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

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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
• Swissmedic, Switzerland

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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 drugsAntibacterials,
  Antimycotics, Antiprotozoals, other Antivirals,
  Anti-cancer drugs

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Submitted Generic Products

• Of the appr. 280 Expressions of Interest were
• 34 files for solutions forinjection 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/ )

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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

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NRTI prequalified
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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

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Prequalification Results of Protease Inhibitors

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

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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

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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

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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

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Conclusion in Project

• Some problems arise again and again, from many
  applicants
• More advice needed !!
• And is possible !

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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

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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

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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 .

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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 !!!!!!

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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

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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.

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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.

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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

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Bio-Creep
Interchangeable Not Interchangeable
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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)

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Note on Choice of Comparators General comments,
FDC

• Such FDCs 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-combinatio
  ns which were used as such extensively in
  clinical trials, thus direct, own evidence for
  their efficacy and safety is available. These
  can be used !!!

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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

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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

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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

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Note on Choice of Comparators Example for FDC

• Appear in List A of Annex 11

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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.

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Note on Choice of Comparators Schema

• Wherever possible, follow
• 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
• Annex 11 (see above, slide 19)

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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

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Note on ChoiceHow to choose

• Innovator
• Easily identifiable for new drugs (only two for
  TB)
• Consult Annex 11, List A, also for Tb several
  drugs listed
• 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)
• Try to find accepted comparator in Note
• If no innovator and no product listed in Annex11 ?

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Note on ChoiceHow to choose

• No innovator, no List A product, nothing in
  NoteDifficult, 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.

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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)

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Template
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Template
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Template Section 3.2
  (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)
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Template Section 3.4
  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) Wit
hdrawals (Identify each withdrawal by subject and
provide the reason for withdrawal and at what
point in the study the withdrawal occurred)
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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)


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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)
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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
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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)
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Template Section 3.5
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Template Section 5
  5.1 Protocol deviations during the clinical
study (Describe any such deviations and discuss
their implications with respect to
bioequivalence)  
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Template Section 7
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
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Template Section 7.1
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Template Section 8
Must always be provided !!
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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)
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Template Section 9
Must always be provided !!
  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)
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Template Section 10
  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)
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Wanted !
Bioequivalence Studies