      packaging, and so on, and so forth.

 

                Now, under the same dosage form, I think

 

      what the complexity of dosage form is particularly.

 

      Yes, I would say several decades ago, that dosage

 

      form is reasonably simple and in most cases I would

 

      say the immediate release product or solutions.

 

                Certainly, with advances of pharmaceutic

 

      industry and the pharmaceutic technologies,

 

      so-called dosage form gets more and more complex,

 

      and we now have the soft gel capsules, we have

 

      ricin [?] product, we have inhersion [?] product,

 

      presents additional challenge to us in terms to

 

      make scientific decisions, in terms of make

 

      scientific evaluations.

 

                We therefore would believe a

 

      pharmaceutical development report,

 

      quality-by-design, designed to be equivalent,

 

      become more and more significant in this regard.

 

                Why does pharmaceutical equivalence

 

      matter?  Because of user experience and

 

      expectations.  Then, bioequivalence test is

 

      normally conducted in healthy subjects.  Certainly,

 

      we have assumption that equivalence in healthy

 

      subjects equals equivalence in patients.  Now, we

 

                                                                89

 

      have many, many generic products out there which

 

      are safe, which is a high quality, which are

 

      effective, which is the equivalent to the reference

 

      list product.

 

                So, certainly, we have tremendous

 

      experience with that, and certainly the

 

      pharmaceutical equivalence presents more and more,

 

      become because you want to make sure the data from

 

      the healthy volunteer does the equivalent in

 

      patient, and against novel drug delivery systems

 

      presents a challenge.

 

                That is why we want to use more and more

 

      pharmaceutical development approach to make a

 

      judgment, pharmaceutical development information to

 

      make a scientific judgment.

 

                Highly variable drugs very often have, as

 

                                                                90

 

      I mentioned, a wide therapeutic index, and the

 

      clinical trials of reference list product have

 

      established the acceptable level of variability,

 

      because I said otherwise, these highly variable

 

      drugs, a big window index, they will be dropped in

 

      Phase II.

 

                So, under an ideal situation, you will

 

      think about variabilities very high, so you will

 

      think it should be easier to pass, easier to design

 

      equivalent product simply because they are so wide,

 

      the target is wide, so it is easier for you to

 

      pass.

 

                Obviously, as I said before, if you use

 

      the preset 80 to 125 bioequivalence confidence

 

      interval, it is not the case.  While we explore our

 

      tentative approaches to deal with the

 

      bioequivalency issues, certainly, the design issues

 

      come out.

 

                So, now, how do we deal with

 

      pharmaceutical development for highly variable

 

      drugs?  Obviously, sponsor need to understand what

 

      are reference products supposed to do with origin

 

                                                                91

 

      of variability, and the purpose of design can be

 

      equivalent, and to evaluate and to verify the

 

      design and hopefully, in the future, use the

 

      bioequivalent study design for highly variable

 

      drugs.

 

                So, we put more emphasis on design in this

 

      regard to establish pharmaceutical equivalence, in

 

      order to establish therapeutic equivalence, which

 

      will be more appropriate.

 

                While we are looking for shared

 

      information for generics with us, there is a reason

 

      for doing that, not only for evaluation for highly

 

      variable drugs, certainly for pharmaceutical

 

      development is required.  It's one of the CTD

 

      format.  It is also outlined in ICH Q8, although

 

      they do not apply to us, but I think some

 

      principles should apply to generic industry also.

 

                Also, more significantly, OGD question

 

      based on review.  Now, this is still a work in

 

      progress, but I want to share some questions, I

 

      think it is important to ask to share.

 

                What is the formulation intended to do? 

 

                                                                92

 

      What mechanism does it use to accomplish this?

 

      Were any other formulation alternatives

 

      investigated and how did they perform?  Is the

 

      formulation design consistent with the dosage form

 

      classification in the label?

 

                So, those questions will help us get

 

      information about a pharmaceutical product, the

 

      report will help us, pharmaceutical product design

 

      and development, make more sound and appropriate

 

      scientific determination or evaluation.

 

                The question often comes up, why do we

 

      need to provide those things to the FDA?  That

 

      again is a quality-by-design paradigm, and

 

      pharmaceutical development report is where you

 

      demonstrate the drug is highly variable.

 

                Now, this demonstrate not necessarily to

 

      study, but you certainly use any source available

 

      to show why this drug or drug product is highly

 

      variable, and may use a different criteria other

 

      than 80 to 125 percent confidence interval.

 

                Also, the pharmaceutical development is

 

      where you justify equivalence of design, why do you

 

                                                                93

 

      think the product which you designed is equivalent

 

      to the reference list product.

 

                During the discussion, the members ask

 

      whether it is drug or drug product.  Now, for

 

      example, Product A, the variability is the active

 

      ingredient into exceptions, so formulation design

 

      could be rapid release, so demonstrated by

 

      dissolution comparison under physiologically

 

      relevant conditions, if this is BCS Class I drug,

 

      which is highly soluble, highly permeable, even

 

      though they are highly variable, you may still

 

      require biowaiver, otherwise, you will have to

 

      conduct some bioequivalence studies to demonstrate

 

      that they are bioequivalent.

 

                Certainly, the approaches to deal with

 

      highly variable drugs, to deal with the

 

      bioequivalence of highly variable drugs are still

 

      in discussion and still in investigation.  I am

 

      hoping in the near future we share with you some

 

      proposal or recommendation we have with respect to

 

      bioequivalence of highly variable drugs.

 

                Another drug could be drug product, the

 

                                                                94

 

      drug product could be highly variable, even drug

 

      substance is I would say low variability, and

 

      certainly design for equivalence begins with the

 

      characterization of the reference list product, and

 

      generic product should target the mean, and the

 

      current system again would have no reward for

 

      narrow or less variability of generic products.

 

      That is why we need to explore the alternative

 

      approaches or more appropriate approaches to deal

 

      with highly variable drug products.

 

                I just want to give you some examples of

 

      what we talk about here.  This is real data.  This

 

      is single subject replicate design, in other words,

 

      you give the same product to the same patient

 

      twice.  Here is the plasma level, obviously, I am

 

      sure that out of 80 to 125 percent confidence

 

      interval, by any standards, it probably does not

 

      need a statistician to figure this out.

 

                You can see here, this is the first period

 

      or this is the second period.  It is not in your

 

      handout or printout because this is in color.  If

 

      you look carefully, these two curves are

 

                                                                95

 

      significantly different, probably different by I

 

      even don't know how many folders.

 

                This is a single-dose study twice,

 

      replicate study design.  Sorry, I should do a

 

      better job next time, use red, so you can see it.

 

                DR. KIBBE:  I am just looking at the curve

 

      and wondering why we got the hump at the back end

 

      and whether the product is intended to have a

 

      second release.

 

                DR. YU:  No, it's simply by design, for

 

      whatever reason this peak has come out.  Obviously,

 

      a second dose, this peak is no longer there.  So,

 

      it's not purpose designed, it's simply because of

 

      physiology involved.

 

                This is happening because enteric coated,

 

      this is coated to release at the target pH, so when

 

      the physiological pH in the gastrointestinal tract

 

      may fluctuate, and those curves will change.

 

                Think about, for example, if we have a

 

      product designed will release a pH 7, so then in

 

      the terminal ileum, at one point is pH 6.8, you

 

      will not see the release.  But a second day,

 

                                                                96

 

      because of food or because of other reasons,

 

      terminal ileum pH becomes 7 or 7.2, you do not see

 

      the release.  Otherwise, you will not see it.

 

                So, simply pH effect or significant impact

 

      the absorption.

 

                DR. KIBBE:  The product had gotten on the

 

      market because it worked clinically?

 

                DR. YU:  Yes.  Even though we see the

 

      significant variation in pharmacokinetics, but we

 

      have no reason to believe this variation will

 

      impact safety and efficacy.

 

                So, in order to do more appropriate

 

      pharmacokinetic studies, we also look into what

 

      additional information, for example, develop

 

      information will help support those cases or

 

      bioequivalence cases, because you can see the

 

      bioequivalence obviously is very difficult to

 

      conduct variability probably up to 2 or 100

 

      percent, and the number of subjects very high.

 

                So, we want to see can we use any

 

      additional pharmaceutical development information

 

      to help us to make more proper scientific

 

                                                                97

 

      decisions.

 

                Again, for example, when we are looking,

 

      in many cases, we do get very consistent, the in

 

      vitro dissolution actually out to say the majority

 

      of cases, those help us out to make a more proper

 

      scientific decision or rational scientific decision

 

      when we recommend any method to demonstrate

 

      bioequivalence, but occasionally, we do get very

 

      strange results, and actually, the variability is

 

      extremely high and does not help you.

 

                I just want to show you another case here

 

      when we conduct the dissolution under physiological

 

      relevant pH condition, and you get dissolution all

 

      over the place.

 

                Now, this is a 6 tablet, same lots, same

 

      bottle, put in 6 vessels, you get a distortion

 

      curve.

 

                So, the next question we ask, this is a

 

      large variability because of the operator or

 

      because of other reasons.  I think the answer is we

 

      are almost certain those difference is because of

 

      product, not because of other factors.

 

                So, what I can present to you today is we

 

      have challenges to deal with bioequivalence of

 

      highly variable drugs.  We use the clinical

 

                                                                98

 

      evaluation and sometimes we are also facing

 

      challenges when we are trying to use in vitro

 

      information to help us make decisions.

 

                DR. SINGPURWALLA:  Lawrence, what is the

 

      difference between each curve, different vessels?

 

                DR. YU:  Yes, six vessels.

 

                DR. SINGPURWALLA:  Six vessels, so it

 

      could be that the vessels are different.

 

                DR. YU:  I think I stated that the

 

      variability because other reasons, for example,

 

      vessel difference, media difference, degassing

 

      difference, operator difference, assay difference.

