Bioequivalence Study Template by eoz25885

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									WHO Procurement, Quality and Sourcing
                  Project:
Access to HIV/AIDS Drugs and Diagnostics
           of Acceptable Quality




 Experience from the Evaluation of
     Drug Dossiers with Respect to
            Bioequivalence Data
Hans Kemmler
                                     1
Swissmedic, Switzerland
    Invited Generic Products

Expressions of Interest were invited for
   Nucleoside Reverse Transcriptase Inhibitors
     – 7: Zidovudine, Didanosine, Lamivudine etc.
   Non-nucleoside Reverse Transcriptase Inhibitors
     – 3 : Nevirapine, Efavirenz, Delarvidine
   Protease Inhibitors
     – 6 : Amprenavir, Saquinavir, Ritonavir etc.
   Other Anti-infective drugs:
    Antibacterials, Antimycotics, Antiprotozoals, other
    Antivirals, Anti-cancer drugs


                                                          2
    Submitted Generic Products

Of the appr. 280 Expressions of Interest
  were
   34 files for solutions for
    injection requiring no BE study
   222 files for tablets/capsules/oral suspensions
    requiring BE study
   19 submissions for oral solutions
   About 80 products up to now have been found
    acceptable, in principle, for procurement by UN
    agencies
    (included in list available : http://mednet3.who.int/prequal/ )
                                                                      3
Summary of Submissions for
HIV/AIDS-Drugs
   Antibacterials      56
   Antimycotics        24
   Antiprotozoals      7
   other Antivirals    18
   Anticancer          6
   Nucleosid RTI       86
   NRTI Combi          34
   Non-Nucleosid RTI   18
   Prot.Inhibitors     18
                             4
                                   Antibacterials
Distribution of submissions
                                   Antimycotics

                                   Antiprotozoals

           18
                                   other Antivirals
     18         56
                                   Anticancer

34                                 Nuclosid RTI

                              24   NRTI Combi

                          7        Non-Nucleosid RTI
                     18
                                   Prot.I
      86        10




                                                       5
    Distribution of prequalifiedAntibacterials
        products (appr. 80)     Antimycotics

                                    Antiprotozoals

                     8
                                    other Antivirals
         10
                                    Anticancer
                           6
    5                               Nucleosid RTI

                               2    NRTI Combi
4
                               4    Non-Nucleosid
                                    RTI
                               2    Prot.I




              32
                                                       6
          NRTI prequalified

                             Nucleoside RTI prequalified

14

12

10

8

6

4

2

0
     Abacavir   Didanosine   Lamivudine   Lam-comb   Stavudine   Zalcitabine   Zidovudine


                                                                                       7
                                  10
                                  12
                                  14




                                   0
                                   2
                                   4
                                   6
                                   8
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                            ir

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    PQ generic
                          om
                            b

                  St
                    av
                      ud
                        i
    Innovators
                            ne

                 Za
                   lc
                                       Nucleoside RTI prequalified




                      ita
                         bi
                           ne

                 Zi
                   do
                     vu
                       di
                          ne
8
Prequalification results of
NRTI
   120 submissions for NRTI and
    combinations with NRTI
   36 prequalified
   Of 36 NRTI prequalified, only 14 are
    generics
   Of 98 submissions for generic NRTI,
    84 not (yet) prequalified

                                           9
Prequalification Results of
Protease Inhibitors


All prequalified PI are from
innovator companies, none
is a generic


                               10
    WHY?
    Deficiencies in BE Studies ? YES
   About 50% of submissions without
    bioequivalence study
   Of submitted studies:
     –   About 50% with inadequate method validation

     – ~ 50% without verification that test product is
         exactly same as applied-for-product

     – ~ 35% without basic statistical evaluation

                                                    11
Other Identified Deficiencies in
BE studies
Minor deficiencies (information not presented,
but easily accessible)
   Individual pharmacokinetic parameters not
    submitted
   Pharmacokinetic and statistical calculations not
    submitted
   Detailed description of study design not
    submitted

                                                  12
Identified Deficiencies in BE
studies

Minor deficiencies (cont.)
   No information on batch size of test product
   Certificate of Analysis of test batch not
    submitted
   In-vitro dissolution profiles not submitted
    – for test product
    – for reference product
    – for different strengths of the same product


                                                    13
    Conclusion in Project
   Some problems arise again and again,
    from many applicants




More        advice needed !!
And        is possible !

