PREQUALIFICATION OF ANTIMALARIAL DRUG PRODUCTS

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PREQUALIFICATION OF ANTIMALARIAL DRUG PRODUCTS
Assessment of product dossiers Clinical and
Bioequivalence part

• Hans Kemmler
• Clinical Reviewer
• Antibacterials and Antimalarials
• Swissmedic
• Bangkok, 19 October 2004

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Overview

• Prequalification Requirements for Finished
  Pharmaceutical Products (FPPs)
• Clinical issues
• The basic requirements
• Results of evaluation
• Conclusions

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Prequalification Requirements for Finished
Pharmaceutical Products (FPPs)

• Website WHO (http//mednet3.who.int/prequal/defau
  lt.htm)
• Manufacturers are requested to submit a covering
  letter, sample and product dossier (generics --
  innovator) including a completed checklist.
• Generics If innovators exist and are approved
  Bioequivalence study, assessed with
  http//www.who.int/medicines/library/qsm/manual-on
  -marketing/who-dmp-rgs-985.doc
• Innovator What data and information needs to be
  submitted in a dossier for an innovator product?

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Artemisinin- Generics for Malaria?

• Currently only very few innovators (artemisinin
  derivatives) approved in ICH- and associated
  countries
• No reference product available for bioequivalence
  studies

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Artemisinin - Innovators?

• What data and information needs to be submitted
  in a dossier for an innovator product?
• For innovator products, registered/licensed in
  the USA, EU or Japan Submit the following
  information
• A WHO-type Certificate of a Pharmaceutical
  Product issued by one of the regulatory authority
  of ICH regions (or other stringent regulatory
  authorities), together with the summary of
  product characteristics (SmPC)
• Assessment report(s) issued by the respective
  regulatory authority
• ........
• Does not apply to most of FPP for which
  Expression of Interest was invited

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Problems for applicant (1)

• Is my FPP an innovator product?
• Then, since not approved in ICH countries
• Full documentation of preclinical and clinical
  efficacy and safety according to ICH requirements
  has to be provided, all claims in SPC have to be
  substantiated
• fully documented clinical studies!! (abstracts
  and even publications normally not sufficient)

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Problems for applicant (2)

• I want my FPP to be evaluated as generic! Which
  reference product can I use for BE-studies?
• Currently no recommendations possible
• Applicant has to research literature for suitable
  reference product, and prove that this product
  has sufficient efficacy and safety data
  available
• Very difficult!
• (But Help from WHOs side maybe coming)

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Questions of applicants (1)

• The active ingredient of my FPP is listed in the
  WHO - Essential Drugs List
• http//www.who.int/health_topics/essential_medicin
  es/en/ Essential medicines are those that
  satisfy the priority health care needs of the
  population. They are selected with due regard to
  public health relevance, evidence on efficacy and
  safety, and comparative cost-effectiveness.
  http//www.who.int/medicines/organization/par/edl/
  eml2002core.doc
• http//www.who.int/medicines/organization/par/edl/
  eml2002comp.doc The complementary list presents
  essential medicines for priority diseases which
  are efficacious, safe and cost-effective but not
  necessarily affordable, or for which specialised
  health care facilities or services may be needed.
• Why do I have to prove efficacy and safety again?

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Model List of Essential Medicines(13th list)

• artemether (2) (injection) P01BE02
• artemether lumefantrine (1) (tablets)
  P01BE52
• artesunate (2) (tablets) P01BE03
• (1) core list, (2) complementary list

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Questions of applicants (2)

• WHO has invited Expression of Interest, so
  efficacy and safety are already known and
  documentation already at WHO?
• Innovators Why do I have to prove efficacy and
  safety again?
• Generics Which is possible reference product?