 

      We do not believe all these reasons can explain.

 

                DR. HUSSAIN:  Yesterday, this same figure,

 

      Cindy actually showed you the reason for this

 

      difference was the coating thickness, and so forth,

 

      so this is the same slide.

 

                DR. MORRIS:  You wouldn't get 2 1/2 hours

 

      difference in dissolution time from different

 

                                                                99

 

      vessels.  That is not the magnitude you would

 

      expect.

 

                DR. SINGPURWALLA:  How am I supposed to

 

      believe that?

 

                DR. YU:  You have to believe in me.  You

 

      don't have any other options.

 

                [Laughter.]

 

                DR. SINGPURWALLA:  I don't believe in

 

      anyone.

 

                DR. KIBBE:  This is a constant pH

 

      throughout, right, we haven't shifted pH during the

 

      process or anything, right?

 

                DR. YU:  Correct.

 

                DR. HUSSAIN:  The reason to believe that

 

      is I think it was done by Cindy, and with our

 

      stringent mechanical calibration.

 

                DR. LAYLOFF:  He demonstrated it with

 

      variable coating.  It's variable coating on enteric

 

      coating material, so if there is a crack in the

 

      coating, it disintegrates much more rapidly.

 

                DR. SINGPURWALLA:  I think I believe Tom.

 

                DR. YU:  Thank you very much.

 

                So, the objective, the case we presented

 

      to you is certainly difficult, I just want to say,

 

      variability issue, whether from clinical evaluation

 

                                                               100

 

      or sometimes for in vitro conditions, in vitro

 

      testing, target main performance question.  I am

 

      sure you will ask where is the main performance.

 

                I just want to show you that these are the

 

      challenges which we are facing, and certainly we

 

      are open to any suggestions or input from you.

 

                So, in summary, we believe pharmaceutical

 

      development information will help.  I quoted here,

 

      that's the conclusion made by you April 14th of

 

      2004.  Understanding what the problem is, as well

 

      as the real fundamentals, for example, physical and

 

      chemical parameters, and make coherent and

 

      scientific science-based decision based on

 

      pharmaceutical development information, I think I

 

      present to you the cases to see hopefully how we

 

      use pharmaceutical development information to help

 

      us in most cases, but in some cases, we still have

 

      challenges and we have opportunities for us to move

 

      forward.

 

                Thank you and any comments are welcome.

 

      Thank you very much.

 

                DR. COONEY:  Thank you, Lawrence.

 

                We now have time for questions from the

 

      Committee.

 

                DR. SINGPURWALLA:  Lawrence, I have two

 

                                                               101

 

      kinds of questions.  Question No. 1.  Is it the

 

      purpose of this presentation of yours to ask the

 

      manufacturers, namely, the industry, to provide

 

      more information to you because there is so much

 

      variability and you are trying to get to the source

 

      of the variability, is that the objective?

 

                DR. YU:  Yes, very precise, certainly much

 

      better than I said.

 

                DR. SINGPURWALLA:  That is the political

 

      question. The scientific question, and I have heard

 

      this before, what does T/R percent mean in your

 

      Slide No. 8?

 

                DR. MEYER:  Test over reference.

 

                DR. SINGPURWALLA:  Test over reference.

 

                DR. YU:  Yes.

 

                DR. SINGPURWALLA:  How was this 80 percent

 

                                                               102

 

      and 125 percent figure arrived at?

 

                DR. YU:  Slide 9.  I am trying to get

 

      Slide 9.

 

                DR. SINGPURWALLA:  That's it, the picture.

 

      So, 80 percent and 125.

 

                DR. YU:  T is the test.

 

                DR. SINGPURWALLA:  No, forget that.  How

 

      did you get 80 and 125?

 

                DR. YU:  That's an excellent question, and

 

      we have been asked many times.

 

                DR. SINGPURWALLA:  It can't be excellent.

 

                DR. YU:  It's back to it was published

 

      when I was in high school, I would say, 20 years

 

      ago, or even more than 20 years ago, when the

 

      pharmacokinetics, the discipline was developed, and

 

      FDA developed the criteria.  Actually, this

 

      evolving process and trying to develop what kind of

 

      standards or criteria can we use to judge a

 

      bioequivalence study is okay or is not okay.

 

                I think at that time, the physicians get

 

      together, as we do today, and the physicians

 

      together made the determination that the 20

 

                                                               103

 

      percent, the difference between product would not

 

      be considered clinically significant, because the

 

      20 percent will not be considered significant

 

      difference, therefore, when translated into in vivo

 

      setting, you have 80 percent.

 

                So, you would think from 80 to 120 instead

 

      of 25. Now, in the normal processing of

 

      pharmacokinetic data, they used log normal to be

 

      much better to describe the distribution.  So, when

 

      you use log normal, 80 is still 80. When you have

 

      the 1 over 80 or 1 divided by 0.80, equals 1.25.

 

      That is why you see 80 to 125.

 

                Now, at the beginning, I would think 20

 

      percent instead of 19 percent or 21 percent, which

 

      is 20 percent, it was decided.  Then, the question

 

      come back to us now can we change 20 percent to 25

 

      to 15, 10, 5 percent, and I guess we have to use,

 

      say, over the 20 or 25 years, we approved product,

 

      they are all safe, they are all equivalent, they

 

      are all high quality, because of those experience

 

      or prior knowledge, determining 80 to 125 percent

 

      works fine.

 

                Now, this does not necessarily mean we

 

      cannot change it, but the criteria we have is very

 

      stringent criteria, we feel confident with that.

 

                                                               104

 

                Now, with a statistical interplay--

 

                DR. HUSSAIN:  Lawrence, if I may.

 

                DR. YU:  Yes, please.

 

                DR. HUSSAIN:  It's a "feel good" criteria,

 

      we felt good about it.

 

                DR. SINGPURWALLA:  I got the answer.  I

 

      think I got the answer.

 

                [Laughter.]

 

                DR. SINGPURWALLA:  The answer is

 

      tradition.

 

                DR. HUSSAIN:  No, it's rational science.

 

                DR. YU:  It is rational science.  I think

 

      I proved it.

 

                DR. SINGPURWALLA:  Let me make a

 

      suggestion.

 

                DR. YU:  Yes, please.

 

                DR. SINGPURWALLA:  That tradition with

 

      some dose of rationality was good 20 years ago when

 

      you were in high school.  Times have changed. 

 

                                                               105

 

      These kind of decisions to either prove equivalence

 

      or prove in-equivalence should be based on risk

 

      considerations and should be based on appropriate

 

      utilities.

 

                So, I think it is time to change, and I

 

      think I said that April 14th, 2004.  Has there been

 

      any progress made towards changing?

 

                DR. YU:  The answer is yes.

 

                DR. SINGPURWALLA:  Oh, good.  What?

 

                DR. YU:  Certainly, you said you want

 

      suggestion of change, and I think under the

 

      leadership of Gary Buehler, that we are exploring

 

      the confidence interval, for example, the window

 

      index drugs, and also we are exploring confidence

 

      interval for highly variable drugs.  In other

 

      words, in the future, I am hoping someday, with

 

      your support and agreement, we will have different

 

      criteria other than 80 to 125 to different class of

 

      drug in consideration of the risk interplay.

 

                Obviously, to make any changes, six months

 

      or one year is not enough.

 

                DR. COONEY:  Marvin, then Ken, then Paul.

 

                DR. MEYER:  Your talk I believe tried to

 

      marry the quality-by-design to the highly variable

 

      drug and show that you could, in part, solve the

 

                                                               106

 

      problem by quality-by-design, that's the objective.

 

                DR. YU:  Yes.

 

                DR. MEYER:  Personally, I think if you

 

      have a competent company, then, your highly

 

      variable drug is biological problem which the

 

      company can't solve.  You have to speak directly to

 

      a higher power to get rid of that variability.

 

                So, I think, yes, there is cases where,

 

      for example, I could cite failure by design if you

 

      want to put an enteric coating on something,

 

      because that is, in my view, not a good dosage form

 

      because it is so dependent on gastric pH and

 

      emptying, and all of that, so you are setting

 

      yourself up for failure.

 

                Now, you can say, well, I dealt with

 

      quality by design by not using enteric coated, I

 

      kind of took the reverse of that.  A competent

 

      company looking at Slide 24, the 6-vessel graph,

 

      would never go to a biostudy with a product that

 

                                                               107

 

      showed dissolution characteristics like that.

 

                So, indeed, some quality built in that

 

      says whoa, let's not spend $100,000 on a biostudy

 

      when our drug is all over the map in dissolution.

 

      So, I think you can deal with some variability, but

 

      that is fairly straightforward I think for a

 

      company.

 

                So, the issue that really faces us is the

 

      physiological variability and do we extend the

 

      confidence limits, do we have point estimate

 

      restrictions or just do we do 600-subject studies.

 

                DR. HUSSAIN:  Marv, may I just sort of put

 

      that in context a bit?  In some ways, what we are

 

      seeing here is this.  Since we are comparing two

 

      formulations of the same drug, the drug is the

 

      same, the variability, the physiologic, the

 

      variability that is coming is the same for the drug

 

      substance.

 

                If we can compare formulations and say

 

      that all the conditions that are critical to

 

      exposure are well controlled, and so forth, and get

 

      confidence, what will give us the confidence to say

 

                                                               108

 

      that the inherent variability is the physiologic

 

      variability, not the quality variability, then, we

 

      can move forward.  I think that is the hope that we

 

      hope.

 

                DR. MEYER:  Do you think practically, you

 

      can look at the restrictions and the SOPs--

 

                DR. HUSSAIN:  No.

 

                DR. MEYER:  --and just see how a company

 

      is formulating and designing and developing a

 

      product?

