Title: PREQUALIFICATION OF ANTIMALARIAL DRUG PRODUCTS
1PREQUALIFICATION OF ANTIMALARIAL DRUG PRODUCTS
Frequently Encountered Deficits in Expression of
Interest for Originators
- Hans Kemmler
- Consultant to WHO
- Guilin, 11.Jan. 2006
2Overview
- Prequalification Requirements for Finished
Pharmaceutical Products (FPPs) - Clinical issues
- The basic requirements
- Results of evaluation
- Conclusions
3Artemisinin-Generics for Malaria?
- Currently only very few innovators (artemisinin
derivatives) approved in ICH- and associated
countries - No reference product available for bioequivalence
studies (one exception Artesunate from Guilin
Pharma)
4Artemisinin - 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
5The main deficiency
- Insufficient reporting of the evidence about the
clinical efficacy and safety..... - No fully documented trial reports
- No full evaluation of published literature
6Clear 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
7Clear 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
8Clear 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.
9Toxicological 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 - Consultant to WHO is currently preparing an
Expert Report for all artemisins Artemisinin
part may be omitted in close future - Attention Some assessment of toxicology of
combinations is still necessary
10Lessons 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
11Note 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
12Note 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
13Basic requirements
- 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) - 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.) - Basic pharmacokinetic characterisation of the FPP
- Summary of Product Characteristics and Package
Insert - Expert reports on pharmaco-toxicological and
clinical evidence for the active ingredient as
well as the FPP
14Basic 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).
15Basic 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.
16Basic 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.
17Basic 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
18Basic 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 )
19Basic 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
20Basic 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.
21Results 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 Guilin Pharma
- Artesunate 50mg Tablets Sanofi-Synthelabo
- Artemether/Lumefantrine Novartis
22Conclusions 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
23Conclusions 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 more reference products
- remove the need for Toxicology Expert Report
24And 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.