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Problems of assessors (1)

• Evidence of efficacy and safety of active
  ingredient is not sufficient evidence for FPP,
  each has to be evaluated on its own merits
• With one exception, the FPPs which have been
  used for inclusion of API in Essential Drugs
  List, are not known to assessors -gt thus even not
  possible to provide guidance for reference
  product

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Problems of assessors (2)

• Within time frame for assessment, no possibility
  to perform own literature review -gt has to be
  provided by applicant for his FPP
• No guidance documents or SOPs from WHO
  applicable -gt assessors developed draft SOP for
  specific problem

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Clear deficiencies in many submissions received

• No characterisation of pharmacokinetic properties
  of FPP For innovators and generics as well
  unacceptable
• General statements
• No interaction known -gt clearly not true
• No (or minimal) adverse events information has
  to be provided through literature survey
• Too broad efficacy claims

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Clear deficiencies

• Galenical development history not provided -gt Do
  results of earlier studies apply to current
  formulation?
• Lacking List of all clinical trials performed
  with
• specific FPP (including information on
  formulation, if possible)
• Active ingredient

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Clear deficiencies

• Far from complete toxicological documentation
  Literature easily available e.g.
  ARTEMISININ-COMPOUNDS LITERATURE LIST
• 1. Abdin MZ, Israr M, Rehman RU, Jain SK.
  Artemisinin, a novel antimalarial drug
  biochemical and molecular approaches for enhanced
  production. Planta Med 69(4)289-299, 2003.
• To
• 352. Zheng GQ Cytotoxic terpenoids and
  flavonoids from Artemisia annua. Planta Med
  6054-57, 1994.
• 353. Ziffer H, Highet RJ, Klayman DL
  Artemisinin an endoperoxidic antimalarial from
  Artemisia annua L. Fortschr Chem Org Naturst
  72121-124, 1997.

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Toxicological data

• In contrast to ICH guidelines full documentation
  not required in these cases
• Are well investigated for API, only FPP specific
  data (e.g. local tolerance) should be presented
• Expert report is sufficient, emphasis on tox-data
  with possible relevance for adverse events

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Lessons learned during assessment

• Applicants
• Several applicants submit very small bits and
  pieces of information relating to their FPP
• Additional pieces of information nearly every
  month
• Assessors
• Bits assessed with each new round of meetings and
  letters sent to applicant
• Very time consuming and inefficient
• Increasingly difficult to have all relevant
  information at hand

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Note to applicants....
1. Demonstrate bio-equivalence with an
established, acceptable reference product. A
suitable reference product has to be identified
by the applicant and must be one that is
acceptable to WHO assessors. 2. Provide direct
evidence in support of the products efficacy and
safety, which in most cases will be based on both
of the following a. general information
pertaining to the active ingredients
pharmacologic properties, including
toxicological, pharmacokinetic, and efficacy and
safety data as published, and resulting from
investigations with preparations different from
the FPP applied for b. specific information
emerging from clinical studies performed with the
proposed product
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Note to applicants....
2. Provide direct evidence in support of the
products efficacy and safety, which in most
cases will be based on both of the
following a. general information pertaining to
the active ingredients pharmacologic properties,
including toxicological, pharmacokinetic, and
efficacy and safety data as published, and
resulting from investigations with preparations
different from the FPP applied for b. specific
information emerging from clinical studies
performed with the proposed product
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Basic requirements

1. Complete list of all clinical trials performed
   with the proposed FPP (compare ICH CTD M4E ,
   section 2.7.3.2 and 2.7.3.6 and tables 2.7.3.1
   and 2)
2. If different galenical formulations of the FPP
   have been marketed or used in clinical trials, a
   galenical development history should be provided
   with clear identification of the respective
   formulations used in the trials included in the
   list (see1.)
3. Basic pharmacokinetic characterisation of the FPP
4. Summary of Product Characteristics and Package
   Insert
5. Expert reports on pharmaco-toxicological and
   clinical evidence for the active ingredient as
   well as the FPP

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Basic requirements Ia

• Complete list of all clinical trials performed
  with the proposed FPP
• The applicants should provide a complete list of
  all clinical trials (phase I, II and III) they
  are aware of and for which their product was
  used. It should be indicated whether the study
  was sponsored by the applicant. As a first step
  in the identification of studies not sponsored by
  the applicant, a consultation of the review of
  the Cochrane database may be useful Artemisinin
  derivatives for treating uncomplicated malaria.
  (McIntosh HM, Olliaro P., In The Cochrane
  Library, Issue 2, 2003 Oxford).