 

                DR. HUSSAIN:  Not with the traditional

 

      work we do about formulations, putting things

 

      together, and so forth, no, it has to be a

 

      structured design approach that goes through

 

      identifying the sources of variability in your

 

      materials, and so forth, and putting a convincing

 

      case together to say based on the assessment, in

 

      this case it's a generic product, and based on

 

      characterization of reference material and your

 

      test product, you can make the case that the

 

      variability that you are seeing in your product is

 

      no more different than of the best argument.

 

                That gives you a leverage to now make a

 

      rational decision with respect to what sort of a

 

      biostudy criteria would be necessary.

 

                                                               109

 

                You can build flexibility, and not go

 

      rigid with, say, the Japanese approach, which was

 

      in your background packet, was to say do we really

 

      need confidence interval criteria here.  We just

 

      want to confirm the mean values.  It's a

 

      confirmation rather than a complete full-fledged

 

      study.  One option could be that.

 

                DR. YU:  I think the message we are trying

 

      to convey is when we explore alternative approach,

 

      which could be a wide confidence interval, or your

 

      scaling approach to show or to demonstrate the

 

      bioequivalence is demonstrated with the additional

 

      information, which is pharmaceutical development

 

      information, will help us to make scientific

 

      coherent decisions.

 

                Right now we don't, we don't have those

 

      informations.  In other words, we are not able to

 

      see how dissolution variability here may change it,

 

      for example, in this case, if we change the pH,

 

                                                               110

 

      dissolution is very beautiful, so that is the data

 

      we got.  We have now seen this data I showed you on

 

      the screen.  Thank you.

 

                DR. COONEY:  Ken.

 

                DR. MORRIS:  A couple of points.  One is I

 

      agree with Marvin in the sense that you wouldn't

 

      expect a company to release dissolution, I mean

 

      going to a biostate with dissolution like that, but

 

      I think those studies were done under different

 

      conditions.  These were done here, so they wouldn't

 

      have seen that under normal dissolution conditions.

 

                My more general question is--

 

                DR. YU:  You are correct, yes, in normal

 

      conditions, especially, for example, USP

 

      dissolution, maybe you are not able to see.

 

      Actually, dissolutions are beautiful.

 

                DR. MORRIS:  Right, so that comes back to

 

      sort of our discussions yesterday in a sense.  The

 

      question I have is to what level or to what extent

 

      do the ICH initiatives, I mean including the CTD

 

      and Q8, impact on the ANDA, I mean is there an

 

      intent that they follow suit with NDAs?

 

                DR. YU:  Obviously, the basic principles

 

      from ICH and CTD, the CTD cure document for drug

 

      substance and drug products, it is not just for NDA

 

                                                               111

 

      only, for both NDAs and ANDAs.  ICH Q8 is, in

 

      principle, a part into NDAs, certainly the basic

 

      principle also apply to ANDAs.

 

                The way I actively look into this to

 

      document and to see what information will help us

 

      to make scientific decisions.  Certainly, as I said

 

      before, we are not looking for information which is

 

      nice to know, we are looking for information which

 

      is essential to know.

 

                DR. MORRIS:  I guess to that end, because

 

      this is something, of course, we have been

 

      discussing for several years, but the idea that

 

      rather than having checklists of what the companies

 

      have to do, if they can make scientific decisions

 

      based on the intended dosage forms and the

 

      properties of the API, which should be a lower

 

      hurdle, I mean that should be known more by the

 

      time you get to the generic.

 

                DR. YU:  Yes.

 

                DR. MORRIS:  Instead of having to do a lot

 

      of the other testing that might normally be done,

 

      if they can focus on the identification of the

 

      critical to quality attributes of the product and

 

      capture that in a development report, it seems like

 

      that is a reasonable way forward.

 

                                                               112

 

                DR. YU:  That is correct.  In fact,

 

      industry is coming forward and they share some of

 

      the pharmaceutical development report with us, we

 

      are actively looking into this to develop some kind

 

      of review templates which will incorporate

 

      pharmaceutical development information into our

 

      review process.

 

                Again, I said we are looking for

 

      information which is essential to know, not nice to

 

      know.

 

                DR. MORRIS:  Maybe this is for Paul, is

 

      that a reasonable stance as far as how you look at

 

      generic development?

 

                DR. FACKLER:  I am not sure exactly what

 

      you are asking.

 

                DR. MORRIS:  I can clarify if you want,

 

                                                               113

 

      but basically, if you could, instead of having to

 

      do sort of checkbox testing, if you could do

 

      testing that was largely prescribed by your need to

 

      establish certain scientific issues, rather than

 

      having to do as many, let's say, sort of--what is

 

      the word--statutory testing, if you will, is that a

 

      reasonable stance for you guys?

 

                DR. FACKLER:  I don't see a problem with

 

      that.  What I didn't hear here was that there are

 

      any different statutory requirements for highly

 

      variable drugs.

 

                If a generic company still needs to pass a

 

      bioequivalence study, and we are going to assume

 

      that the pharmaceutical equivalence is simple, I

 

      don't understand what the generic company

 

      understanding the origin of the innovator's

 

      variability has to do with the approvability of a

 

      lot of material that is shown to be

 

      pharmaceutically equivalent and therapeutically

 

      equivalent through a bioequivalence study.

 

                I guess that is the piece I am missing.

 

      Why is the burden on the generic company to

 

                                                               114

 

      understand the variability of the reference listed

 

      drug, and what value does that have if really all

 

      the generic company needs to do still is

 

      demonstrate a bioequivalent product?

 

                DR. MORRIS:  You are talking about BE

 

      variability now, not pharmaceutical?

 

                DR. FACKLER:  Yes.

 

                DR. YU:  Paul, if we use

 

      one-size-fits-all, which is 80 to 125 percent to

 

      some of drugs, you may have difficulty to pass the

 

      confidence interval.  So, when we are exploring the

 

      alternative approach including the scaling

 

      approach, you will have to demonstrate this product

 

      is highly variable or not highly variable.

 

                You have to know that because otherwise,

 

      suppose someday in the future, if the scientific is

 

      mature enough, we have a scaling approach, for

 

      example, for highly variable drugs, your submitted

 

      application did not show these are highly variable

 

      drugs, how would we know these are highly variable

 

      drugs.

 

                So, you have to show, in your development

 

                                                               115

 

      report, that is a highly variable drug before we

 

      move forward.

 

                DR. FACKLER:  Agreed, but wouldn't a

 

      replicate design bioequivalence study inherently

 

      capture the variability of the reference listed

 

      drug?

 

                DR. YU:  Yes, if you choose to do so, use

 

      replicate design, certainly, you are able to

 

      demonstrate that reference list product is highly

 

      variable or not.

 

                DR. FACKLER:  But that is already part of

 

      an ANDA application is my point.

 

                DR. YU:  I guess, Paul, we have not

 

      reached a consensus or we have not made a

 

      determination you have to use replicate design.

 

                DR. MORRIS:  Is part of that the fact that

 

      you are still struggling with the concepts that are

 

      entailed in that dissolution plot where you can't

 

      factor into the pharmaceutical variability, factor

 

      the pharmaceutical variability from the clinical?

 

                DR. YU:  I guess the struggle we have here

 

      is, look, Lawrence, in order for you to get this

 

                                                               116

 

      direct for pass, whether you use scaling approach

 

      or you use widen the confidence interval, you

 

      simply widen the confidence interval, let them to

 

      pass.  You need to explain why.  You need to

 

      explain why you think that is a feasible approach,

 

      you think that is scientifically sound.

 

                So, when you say explain why the

 

      pharmaceutical development report can help us

 

      provide additional information to explain why.

 

                DR. FACKLER:  I agree that certainly you

 

      need to understand the variability of the reference

 

      listed drug especially if a generic applicant is

 

      claiming that the variability is an issue for this

 

      particular product.

 

                DR. YU:  Correct.

 

                DR. FACKLER:  I am not sure what value the

 

      steps that were taken has to that determination of

 

      variability.  Variability sometimes is listed in

 

      the label for a reference listed drug; other times

 

      applicants do replicate design studies or run

 

      reference versus reference to measure that inherent

 

      variability, but that would all be part of an

 

                                                               117

 

      application already, as I understand it.

 

                DR. YU:  Yes, in many cases actually

 

      lately for some of complex dosage forms.  Dosage

 

      form, we very often sent many, many deficiency

 

      letters.  Actually, company provide information

 

      during the cycles, and as I said, at the GPA Chair

 

      meeting, we have four or five or six cycles,

 

      provide additional information to us, and

 

      eventually, the product get approval.  I am not

 

      saying you not provide that information.

 

                What I am trying to say is with the arena

 

      of pharmaceutical development report in the ICHQ

 

      paradigm, can you provide that information in the

 

      application instead of for us to send many

 

      deficiency letters.

 

                When we see the OGD list receive 25

 

      percent or more of the applications every year,

 

      where do you want to put resource into those

 

      reviews.  Suppose you provide those additional

 

      information, which I believe will help us in our

 

      reviews, and they reduce the cycles, I see it's a

 

      win/win situation for you and for us.

 

                DR. COONEY:  Ajaz.

 

                DR. HUSSAIN:  I think look at it from this

 

      perspective in the sense the whole aspect is you

 

                                                               118

 

      are trying to make a decision and you are trying to

 

      choose the right measurement system here.

 

                Now, the Code of Federal Regulations

 

      essentially has a hierarchy of methods that you

 

      choose for bioequivalence.  Our current criteria is

 

      a PK crossover, PK-based, pharmacokinetic-based

 

      study is the most discriminating one.