                                           14
        Two New Documents
          soon available
1.   Note to Applicants on Choice of
     Comparator Products in the
     Prequalification Project
2.   Template: ASSESSMENT REPORT FOR
     PREQUALIFICATION OF MULTI-
     SOURCE (GENERIC) FINISHED
     PHARMACEUTICAL PRODUCTS (FPPS)
     NOT REGISTRED IN ICH REGIONS OR
     RELATED COUNTRIES


                                       15
         Note on Choice of
         Comparator Products:
            Current status
   Note to Applicants on Choice of
    Comparator Products in the
    Prequalification Project:
    – First draft (Jan. 2005) was circulated
      among experienced assessors from
      several countries
    – After receiving and evaluating
      comments, few changes to be expected

                                               16
Note on Choice of Comparators

    Objective:
    This note is intended to provide to
     applicants some additional guidance
     and clarification on existing guidance
     documents how to select an
     appropriate comparator product for a
     bioequivalence study necessary for
     generic products submitted into the
     WHO prequalification project .


                                              17
Note on Choice of Comparators

    Background 1:
    The following information is already
     provided on the web site, see (http://mednet3.
     who.int/prequal/ , Documents and Materials, Bio-equivalence)

    “What data and information needs to be
     submitted in a dossier for a generic
     product?”
    “A set of bio-equivalence study data is
     required for all oral preparations” !!!!!!


                                                                    18
Note on Choice of Comparators
    Background 2:
    With regard to the choice of comparator
     products reference is made on the website to
     “International comparator products for bio-
     equivalence testing"
    Annex 11 of Thirty-sixth Report of the WHO Expert
     Committee on Specifications for Pharmaceutical
     Preparations. WHO Technical Report Series, No. 902,
     2002: 161-180: Guidance on the selection of
     comparator pharmaceutical products for
     equivalence assessment of interchangeable
     multisource (generic) products. [Annex 11]


                                                           19
Note on Choice of Comparators:
     General comments:

    The innovator pharmaceutical product
     is usually the most logical comparator
     product for a multisource
     pharmaceutical product because its
     quality, safety and efficacy should have
     been well assessed and documented in
     premarketing studies and post-
     marketing monitoring schemes.


                                                20
Note on Choice of Comparators:
     General comments:
    Whenever possible the innovator
     products should be obtained from a
     well regulated market with stringent
     regulatory authority (countries such as
     Australia, Canada, EU Member States,
     Japan, USA, Switzerland) , and the
     Product Information (or Summary of
     Product Characteristics) of the
     respective country should be used for
     reference for future up-dates of safety
     relevant informations.

                                               21
Note on Choice of Comparators:
     General comments:

    Never should a generic drug be used as
     comparator as long as an innovator
     drug is available, because this could
     lead to a “bio-creep” phenomenon,
     resulting in progressively less reliable
     similarity of future multisource
     products and to lack of
     interchangeability with the innovator.
    Lacking of availability on local market is
     no excuse

                                                  22
              „Bio-Creep“

                                 Relative BA                   Interchangeable
                                                               Not Interchangeable
 120
 100
  80
% 60                                                                   Relative BA
  40
  20
   0
       Generic 1   Innovator   Generic 2   Generic 3   Generic 4

                                                                                 23
Note on Choice of Comparators:
     General comments, FDC:

    Similar considerations apply to the use
     of fixed-dose-combinations, which were
     approved exclusively on the basis of
     bioequivalence studies comparing with
     the individual components

     (individual components were, however, used as
     free combinations (i.e. individual products co-
     administered) in comprehensive efficacy and safety
     studies)


                                                          24
Note on Choice of Comparators:
     General comments, FDC:
    Such FDC’s should normally not be
     used as comparators – even if approved
     by ICH countries – instead again the
     individual components should be used
     as comparators. (otherwise „bio-creep“)
    However, there are also some fixed-
     dose-combinations which were used as
     such extensively in clinical trials, thus
     direct, “own” evidence for their efficacy
     and safety is available.
     These can be used !!!
                                                 25
Note on Choice of Comparators:
     Example for 4-FDC:
    Bioequivalence study, 1999,
     accepted in EU, Switzerland and
     by WHO:
    Rimstar 4-FDC®
    versus
    Rimactane ® + Isozid ® + Rolab
     Pyrazinamide ® + Myambutol®

                                       26
Note on Choice of Comparators:
     Example for 4-FDC:
    Rimstar 4-FDC® (Rifampicin 150, Isoniazid 75,
     Pyrazinamide 400, Ethambutol 275mg) 4 tablets given
     in a single dose

    versus
    Rimactane ® (Novartis, Switzerland*) 4 capsules each
     containing 150mg rifampicin
    Isozid ® (Fatol, Germany) 3 tablets each containing
     100 mg isoniazid
    Rolab Pyrazinamide ® (Rolab, South Africa) 3 tablets
     each containing 500 mg Pyrazinamide
    Myambutol® (Lederle Arzneimittel GmbH & Co) 2
     tablets containing 400mg and 3 tablets containing
     100mg ethambutol