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Basic requirements Ib

• Complete list of all clinical trials performed
  with the proposed FPP
• This list should be updated each time when
  substantial new information, i.e. new clinical
  studies with the FPP, is submitted
• Existing full study reports and publications
  based on these studies should be submitted. If no
  study report or publication exists for any of the
  aforementioned clinical trials, the applicants
  should comment on reasons known to them and
  either confirm that they are not aware of any
  negative findings in unpublished trials or
  comment on all unreported and unpublished
  evidence.

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Basic requirements II

• If different galenical formulations of the FPP
  have been marketed or used in clinical trials, a
  galenical development history should be provided
  with clear identification of the respective
  formulations used in the trials included in the
  list
• If different galenical forms were manufactured in
  the development history of the product, then the
  applicant should provide a list in order to
  clearly identify the different forms used in the
  respective studies. If the applicant is not able
  to identify the specific galenical form (e.g. for
  an independently performed trial) then they
  should comment on which form was most likely
  used. It should be confirmed unambiguously if
  only one galenical formulation was ever used in
  humans.

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Basic requirements III

• Basic pharmacokinetic characterisation of the FPP
  
• In most cases, the most important part of the
  evidence about the pharmacokinetic properties of
  the active ingredient will come from the
  (abundant!!) literature. However, at least some
  information about the pharmacokinetics/bioavailabi
  lity of the FPP is absolutely necessary, too, in
  order to allow a judgement as to whether results
  from clinical trials with other FPPs can at least
  to a sufficient degree be extrapolated to the FPP
  applied for. This information may come from
  studies in healthy volunteers or in patients. In
  all cases the results will have to be discussed
  and compared to results from published studies in
  the Clinical Expert Report. The results from
  pharmacokinetic investigations must be described
  briefly in the SPC of the product.
• Statements that plasma levels of artemisinin
  derivatives are too difficult to measure and not
  necessary only show lack of knowledge of recent
  literature

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Basic requirements IV

• Summary of Product Characteristics and Package
  Insert
• The SPC and package insert should be specific
  with regard to the infections which can be
  reasonably treated with the FPP.
• In most cases the FPP will not be equally well
  suited for both uncomplicated and complicated
  malaria, or for all species of Plasmodia.
• Efforts should be made to keep the SPC up to
  date, especially with regard to safety-relevant
  information.
• (compare e.g. to Co-Artem )

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Basic requirements V

• Expert reports on pharmaco-toxicological and
  clinical evidence for the active ingredient as
  well as the FPP
• Expert reports will have to be updated just
  like the list of all trials as soon as new
  substantial information is added

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Basic requirements Consequences for assessment
All documentation, new or additional, provided
with current or future Expressions of Interest
will first be checked whether these basic
requirements are fulfilled. If the basic
requirements are not met then no assessment
will be conducted on the clinical data. The
applicant will be notified of the deficiencies.
When the basic requirements are met an assessment
of the data provided will commence and more
comprehensive communications will be sent to the
applicant as required.
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Results of evaluation

• Initially, only the documentation of a small
  number of FPPs has fulfilled basic
  requirements and for even less the
  documentation could be considered sufficient
• Artesunate 50mg Tablets Sanofi-Synthelabo
• Artemether/Lumefantrine Novartis

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Conclusions Past

• Artemisinin derivatives could not be evaluated
  according to published WHO Prequalification
  Requirements for Finished Pharmaceutical
  Products
• In the beginning uncertainties on both sides,
  assessors and applicants
• Very insufficient dossiers of many want-to-be
  innovators
• No bioequivalence studies submitted for multi
  source products
• No reference products identified

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Conclusions Presence and Future

• Draft SOP for evaluation developed
• Basic requirements for innovator products
  published
• WHO experts working on literature survey, which
  should
• Provide help for innovators
• Enable WHO to name possible reference products

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And finally The bare necessities

• Apart from the intrinsic efficacy/safety of the
  active ingredient, the bioavailability is THE
  clinical quality mark of a FPP, therefore
• Without pharmacokinetic characterisation in
  humans,
• either through Phase I Studies for innovators or
  through bioequivalence studies for multi-source
  products
• no Finished Pharmaceutical Product will pass the
  prequalification.