 

                So, you are looking at, you are trying to

 

      now judge approvability of a generic drug, and for

 

      that you need to establish its pharmaceutical

 

      equivalence and its bioequivalence.  The

 

      bioequivalence measurement system that we have has

 

      inherent variability, and much of that variability

 

      is coming from the measurement system, and may not

 

      be coming from the test samples that you are doing.

 

                So, is this measurement system the ideal

 

      measurement system right now or not?  That is

 

      really the question.

 

                The dilemma that we have is the in vitro

 

                                                               119

 

      characterization and in vitro testing with

 

      dissolution often is not reliable enough by itself

 

      to make that call.  If it was, you would not be in

 

      this dilemma.

 

                So, if you really then look at it, what

 

      are we saying, is we have information generally

 

      that even if I give this drug intravenously or as a

 

      solution, and so forth, the variability is coming

 

      from the subjects, it is coming from physiology,

 

      which is inherently variable.  If I sleep on my

 

      lefthand side or righthand side, it will make a

 

      difference, I mean it literally happens.

 

                So, that is the measurement system, but

 

      then you are putting your product into that system

 

      and trying to see is there a difference of 20

 

      percent or not, and to meet that confidence

 

      interval criteria, you need 600 subjects or 300

 

      subjects, and so forth.

 

                Can we utilize the signs of design to say,

 

      to confirm, not necessarily to have a confidence

 

      interval, a confirmation that the new formulation

 

      actually is not contributing to that variability,

 

                                                               120

 

      is there sufficient science to do that or not.

 

                If it is, then it opens the door for

 

      saying that the bioequivalence assessment then

 

      could be tailored based on that understanding.

 

                DR. COONEY:  Before we go on to some other

 

      questions, I would like to see if your question,

 

      Paul, has been addressed.

 

                I think the question was--well, first,

 

      Lawrence is proposing that there be a

 

      pharmaceutical development report added to the

 

      information that is part of the application, and

 

      you are asking what will be the implications of

 

      providing that additional information and

 

      facilitating the next step, which is approval of a

 

      bioequivalence.

 

                DR. FACKLER:  That is part of the

 

      question.  The other part was what would be in a

 

      pharmaceutical development report that isn't

 

      already part of an ANDA.  That is really what I am

 

      trying to understand, and, of course, then, what

 

      value would that provide.

 

                DR. COONEY:  Is there clarity to that

 

                                                               121

 

      question?  So, that is back to Lawrence, to Paul's

 

      question.  What would be in that pharmaceutical

 

      development report that is not already part of the

 

      application?

 

                DR. YU:  I thought that was a topic of our

 

      next advisory committee meeting.

 

                DR. HUSSAIN:  Let me put it this way.

 

      There is nothing there right now.  There is nothing

 

      there to even gauge the aspects of.  So, what we do

 

      is our decisions are made based on one batch test

 

      results and the biostudy.  That is what it is.

 

                DR. MORRIS:  Can I just weigh in?  I think

 

      part of this is that a lot of what would go in the

 

      development report is stuff that people are already

 

      doing, but doesn't just get included in a summary

 

      fashion, much like we have discussed earlier, that

 

      there is development studies you do, but you don't

 

      put together.

 

                That is what we were talking about

 

      yesterday, is that, as a reviewer, if you have to

 

      try to piece together a development rationale from

 

      data here and there, you end up with sort of a

 

                                                               122

 

      development rationale that the person filing really

 

      wouldn't want to be there displayed to the world,

 

      you know, sort of a Frankenstein development

 

      report.

 

                So, if the company does it, then, they can

 

      see the logic that you use.  Whether they agree or

 

      not is a different question.  So, in my sort of

 

      concept of this, which may be flawed, of course, if

 

      the company, let's say, had used Cynthia's

 

      dissolution method, because they said this is what

 

      has really mattered, and they got those curves to

 

      overlay, then, that is a big step forward to say

 

      that the variability that may come out of the BE

 

      studies are not due to our change.

 

                So, if you see the variability of the BE

 

      studies and you have demonstrated that it is not

 

      due to the lack of adherence to a design space, for

 

      lack of a better word, then, that has got to be as

 

      good as the innovator.  That is my concept.  This

 

      may be down the road, as Jerry said.

 

                DR. YU:  I want to make comments that when

 

      we say the pharmaceutical development information,

 

                                                               123

 

      I think I emphasize those information that is

 

      essential to know, not just for nice to know.

 

                We are looking into this, what additional

 

      information will help us in making decisions, and I

 

      think we are happy to share with you in the future,

 

      but at this point, we cannot say that for every

 

      single ANDA or for every single product, you need

 

      the pharmaceutical developed, because you have a

 

      prior knowledge, some of the information already

 

      there, so this need clarification when you are

 

      understanding what additional information is

 

      provided.  I think we need to discuss and work it

 

      out.

 

                DR. FACKLER:  I understand.  To Ken's

 

      point, you start over here and the bioequivalent

 

      product is over here, and sometimes you take a

 

      direct approach to it and sometimes you don't.  You

 

      are right, oftentimes it is over here and then you

 

      realize you need to be over here, and then finally,

 

      you get where you need to be.

 

                But I am not sure I understand the value

 

      or what it matters what path you took as long as

 

                                                               124

 

      you end up in the right place.  All this

 

      information does exist, of course, and the field

 

      inspectors have access to it, and we are just

 

      reluctant to expand the content of an ANDA in the

 

      fear that it will slow down an already overburdened

 

      review process.

 

                So, where the information is critical to

 

      understanding whether a product is pharmaceutically

 

      or therapeutically equivalent, of course, it ought

 

      to be submitted, but where it is not essential for

 

      that evaluation, I just question whether or not it

 

      ought to be added to the burden of the reviewers.

 

                DR. COONEY:  Art, then Marvin.

 

                DR. KIBBE:  Let's get back to what we are

 

      trying to determine, and that is whether or not a

 

      clinician who prescribes this medication for its

 

      effect has got a reasonable expectation of a

 

      therapeutically similar outcome when he uses the

 

      innovator or when he uses the generic.  That is

 

      where we are.

 

                If a product is inherently variable, as

 

      manufactured by the innovator, then, we ought to

 

                                                               125

 

      know that early on, and as Les correctly points

 

      out, if that was the case during development and

 

      prior to approval, it wouldn't make it on the

 

      market if it wasn't that that breath of variability

 

      was allowable for clinical outcome, because if the

 

      clinical outcomes wouldn't--there were times when

 

      there were failures and times when they were

 

      toxicities apart, never gets on the market. which

 

      means that we have already historically established

 

      large variability is okay, because we have that

 

      product on the market.

 

                Now, if I am a generic company, all I want

 

      to do is say that I am going to be no more than, or

 

      perhaps less variable, and I am going to get to the

 

      same therapeutic outcome.

 

                If I can test a replicate design that

 

      shows that my level of variability is lower than or

 

      equal to the variability of the innovator, and my

 

      means are on target, then, I can with reasonable

 

      assurance argue that my product used in the

 

      marketplace on patients is going to have the same

 

      efficacy and failure rate as the innovator.

 

                The second thing is we already have agreed

 

      that dissolution is a hammer when we need a

 

      surgical scalpel to figure out what is going on,

 

                                                               126

 

      and if you make a shift in a dissolution criteria

 

      and all of a sudden you can differentiate tablets

 

      from the same batch, but that batch used in people

 

      isn't differentiatable, then, you are making a

 

      differentiation which is of no value to anyone

 

      except if you want to go back and process improve.

 

                In fact, that is what it should be used

 

      for.  The companies ought to be investing time and

 

      energy in process improvement by looking for better

 

      differentiators for their own internal consistency,

 

      and perhaps they could narrow the variability if

 

      they found them.

 

                I think the justification for going to the

 

      study that you said that if they used the USP

 

      numbers, they would all pass, and going to your

 

      numbers, we have this high variability, but that

 

      high variability doesn't relate to clinical

 

      outcomes.

 

                Now, I am coming on the market as a

 

                                                               127

 

      generic.  If I can establish that I am not more

 

      variable than they are, and my means are the same

 

      as they are in a biostudy, how much more

 

      information does the agency need?  I don't think it

 

      needs much more.

 

                DR. HUSSAIN:  Art, you are missing the

 

      point in the sense to demonstrate that your

 

      variability is acceptable, you actually have to do

 

      more now through a bioequivalence or replicate

 

      design, and so forth.

 

                What we are saying is in the sense, there

 

      are ways or there should be ways to sort of the

 

      justification that goes into a formulation that you

 

      move forward, could then become a basis to say you

 

      don't have to go through extraordinary means to say

 

      the variability is unacceptable.

 

                So, if we know a drug substance is highly

 

      variable, you mostly have that information that

 

      says you sort of at least definitely will when you

 

      approve the product, then, the signs of formulation

 

      design could provide you a basis for saying there

 

      is no reason your particle sizes, which are

 

                                                               128

 

      critical for your dissolution, your coating

 

      thickness, which are your release mechanism, are

 

      essentially being controlled, and so forth.

 

                So, why should a generic form then have to

 

      do a large study with replicate or with whatever?

 

      Isn't there an option available for something--

 

                DR. KIBBE:  So, what you are really

 

      talking about is a waiver of what we would say

 

      would be a standard replicate design to get around

 

      variability.

 

                DR. HUSSAIN:  Exactly, so that is what we

 

      are suggesting.

 

                DR. KIBBE:  So, the company then would

 

      come with its own development data and show that a

 

      broad range of dissolution numbers are not highly

 

      variable or something.

 

                DR. HUSSAIN:  Yes, the way I would think

 

      about that is in a sense if it's a tablet, I will

 

      go to the basic mechanisms of what the dissolution

 

      will be affected, and here is my assessment of my

 

      particle size, here is my control strategy, here is

 

      the prior knowledge of similar dosage forms.  There

 

                                                               129

 

      is no apparent reason for this to be variable from

 

      that perspective.