                                                            27
Note on Choice of Comparators:
     Example for FDC:
    However, even if approved in
     many countries, Rimstar ® is still
     not an acceptable reference,
     because approval was based
     exclusively on BE-studies
    In contrast, with Rifater ® (3FDC)
     and Rifinah ® (2FDC) extensive
     clinical studies have been done,
     these would be acceptable

                                          28
Note on Choice of Comparators:
     Example for FDC:
    Appear in List A of Annex 11:




                                     29
Note on Choice of Comparators:
     General comments, Principle:
    General principle for selection of
     an appropriate comparator:


    As near as possible in the
     chain of evidence to the
     product for which efficacy
     and safety has been directly
     shown.

                                          30
Note on Choice of Comparators:
             Schema
    Wherever possible, follow:
1.   “Blue book” Marketing Authorization of
     Pharmaceutical Products with special
     Reference to Multisource (Generic)
     Products : a Manual for a Drug
     Regulatory Authority,
     WHO/DMP/RGS/98.5
2.   Annex 11 (see above, slide 19)


                                              31
Note on Choice of Comparators:
             Schema
However:
   The “Blue book” and the “Annex 11”
    were developed for national regulatory
    agencies regulating single national
    markets
   Not all recommendations applicable to
    international markets
   The concept of a “national market
    leader” cannot be used for
    prequalification project

                                             32
                Note on Choice
                 How to choose
1.   Innovator
     a)   Easily identifiable for new drugs (only two
          for TB)
     b)   Consult Annex 11, List A, also for Tb several
          drugs listed
2.   Pharmaceutical products approved in the WHO
     prequalification project for which a full dossier
     for quality, safety and efficacy was submitted
     and evaluated. (currently only anti-malarials)
3.   Try to find accepted comparator in “Note”
4.   If no innovator and no product listed in
     Annex11 ?

                                                          33
               Note on Choice
                How to choose
4.   No innovator, no List A product, nothing in
     „Note“:
     Difficult, extensive justification is necessary:
     The most important selection criterion will be
     based on extensive – documented – use in
     clinical trials reported in peer-reviewed
     scientific journals, and after this, approval in
     ICH- and associated countries.




                                                        34
Template: ASSESSMENT REPORT FOR
PREQUALIFICATION OF MULTI-
SOURCE (GENERIC) FPPS

   Used by assessors of BE-studies for
    harmonisation of approach and
    completeness of evaluation
   In project used since appr. July 2004
   Derived with small adjustments from
    template of Canadian drug regulatory
    authority (there used since many
    years)
                                            35
                          Template

                              BIOEQUIVALENCE TRIAL INFORMATION


1 SUMMARY OF BIOAVAILABILITY/BIOEQUIVALENCE STUDIES PERFORMED
(Provide a brief description of each comparative bioavailability study included in the submission)

2 Has comparative bioavailability data been submitted for all strengths?
(If comparative bioavailability data has not been submitted for all strengths, provide a scientific justification for not
submitting such data)


Sections 3.0 – 9.0 below should be copied and completed separately for each
bioequivalence study performed.

3.0 CLINICAL STUDY REPORT


                                                                                                                   36
                  Template

3.0 CLINICAL STUDY REPORT

Study #:
Study Title:
Location of Study Protocol:
Start and stop dates for each phase of the clinical study:

3.1 ETHICS

(a) Name of review committee, date of approval of protocol and consent form, location of
   approval letter in the submission

(b) State location of a reference copy of the informed consent form



                                                                                       37
    Template Section 3.2

3.2 INVESTIGATORS AND STUDY ADMINISTRATIVE
STRUCTURE

(a) Name of principal investigator(s) (State location of C.V. in the
submission)

(b) Clinical Facility (Name and full mailing address)

(c) Clinical Laboratories (Name and full mailing address)

(d) Analytical Laboratories (Name and full mailing address)

(e) Company performing pharmacokinetic/statistical analysis (Name and
full mailing address)




                                                                       38
 Template Section 3.4
3.4 INVESTIGATIONAL PLAN


  3.4.1 Overall Study Design and Plan – Description
          (Describe the type of study design employed in 1-2 sentences)

  3.4.2 Selection of Study Population

          3.4.2.1 Inclusion Criteria

           3.4.2.2 Exclusion Criteria
        (List the exclusion criteria applied to subjects)

  3.4.2.3 Removal of Patients from Therapy or Assessment

             (a)         Number of subjects enrolled in the study
             (All subjects including alternates, withdrawals, and dropouts)