 

                So, that becomes a basis for a decision

 

      criteria saying that why would we expose normal

 

      healthy subject volunteers, a large number of them,

 

      to simply get our numbers within the confidence

 

      interval criteria, which is somewhat arbitrary.

 

      That is the crux of this.

 

                DR. YU:  I don't know if I can clarify,

 

      the point we are trying to make is that if you can

 

      conduct bioequivalence study now to best pass the

 

      confidence interval, this is good enough.  I am not

 

      saying this is not good enough.  We are not asking

 

      additional information.

 

                The problem which we are facing is you

 

      will not have difficulty, it is not impossible if

 

      you have recruited 1,000 or 2,000 subjects, it is

 

      almost impossible to do by a current study, and

 

      this is scenario that pharmaceutical variability

 

      information may come into play and to help us out.

 

      That is what we are trying to convey.  Thank you.

 

                DR. MEYER:  I think part of my problem is

 

                                                               130

 

      that I believe what you are putting forth is a

 

      concept without any data, which obviously you can't

 

      have yet, because the concept hasn't even been

 

      implemented, it is just a concept.

 

                I think certainly from my perspective, if

 

      you have some ideas that might streamline the whole

 

      system, I would say go for it and then let's see

 

      the meat once the skeleton is exhumed, so to speak.

 

                That is the bottom line, but I think there

 

      are some other ideas in there that are perhaps

 

      easier for me to understand, characterize the

 

      reference listed drug and then presumably, if you

 

      have done that, FDA will take that into

 

      consideration to explain why you have confidence

 

      limits that aren't up to par perhaps.

 

                For example, a simple example, the RLD has

 

      an overage in it of 10 percent.  They claim that

 

      isn't released ever, so they just have it in there

 

      because their release mechanism doesn't allow for

 

      except 100 percent.

 

                You have some evidence that says well, in

 

      fact, it is released 110 percent sometimes, so the

 

                                                               131

 

      poor generic company is already 10 percent in the

 

      hole when it comes to AUC.  If that can be

 

      demonstrated in some reasonable scientific fashion,

 

      that ought to maybe taken into account.

 

                A better example maybe is with the osmotic

 

      pump.  We have done studies where you can harvest

 

      the ghost out of the feces, and sometimes it has 50

 

      percent drug in it, sometimes it has 10 percent,

 

      sometimes it has no drug in it. It seems to be a

 

      direct function of intestinal transit time.

 

                Well, if you are a generic trying to match

 

      without using an osmotic pump, you don't have a

 

      snowball's chance in hell of coming across and

 

      matching a product that sometimes is 50, sometimes

 

      is 100, sometimes is 10 percent.

 

                So, I think as long as you hit the means,

 

      and you bring that kind of data to FDA, they ought

 

      to have the latitude of saying yeah, we know that's

 

      a problem with the RLD, and we can therefore adjust

 

      our thinking when it comes to the generic.

 

                Obviously, that is going to take a fair

 

      amount of work, but I think that these things need

 

                                                               132

 

      to be thought of, as well as more statistically

 

      based ways of dealing with high variability.  That

 

      is kind of a short-term fix which ultimately once

 

      the statisticians get done fighting, then, the rest

 

      of us can agree, but the other is certainly a

 

      concept worth pursuing, I think.

 

                DR. SINGPURWALLA:  I would like to respond

 

      to that.

 

                DR. HUSSAIN:  If I may, there is an aspect

 

      what Marv just said in the sense a practice that

 

      all of us know exists is when you have variability,

 

      then, you pick and choose what your comparator is.

 

      I mean it bothers me in a sense to say that, you

 

      know, you can pick and choose what lot you will

 

      compare to, and so forth.

 

                Why do we have to sort of have those type

 

      of decisions where, you know, I think we can be

 

      better than that, so I think just to build on what

 

      Marv says, to say that I think we can really be

 

      confident in what we are doing, and not to feel a

 

      bit guilty that we are picking and choosing what we

 

      test, and so forth.

 

                DR. MEYER:  As you well know I am sure,

 

      there are a number of countries.  You do your

 

      dissolution on three lots of the RLD and then you

 

                                                               133

 

      pick the one in the middle, not the one that is

 

      closest to what your product happens to be.

 

                DR. YU:  I want to make comments about

 

      Marvin's comments.  Yes, in the case here, what you

 

      present, actually, those information is not in the

 

      original ANDA submission, but those information

 

      eventually is shared with us.

 

                So, go through many cycles, many, many

 

      months, or even several years to get us that

 

      information.  What we are seeing is that we think

 

      if those information, which you eventually shared,

 

      only a couple that go through the five or six or

 

      seven cycles, shared in first place will help us to

 

      make decisions, will help us to reduce cycles, will

 

      help us actually use the resource wisely.  That is

 

      what we are trying to say.  Thank you.

 

                DR. COONEY:  Nozer.

 

                DR. SINGPURWALLA:  General comments.

 

      First thing, Ajaz, don't use the word confidence

 

                                                               134

 

      limits for those two boundaries.  Call them control

 

      limits.  Confidence limits are completely

 

      different.

 

                The second thing is you are fighting, at

 

      least there is a lot of discussion because there is

 

      a lot of variability.  What you seem to have done

 

      is taken reactive approach, have said variability

 

      is there, what shall we do about it.

 

                Well, yesterday, you talked about 6 sigma

 

      in one of your slides.  Well, I think wherever you

 

      have these high variability issues, whether they be

 

      in industry or whether they be within your own

 

      system, I would encourage you to put into practice

 

      what you were preaching yesterday about 6 sigma.

 

                I would say, you know, has anybody thought

 

      about that, because 6 sigma came about in industry

 

      because there was a lot of variability, and they

 

      said how do we control it.  Well, you just don't

 

      control it by doing statistical methods.  You

 

      control it by proper management and proper

 

      procedures, and I would say that you should try to

 

      bring that into the arena.

 

                DR. COONEY:  Paul.

 

                DR. FACKLER:  The generic industry is just

 

      as interested in minimizing the number of 6 and 7

 

                                                               135

 

      cycle reviews on products.  Clearly, we have the

 

      same goal in mind.

 

                I guess what I would suggest is that for

 

      highly variable drugs, for instance, it would be

 

      useful for the agency to tell industry the kind of

 

      information that is generally lacking, but with 500

 

      applications a year, or 800, whatever the numbers

 

      might be these days, coming into the agency, I

 

      don't think it is wise to require this information

 

      on all of the applications.

 

                I would suggest maybe we clarify the

 

      additional information that is often being left out

 

      of submissions for highly variable products, and

 

      presumably, generic companies in the interest of

 

      having a minimum number of review cycles will

 

      submit it the first time rather than an iterative

 

      process to give you all the information that you

 

      need to make a fair decision.

 

                DR. COONEY:  Gary.

 

                DR. BUEHLER:  For the development reports

 

      in general, I thank you for not wanting to

 

      overburden us with additional information.  We do

 

      have a lot to look at.  If we do get additional

 

      information, we will look at it for sure.

 

                I know that we get some amount of this

 

                                                               136

 

      information sprinkled through the ANDAs and I would

 

      think Ajaz was a bit draconian when he said all we

 

      get is the batch record and whatever.  I mean there

 

      are explanations.  We do demand explanations when

 

      there aren't any deviations from what we normally

 

      see, that is in ANDAs and we do look at that.

 

                Lawrence and a group is working on a

 

      question-based review for the Office of Generic

 

      Drugs.  It is a very detailed project.  He is

 

      working with experienced reviewers in our office,

 

      and he is developing this in a very stepwise

 

      manner, both first by involving both the

 

      supervisors and reviewers in our own office, and

 

      then at a certain point we want to sort of unveil

 

      it to industry.

 

                We want to make sure that when we do bring

 

                                                               137

 

      this new review method and these new requirements

 

      or whatever you want to call them with respect to

 

      pharmaceutical development reports, the industry is

 

      very aware of what we want and why we want it, so

 

      that they will feel good about giving us this

 

      information, and like Lawrence said, it will

 

      hopefully reduce the number of cycles we have, it

 

      will not overburden the reviewers, but, in fact,

 

      reduce the burden on the reviewers, because they

 

      won't have to see the same applications four, five,

 

      or six times, and they will understand why we need

 

      this information.

 

                It is also a risk-based system, so that

 

      there are some applications that you won't have to

 

      provide this type of information, because there are

 

      some applications obviously that are easier than

 

      other applications, and the applications for

 

      complex dosage forms and unique dosage forms

 

      obviously, we are going to ask for more information

 

      than for the vary standard solid orals that are

 

      fairly easy to manufacture.

 

                But we are doing this over a two-year

 

                                                               138

 

      period and hopefully, sometime toward the end of

 

      this year, we will be able to begin to tell

 

      industry what we hope to expect in the future

 

      applications and industry will be comfortable with

 

      it.

 

                DR. MORRIS:  I just have a quick question

 

      for Gary.  I am assuming that development reports,

 

      as you say, depending upon the complexity of the

 

      dosage form, I mean they can be relatively brief if

 

      it's a very simplistic or simple dosage form, so I

 

      am not so sure that it's the burden if the payback

 

      is fewer review cycles or less clinical studies.

 

      Clinical studies are a lot more expensive than

 

      writing a development report and doing a few more

 

      development studies.

 

                Is that more or less the case, Gary?

 

                DR. BUEHLER:  I am not sure it is going to

 

      be able to be submitted in lieu of a study or

 

      whatever.

 

                DR. MORRIS:  No, I meant the extensiveness

 

      of a development report.

 

                DR. BUEHLER:  Some development reports

 

                                                               139

 

      will say we wanted to develop a bioequivalent

 

      formulation, and, you know, here it is, and it

 

      could be a page or two.  I mean clearly, it won't

 

      be very long for a generic, because the goal of a

 

      generic is pretty evident, but other development

 

      reports will be more extensive, so yeah, you know.

 

                DR. COONEY:  It sounds like there is a

 

      need for clarity on what will be requested and

 

      expected, and also for clarity on what the

 

      implications of that will be.  It sounds like that

 

      will be forthcoming.

 

                Ajax, what I would like to do is move on

 

      to the next presentation.

 

                DR. HUSSAIN:  Just go back to the original

 

      intent.  Our initial thoughts that we wanted to get

 

      the discussion started, so we never intended this

 

      to make a proposal, so these are initial thoughts

 

      and we are moving forward with this.

 

                If industry wants to be proactive, they

 

      had better start thinking about it and how they can

 

      use this opportunity instead of asking us what do

 

      we want.  I think it is equally burdensome on

 

                                                               140

 

      industry to think about how to develop the products

 

      for the intended use, and make the case, and grab

 

      that opportunity.

 

                If not, the system as it stays, we are

 

      perfectly happy with it.

 

                DR. COONEY:  So, there is an opportunity

 

      here for dialogue and there is no doubt from the

 

      last 45 minutes that there will be dialogue.

 

                I would like to ask Robert Lionberger to

 

      proceed with the next presentation.

 

            Using Product Development Information to Support

 

                Establishing Therapeutic Equivalence of

 

                            Topical Products

 

                DR. LIONBERGER:  Today, I am going to be

 

      discussing how to apply the concepts of

 

      pharmaceutical equivalence to topical dosage forms

 

      and look at how this is related to quality by

 

      design.

 

                Here, I am going to focus on topical

 

      dosage forms that are in the local delivery, so not

 

      products such as transdermal products that are

 

      trying to deliver drugs systemically.

 

                In the Office of Generic Drugs, as you

 

      have heard several times before this morning, our

 

      mission is to provide therapeutically equivalent

 

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      products to the public.  When someone uses a

 

      generic drug, they should expect the same clinical

 

      effect and safety profile as the branded reference

 

      product.

 

                Just to summarize some things that Ajaz

 

      talked about in his introductions, the preface to

 

      the Orange Book explains how we do that.  Products

 

      must be pharmaceutically equivalent and

 

      bioequivalent.  But I want to dig a little bit

 

      deeper into this and ask why do we actually require

 

      both, why isn't bioequivalence by itself enough to

 

      determine that the products are the same.

 

                One aspect of that is that consumers have

 

      some expectation about product behavior.  If the

 

      reference product is a capsule, you don't want to

 

      replace that with a solution.  So, there is some

 

      user experience and expectation.

 

                So, pharmaceutical equivalence

 

      encapsulates concepts related to like the user

 

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      interface of the product, but then there is another

 

      aspect to it, and I have tried to express it here,

 

      is that pharmaceutical equivalence supports the

 

      determination of therapeutic equivalence based on

 

      bioequivalence study.

 

                We don't say that just because two

 

      products pass a bioequivalence study, they are

 

      therapeutically equivalent products.  An example

 

      might be an oral solution and a tablet.  There can

 

      be many products for which those two dosage forms

 

      would be bioequivalent, but we wouldn't say that

 

      they are therapeutically equivalent products.

 

                One aspect of that is that our current

 

      determination of bioequivalence is really very

 

      strongly based on in vivo testing.  So, again,

 

      there are limitations to testing.  We test these

 

      products in a small population  and then we

 

      extrapolate that conclusion to all people who are

 

      going to use the products from all batches in the

 

      future.

 

                So, to sort of back up that extrapolation,

 

      there is some other information.  Right now that's

 

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      the pharmaceutical equivalence between the products

 

      that supports that.

 

                In the occasions when we do equivalence

 

      studies in patients, there are other differences.

 

      Sometimes the clinical endpoints aren't very

 

      sensitive to small differences, bringing in

 

      examples from topical products, you can imagine

 

      there are cases where, say, a cream and an ointment

 

      formulation might have the same therapeutic effect,

 

      but they wouldn't be considered pharmaceutically

 

      equivalent products or therapeutically equivalent

 

      products even though the clinical endpoint study

 

      might show equivalent efficacy.

 

                Again, from the sort of pharmacokinetic

 

      studies for one of the challenges that is often

 

      made to some of our bioequivalent studies for

 

      topical products is since the skin is a barrier,

 

      you say, well, healthy subjects have healthy skin

 

      barriers.  There is a question.  Sometimes people

 

      will claim in patients, the skin might be diseased

 

      or damaged, so that is a common concern.  There is

 

      a common challenge to some of our bioequivalence

 

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      determinations here.

 

                So, inside of the pharmaceutical

 

      equivalence concept, there is some idea of other

 

      things we want to know about the products to sort

 

      of generalize this idea of equivalence.

 

                If you think about this and want to sort

 

      of tie this to quality by design, one way that

 

      might be useful for you to think about this is that

 

      our current definition of pharmaceutical

 

      equivalence might be considered a first step toward

 

      a quality by design.

 

                If you were going to design equivalent

 

      products, the first things you would start with

 

      were some of the concepts that are in our current

 

      definition of pharmaceutical equivalence.  You

 

      would want to have the same active ingredient.  You

 

      would want to have the same strength, the same

 

      dosage form.

 

                So, if we look at sort of a different way

 

      of looking at our paradigm, maybe instead of a

 

      regulatory framework, a more scientific framework,

 

      what we are doing when we review a generic product,

 

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      is we are looking to see is the product designed to

 

      be equivalent, and then does it demonstrate

 

      bioequivalence in an in vivo study.

 

                So, you can see sort of this combination

 

      sort of parallels our current sort of regulatory

 

      framework of pharmaceutical equivalence and

 

      bioequivalence leading to a determination of

 

      therapeutic equivalence, where we might say that on

 

      sort of a scientific level, what we might want to

 

      be doing in the future might be to say look at the

 

      quality by design, look at the generic product that

 

      is designed to be equivalent to a reference

 

      product, and then based on this design, choose the

 

      appropriate either in vitro or in vivo

 

      bioequivalence testing for this product to complete

 

      the determination of therapeutic equivalence.

 

                So, I want to bring this sort of

 

      conceptual framework and bring it into this sort of

 

      particular example for topical products.  Sort of

 

      to motivate that, I just want to outline some of

 

      the complex issues that we deal with that are

 

      related to pharmaceutical equivalence for topical

 

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      products.

 

                Again, we have a lot more experience with

 

      immediate release, oral dosage forms in effective

 

      excipients, what excipients you can change, what

 

      excipients you can't change.  For topical products,

 

      a lot of times the excipients may or may not affect

 

      the barrier properties of the skin and drug

 

      delivery.

 

                We don't have as much experience about

 

      that, so a lot of times we are worried about what

 

      differences in formulation are appropriate for

 

      comparing a test in a reference product - is a

 

      change in solvent appropriate, what if the base of

 

      the formulation in ointment or cream has changed

 

      from being hydrophilic to lipophilic, how much

 

      water content should there be in the product.  You

 

      might affect evaporation, the feel of the product.

 

                A lot of these sort of differences in

 

      formulation get wrapped up into the question of are

 

      two products the same dosage form.  I will talk a

 

      little bit more in detail about that in the rest of

 

      the products.

 

                We also have questions, when we don't have

 

      good bioequivalence methods for use for topical

 

      products, what indications should be used for the

 

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      clinical equivalence studies.  Perhaps the product

 

      has multiple indications, which one is the most

 

      appropriate one to use.

 

                These are the kinds of issues that we deal

 

      with in generic topical products.  Some of the

 

      implications of these for the ANDA sponsors are

 

      that the approval times for these products can be

 

      longer.  If there are these issues that we don't

 

      have a good understanding internally, we have to

 

      schedule meetings with the appropriate people, have

 

      to have internal discussions.

 

                When the sort of standards aren't clear,

 

      this is an opportunity for the reference listed

 

      drug sponsors to challenge correspondence to OGD or

 

      through the citizen petition process that we have

 

      to address the scientific issues there that aren't

 

      sort of clearly defined.

 

                A lot of times, at the end of these

 

      discussions, we will end up going back to the

 

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      sponsors and asking them for more information to

 

      help us resolve these issues, and then usually that

 

      is done through deficiency letters to them, and it

 

      ends up with sort of multiple review cycles.

 

                So, as we heard in Lawrence's talk, there

 

      is the question of more product development

 

      information in the ANDA itself may help OGD deal

 

      with these issues more efficiently.

 

                This is sort of very similar to some of

 

      the things that Lawrence talked about, that there

 

      are harmonization efforts underway that describe a

 

      product development report, but I think it is clear

 

      that these are mainly aimed at new drug

 

      applications, so it is not sort of obvious or clear

 

      how these should apply to ANDA sponsors.

 

                I think the theme of this talk to see this

 

      as an opportunity, these development reports, as an

 

      opportunity to provide information that will help

 

      the agency set rational specifications for products

 

      that are complex, for immediate release oral dosage

 

      forms we have various standard systems set in

 

      place, but for topical products, where we have less

 

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      experience, the more information that is provided

 

      about, say, why was an excipient changed, and why

 

      do you know that it is not going to have any effect

 

      could be very helpful to us in making efficient

 

      decisions.

 

                Again, the product development reports are

 

      the place in the application to emphasize the

 

      quality by design, that the product is designed to

 

      be equivalent.  That will help us set the right

 

      requirements for the bioequivalence testing for

 

      particular products.

 

                This is just a few examples of what some

 

      of these harmonization documents say about a

 

      pharmaceutical development report.

 

                In this case, again, the key part here

 

      might be to establish that the dosage form and the

 

      formulation are appropriate for the purpose

 

      specified in the application, or in the Q8

 

      document, it talks about an opportunity to present

 

      the knowledge gained through the application of

 

      scientific approaches.