              (b)         Withdrawals
  (Identify each withdrawal by subject and provide the reason for withdrawal and at
  what point in the study the withdrawal occurred)

                                                                                 39
Template Section 3.4

3.4.2    Treatments Administered

3.4.3.1 Test Product

(a) Batch number and date of manufacture for the test product


(b) Potency (measured content) of test formulation as a
percentage of label claim
          (This information should be cross-referenced to the
location of the certificate of analysis in the submission)




                                                                40
  Template Section 3.4.3.2
Reference Product

(a) Name and manufacturer of the reference product

(b) Batch number and expiry date for the reference product


(c) Potency (measured content) of the reference formulation as a
percentage of label claim (This information should be cross-
referenced to the location of the certificate of analysis in the
submission)


(d) Justification of choice of reference product
(Provide short summary here and cross-reference to location of
comprehensive justification in study protocol)

                                                                 41
Template Section 3.4.6

 Blinding

    3.4.6.1 Identify which of the following were blinded. If
 any of the groups were not blinded, provide a justification for
 not doing so

 (a)        study monitors
 (b)        subjects
 (c)        analysts

    3.4.6.2 Identify who held the study code and when the
 code was broken



                                                             42
Template Section 3.4.7
3.4.7 Drug Concentration Measurements

    3.4.7.1 Biological fluid(s) sampled

    3.4.7.2 Sampling Protocol

(a) Number of samples collected per subject
(b) Volume of fluid collected per sample
(c) Total volume of fluid collected per subject per phase of the
study
(d) List the study sampling times

(e) Identify any deviations from the sampling protocol
(State location of summary in the submission)
(Describe and explain reasons for deviations from sampling
protocol. Comment on impact on study. Indicate whether the
deviations were accounted for in the pharmacokinetic analyses)

                                                               43
       Template Section 3.5



3.5 Comments from review of Section 3.0 – WHO
use only




                                                44
  Template Section 5

5.0 PROTOCOL DEVIATIONS


5.1 Protocol deviations during the clinical study
(Describe any such deviations and discuss their
implications with respect to bioequivalence)




5.2 Comments from review of Section 5.0 – WHO use
only

                                                    45
 Template Section 7

7.0 EFFICACY EVALUATION –
    Efficacy Results and Tabulations of Individual Patient Data




7.1 Presentation of Data

   (a) State location in submission of tables of mean and individual
subject concentrations

   (b) State location in submission of (mean and individual) linear
and semi-logarithmic subject drug concentration vs. time plots



                                                                46
                Template Section 7.1



7.2 PHARMACOKINETIC (PK) PARAMETERS

                                        % Ratio of
    Parameter    Test     Reference                     90 % Confidence Interval
                                      Geometric Means

AUCT (units)
AUCI (units)

Cmax (units)




                                                                              47
                Template Section 8
                                         Must always be provided !!
8.0 ANALYTICAL STUDY REPORT


8.1 ANALYTICAL TECHNIQUE

    8.1.1 Analytical protocol
         (State the location of the analytical protocol)

    8.1.2 Identify analyte(s) monitored

    8.1.3 Identify analytical technique employed



                                                                  48
   Template Section 8.6
                      Must always be provided !!
8.6 Chromatograms
(State the location in the submission where the sample chromatograms
can be found. The chromatograms should be obtained from a minimum
of two analytical batches and include at least 20% of the subjects, up to
a maximum of five. A complete set includes standards, QC samples,
pre-dose and post-dose subject samples for both phases. Each
chromatogram should be clearly labelled with respect to the following:
date of analysis; subject ID number; study period; sampling time;
analyte; standard or QC, with concentration; analyte and internal
standard peaks; peak heights and/or areas)




                                                                            49
 Template Section 9
                Must always be provided !!
9.0 ANALYTICAL VALIDATION REPORT



    9.1 Precision and Accuracy

      (a) Summarize inter-day and intra-day accuracy and
          precision during assay validation

      (b) Summarize inter-day and intra-day accuracy and
          precision during assay re-validation
           (If applicable)


                                                           50
Template Section 10
10.0 QUALITY ASSURANCE


10.1     Internal quality assurance methods
       (State locations in the submission where internal
       quality assurance methods and results are
       described for each of study sites (see 3.2 b-d)

10.2        Monitoring, Auditing, Inspections
       (Provide a list of all monitoring and auditing reports
       of the study, and of recent inspections of study sites
       by regulatory agencies. State locations in the
       submission of the respective reports for each of
       study sites (see 3.2 b-d)

                                                           51
Wanted !




           52

								
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