 

                Here, it is talking specifically about

 

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      sort of formulation and development for the topical

 

      products, that there is information that the

 

      company that is developing the generic product

 

      knows about why they made certain choices in the

 

      formulation.  It would be very helpful to us in

 

      deciding that that is acceptable, where the agency

 

      itself has less experience with particular dosage

 

      forms.

 

                I have emphasized this concept of quality

 

      by design or, in the case of the generic products,

 

      quality by design means you are designing the

 

      product to be equivalent to the reference product.

 

                So, I want to try to be a little bit more

 

      specific about what that means.  There are two

 

      cases.  One, the mechanism of release.  Clearly,

 

      the mechanism of release between a generic product

 

      and the reference product can be different, but the

 

      intent of those different mechanisms ought to be to

 

      produce the same rate and extent of absorption.

 

      This is the bioequivalence criteria.

 

                Again, we also recognize that depending on

 

      the particular product, that the release rate from

 

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      the product might not be the rate controlling step

 

      at absorption.  So, the determination of how close

 

      release rates might have to match would depend on

 

      the absorption process involved and what is the

 

      rate-limiting step in the absorption process.

 

                Again, between generic products and

 

      reference products, the excipients can be

 

      different.  Again, it is a good thing to understand

 

      the differences between the excipients.

 

                The IIG limits are a starting point.  They

 

      tell you that this excipient has been used in this

 

      dosage form up to a certain amount, and that really

 

      addresses, specifically in the case of topical

 

      products, safety-related exposures, so you know

 

      that level of exposure.

 

                The thing that complicates the topical

 

      products is when you change the excipients, the

 

      real question that we often deal with is do the

 

      changes in the excipients to the products affect

 

      the permeation of the drug through the skin. I

 

      think that is the sort of challenging question

 

      there for the topical products that we occasionally

 

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      have to deal with.

 

                Again, as I said, the purpose of quality

 

      by design is to design the equivalent product.  I

 

      want to just give sort of three sort of examples of

 

      this process here.

 

                The first is talking about Q1 and Q2

 

      equivalent products for topical products, and then

 

      look at what happens when you make changes to the

 

      formulation, they become Q1 and Q2 different, and

 

      then this leads into the discussion of issues

 

      related to the dosage form classification and how

 

      product development information might help us make

 

      a better decision or more scientific based

 

      decisions on dosage form classifications.

 

                First, I want to start off with the

 

      definition of Q1, Q2, Q3.  So, products that are Q1

 

      have the same components, so both the generic and

 

      the reference product would have the same

 

      components.

 

                If products are Q2, they would have the

 

      same components, but they would also have the same

 

      amount of each ingredient.

 

                The Q3 concept is same components, same

 

      concentration, but here I am saying same

 

      arrangement of material or microstructure, and this

 

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      is particularly important for topical products that

 

      are semisolid dosage forms, so non-equilibrium

 

      dosage forms, where you might have, say, an

 

      emulsion with exactly the same components, exactly

 

      the same concentrations, but say, for example, the

 

      droplet size might depend on how you have

 

      manufactured that product.

 

                So, there is potential differences for

 

      semisolid dosage forms depending on how they are

 

      produced even if overall the composition is exactly

 

      the same.

 

                A contrary example would be a solution.

 

      If a solution is Q1 and Q2, because the solution is

 

      at thermodynamic equilibrium, you would be able to

 

      say we know that this product has exactly the same

 

      arrangement of material in the product.

 

                The importance of the Q3 concept is when

 

      you know that the products have the same

 

      arrangement of material, you know that they are

 

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      going to be bioequivalent, there is no question

 

      about that.  An example of that is again a solution

 

      where you know that the products are in

 

      thermodynamic equilibrium if the compositions are

 

      the same, the structure and arrangement of the

 

      material is the same.

 

                Unfortunately, for most topical semisolid

 

      dosage forms, they are not necessarily equilibrium

 

      arrangements of material, and so a direct

 

      measurement of Q3 level equivalence is challenging.

 

                So, if we have the topical products where

 

      Q1 and Q2 are identical, again, the only potential

 

      differences are differences in this Q3 parameter,

 

      which can come from differences in manufacturing

 

      processes, because they are not going to be

 

      manufactured by exactly the same process.

 

                We know for particular semisolid dosage

 

      forms, such as emulsions, that rheology and in

 

      vitro release rates can be very sensitive

 

      measurements of microstructure and are related to

 

      product performances.

 

                So, the sort of idea that sort of

 

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      advancing here from a scientific point of view is

 

      when the products are Q1 and Q2, that in vitro

 

      tests should be equivalent to ensure bioequivalence

 

      of the two products, because again here, the issues

 

      are detecting differences due to differences in

 

      manufacturing processes, and the argument would be

 

      that in vitro tests are the best evaluation method

 

      to detect whether any differences in manufacturing

 

      process have significant differences in the product

 

      formulation or performance.

 

                Now, things get more complex when a

 

      generic product and a reference product have

 

      different compositions, and this connects with the

 

      dosage form classification, and these differences

 

      occasionally could be barriers to generic

 

      competition.

 

                A generic company might want to formulate

 

      products that are Q1/Q2 different because the

 

      innovator has formulation patterns, so there might

 

      be either legal reasons or perhaps manufacturing

 

      process reasons why you might want to formulate a

 

      product that is not exactly identical in

 

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      composition to the reference product.

 

                One of the products, again, one of the

 

      members of the Committee mentioned the sort of

 

      economic effect of uncertainty on product

 

      development if you don't know what dosage form the

 

      product is going to be classified as.  That adds

 

      cost to the development process because of

 

      uncertainty of what is going to happen to the

 

      product.

 

                In particular, if we think about methods

 

      by which we would classify the dosage form of

 

      topical products, here, I have generated a list of

 

      four possible ways that you could approach this.

 

                One is we would just use whatever the

 

      sponsor says their product is as long as it is

 

      consistent with some of the traditional definitions

 

      that are available in various sources, and we will

 

      look in sort of detail at some of those traditional

 

      definitions.

 

                You might say, well, the generic product

 

      is the same dosage form if it feels the same to me,

 

      so I will just try it out and see if it is the

 

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      same, if it passes.  You know, if the look and feel

 

      of the products are the same. That is getting to

 

      the aspect of pharmaceutical equivalence, a sort of

 

      patient experience rather than sort of scientific

 

      issues related to product performance.

 

                Then, I am going to sort of discuss recent

 

      work that the FDA group led by Cindy has done on

 

      looking at a whole bunch of products and coming up

 

      with a quantitative decision tree to classify

 

      topical products.

 

                Then, sort of the fourth aspect of that is

 

      looking at whether or not issues about dosage form

 

      classification for complex issues would be

 

      something that you would want to include in a

 

      product development report, so justifying the

 

      formulation development as being the same as the

 

      reference product.  That sort of might be a more

 

      scientific way to look at these issues.

 

                First, if we look a some of the

 

      traditional definitions.  Here, I will just focus

 

      on the difference between a cream and an ointment.

 

      One source is the CDER's data standards

 

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      definitions.  These are sort of similar to USP

 

      definitions of these products.

 

                The cream is a semisolid dosage form

 

      containing one or more drug substances dissolved in

 

      a suitable base, and then it says more recently the

 

      term has been restricted to products consisting of

 

      oil-in-water emulsions.  That is obvious what a

 

      company should do - does a cream have to be an

 

      oil-in-water emulsion or not.

 

                Then, it talks about products that are

 

      cosmetically and aesthetically acceptable, is part

 

      of the definition of the cream, so that is not very

 

      quantitative. It is hard to say is this product

 

      aesthetically acceptable. That is really opinion

 

      based.

 

                An ointment is a semisolid preparation

 

      intended for external application.  It seems to me

 

      that a cream could be a semisolid preparation and

 

      fit under the ointment definition.  So, it doesn't

 

      seem that those two definitions are really

 

      exclusive.

 

                In another FDA guidance, this is the SUPAC

 

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      semisolid guidance.  It has a glossary with

 

      definitions of dosage forms, but these aren't the

 

      same as the previous ones.  A cream is a semisolid

 

      emulsion, and an ointment is an unctuous semisolid

 

      and typically based.  So, typically based is not

 

      sort of a definition, it doesn't have to be based

 

      on petrolatum.

 

                This definition talks about an ointment

 

      being one phase, and not having sufficient water.

 

      Again, the USP definition is sort of similar to the

 

      one in the CDER data standards, but it is not

 

      word-for-word identical, and talks about four

 

      different classes of ointments.

 

                So, again, the problem with the

 

      traditional classifications is they are not really

 

      consistent, and not very quantitative.  So, a lot

 

      of the sort of decision process would depend on

 

      what your opinion was of a particular product, and

 

      they might be overlapping, like you might be able

 

      to call--under a particular definition of a

 

      particular product, you might be able to call it a

 

      cream or an ointment.

 

                So, the result of this Topical Working

 

      Group led by Cindy has been presented to previous

 

      advisory committee meetings, and they recently

 

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      published a paper outlining this classification

 

      scheme.

 

                What they did was they surveyed existing

 

      products and devised a classification scheme, and I

 

      just included the classification scheme here just

 

      for reference in the presentation.

 

                These are just some slides from their

 

      previous presentations to give you the general idea

 

      of what they did. They measured particular aspects

 

      of products, say, creams and ointments, they

 

      measured viscosity.

 

                They looked at the loss on drying, and

 

      then based on these products that were either on

 

      the market or manufactured for them, they came up

 

      with a classification scheme that sort of put the

 

      products in the right category based on existing

 

      products.

 

                The real advantage of this is it is

 

      quantitative. If you take a product and you go

 

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      through and you measure the things outlined in

 

      their decision tree, you will always end up in the

 

      same place, and it will always be consistent.

 

                In addition to that, this is a very data

 

      driven approach.  They looked at the products and

 

      then drew the lines.  It wasn't said here is sort

 

      of a mechanistic definition of what a cream or an

 

      ointment should do.

 

                So, the question is, could this be overly

 

      restrictive.  If you follow this classification

 

      scheme, you would be restricting products to

 

      essentially what has been done before, and then

 

      there is a question.

 

                They didn't survey every product that is

 

      on the market now, so there is a question, if a

 

      reference listed drug falls into a different part

 

      of this classification scheme, then, it's labeling.

 

      So, it might be labeled as a cream, but by the

 

      definition, it would be classified as an ointment.

 

      What should a sponsor do in that case?

 

                So, the final sort of approach to dosage

 

      form classification might be to look at a more

 

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      scientific view of the formulation design.  I just

 

      want to point out that sort of the legal aspects,

 

      referring to topical use, sort of point toward this

 

      here from the CFR.

 

                It talks about inactive ingredient changes

 

      for topical products.  It says again that

 

      abbreviated applications can use different

 

      ingredients if they identify and characterize the

 

      difference and provide information demonstrating

 

      that the differences do not affect the safety or

 

      efficacy of the proposed drug products.

 

                So, a current way of looking at is a

 

      change in formulation acceptable, you should check

 

      the new excipients against the IIG.  As I said

 

      before, this looks at the safety of the individual

 

      excipients.

 

                We also really consider that passing

 

      bioequivalence tests are evidence that the

 

      formulation change is acceptable.  That is one

 

      strong piece of evidence against that.  But again

 

      the product development report is an opportunity

 

      for sponsors to characterize the differences.

 

                Again, this could be important, you know,

 

      if you are formulating a product and you are on the

 

      boundaries of these, we have this empirical

 

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      decision tree, what happens if you are on the

 

      boundaries, how do you explain that this product

 

      should be considered the same as the reference

 

      product, you know, from a scientific point of view

 

      rather than empirical classification scheme, of if

 

      someone says, well, no, your product is not really

 

      an ointment because it doesn't meet a particular

 

      published definition.

 

                So, again, the product development report

 

      is the opportunity for a sponsor to characterize

 

      the difference that is sort of requested in the

 

      statutes.

 

                Again, also, in the statutes, they list

 

      reasons to reject ANDAs, and they talk about drug

 

      products for topical administration where there is

 

      a change in lipophilic properties of the vehicle.

 

                Again, in this case, a product development

 

      report is an opportunity for sponsors to explain

 

      why the changes, Q1 and Q2 differences are

 

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      appropriate for this particular product.

 

                If this issue comes up, a lot of times we

 

      will actually have to go from the review process,

 

      you will have to go back and ask sponsors for more

 

      information about these particular issues.  So, the

 

      development report is sort of an up-front way to

 

      explain the reasons for doing that.

 

                Just to sort of conclude the discussion

 

      here, the first concept is the importance of Q1,

 

      Q2, Q3 classification to identify appropriate

 

      bioequivalent studies for the level of difference

 

      in the product design.  If a few products have

 

      exactly the same active and inactive ingredients,

 

      you might want to request different in vivo

 

      bioequivalence studies than for a product where

 

      there has been a change in inactive ingredient that

 

      may affect the absorption of the drug product.

 

                So, here again, we are looking at the

 

      second concept, we are looking at the evolution of

 

      the concept of pharmaceutical equivalence where we

 

      have these traditional dosage form definitions,

 

      maybe now backed up by empirical decision trees,

 

                                                               165

 

      but in the future, looking for a quality-by-design

 

      aspect where the determination of whether a product

 

      should be considered equivalent would depend on the

 

      mechanistic understanding and the formulation

 

      design rather than some traditional definitions,

 

      and that the ideal state would be that this

 

      understanding would reduce the need or allow us to

 

      set the appropriate in vitro testing for a

 

      particular product, and also to expand sort of the

 

      formulation design space beyond past experience.

 

                If you want to formulate a product that

 

      goes beyond, say, an empirical dosage form

 

      classification, this is the sort of way that you

 

      would approach it, by providing the scientific

 

      information to show that the formulation you have

 

      chosen gives equivalent performance in the key

 

      attributes as the reference product.

 

                With that, I will conclude my

 

      presentation.

 

                DR. COONEY:  Thank you.  I believe the

 

      purpose of your presentation today is to bring us

 

      up to date on the current thinking where you are

 

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      and where you are going as opposed to requesting a

 

      specific action on our part, is that correct?

 

                DR. LIONBERGER:  Yes, that's right.

 

                DR. COONEY:  I would like to invite

 

      questions and comments from the Committee.  Yes,

 

      Cynthia.

 

                DR. SELASSIE:  This is a very general

 

      question.  With all these product development

 

      reports that you get, obviously, there is going to

 

      be a lot of information that is extraneous and

 

      won't be useful for that particular application,

 

      but will you all retain this information like in a

 

      database, so that it could have use down the line?

 

                DR. LIONBERGER:  I don't know if we would

 

      retain it in a database, but I would say that like

 

      as Lawrence said, we are looking at our review

 

      process, and in that, had the opportunity to read

 

      several product development reports.

 

                I find that they are a very useful way to

 

      get an overview of what is going on with a

 

      particular product.  You know, an hour of reading

 

      the development report, it seems like a very good

 

                                                               167

 

      way to start the review of the application in more

 

      detail, so I think it can be very valuable.

 

                We don't have much experience with using

 

      them yet, so in that sense, it could be valuable,

 

      but we don't know how we would use that information

 

      or store that information in the future.

 

                DR. HUSSAIN:  If you are suggesting that

 

      there is a need to capture and create databases, I

 

      think we do want to move in that direction, and we

 

      tried to do that.  Currently, our systems does

 

      capture some of the key aspects. The inactive

 

      ingredient guide is a process that we capture every

 

      inactive ingredient that comes, but developing a

 

      formal knowledge base would really be helpful, and

 

      I think we have been thinking about it.

 

                I tried to do that with immediate release

 

      dosage forms and actually did some modeling with

 

      that data that we have, and so forth, so we will

 

      look into that.

 

                DR. COONEY:  Are there any other questions

 

      from the Committee?  Marv.

 

                DR. MEYER:  Just a quick comment.  You

 

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      have my sympathies.  I thought it was difficult to

 

      determine how to do the BE studies on topicals, and

 

      now I have been reinforced, you don't even know

 

      what slot to put them in the Orange Book if they

 

      are bioequivalent, so you have a big job ahead of

 

      you.

 

                DR. COONEY:  If there are no further

 

      comments, Robert, thank you very much.

 

                There have been no requests for

 

      participation in the open public hearing at 1

 

      o'clock, so we will proceed with the continuation

 

      of the discussion on quality by design precisely at

 

      1 o'clock when we come back from lunch.

 

                We will begin that by a presentation of a

 

      summary of the plan by Ajaz, and then we will

 

      continue the discussion that we began earlier this

 

      morning.

 

                So, enjoy lunch and we will see you back

 

      at 1 o'clock.

 

                [Whereupon, at 11:59 a.m., the proceedings

 

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

 

                                                               169

 

                A F T E R N O O N  P R O C E E D I N G S

 

                                                       [1:00 p.m.]

 

                DR. COONEY:  I would like to welcome

 

      everyone back from lunch.

 

                We will proceed with the afternoon

 

      schedule.  The first topic this afternoon will be

 

      Ajaz Hussain, who will provide a summary

 

      description of the plan to go forward.

 

                  Quality-by-Design and Pharmaceutical

 

                        Equivalence (Continued)

 

                            Summary of Plan

 

                DR. HUSSAIN:  I am going to go back to the

 

      slides I used in the morning instead of the ones I

 

      had for this session.  That was based on the

 

      discussion that occurred.

 

                Just on reflection, I just want to make a

 

      couple of points.  Yesterday, in a sense, as part

 

      of the tactical plan to start our journey towards

 

      the desired state, in a sense what we have done at

 

      this meeting is to take a look back last 10 years

 

      or so to see how our policies have evolved and how

 

      they could evolve with two tools that we have

 

                                                               170

 

      introduced, the PAT guidance and ICH Q8.

 

                Tom Layloff reminded me that in many ways,

 

      some of the topics we have discussed, we have been

 

      discussing for 30 years, and we keep discussing

 

      those topics again and again, and the difference

 

      that we have tried, at the training session that

 

      some of you attended, I am clearly cognizant of the

 

      fact that we are discussing topics that we have

 

      been discussing for 30 years, and the quote I had

 

      was the thing that if you tried to approach the

 

      problem with the same tools and the same approach

 

      again, we are bound to find the same solutions, so

 

      we need something new.

 

                What is new at the issue of this problem

 

      is the science of formulation design, of science of

 

      product design. The key aspect, much of that has

 

      always been considered as an art, and as the

 

      complexity of products is increasing, that art will

 

      not be sufficient to really achieve the performance

 

      we are trying to achieve.

 

                So, it is a reflection back of saying all

 

      right, 30 years of pharmaceutical sciences in

 

                                                               171

 

      particular pharmaceutics, industry, pharmacy, and

 

      so forth, what have we learned and what we need to

 

      learn more to do things differently.

 

                In some sense, that is the heart of the

 

      debate.  I also sort of mentioned to you, and this

 

      is my original starting point in the thought

 

      process was that you really need at FDA more people

 

      with that background to really make that happen.  I

 

      changed my thoughts over the last several years.

 

                What we have at FDA is scientists from

 

      many, many different disciplines who sort of work

 

      together.  The reason I changed my mind was I think

 

      looking at some of the practices and formulation