who training course on prequalification introduction efficacy and safety issues hans kemmler...
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WHO Training Course on Prequalification
Introduction Efficacy and Safety Issues
Hans KemmlerConsultant to WHOAccra, 5.Nov. 2008
Artemisinin combined medicines, Kampala, February 20092 |
The Prequalification ProjectThe Prequalification Project
The Prequalification Programme, set up in 2001, is a service provided by the World Health Organization (WHO) to facilitate access to medicines that meet unified standards of quality, safety and efficacy for HIV/AIDS, malaria and tuberculosis. From the outset, the Programme was supported by UNAIDS, UNICEF, UNFPA and the World Bank as a concrete contribution to the United Nations priority goal of addressing widespread diseases in countries with limited access to quality medicines.
Artemisinin combined medicines, Kampala, February 20093 |
OverviewOverview
Defining efficacy and safety of a medicine (finished pharmaceutical product = FPP)
Dossier requirements
Use of guidelines
Difficulties in understanding
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Defining Efficacy and SafetyDefining Efficacy and Safety
The “Clinical The “Clinical Quality” of a Quality” of a
MedicineMedicine
Efficacy and safety of the
active ingredient
Galenical formulation
Information on the appropriate
and safe use
All aspects are assessed during prequalification
Artemisinin combined medicines, Kampala, February 20095 |
Efficacy and Safety of the Active IngredientEfficacy and Safety of the Active Ingredient
Investigated and documented in preclinical and clinical trials of – possibly – different galenic formulations
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Galenic FormulationGalenic Formulation
Has an influence on e.g.– Bioavailability
• Best active ingredient will be of no use if contained in a stainless steel capsule
– (local) tolerability
Because different formulations can have different bioavailability or tolerability, the
information about which formulation has been
used in which trial(s) is essential for the assessment
of the FPP.
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Information on the Appropriate and Safe UseInformation on the Appropriate and Safe Use
Best active ingredient in best galenical formulation will be of no use if used for wrong condition, e.g. antimalarial used to treat headache
It will be even dangerous if safety relevant information is not complete
Information in SPC and PIL must be justified by and referenced in the
documented evidence.
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Dossier requirementsDossier requirements
Manufacturers interested in participating in the prequalification project have to submit a product dossier for assessment
The product dossiers have to contain the required data and information as stipulated in the Guidelines
Guidelines available: http://www.who.int/prequal
Artemisinin combined medicines, Kampala, February 20099 |
Dossier requirementsDossier requirements
Particulars for artemisinin containing FPP:
1. Note to applicants expressing interest for supplying artemisinin-containing drug products
Because all products on current Expression of Interest list are combinations, the consideration of the combinations guideline is of utmost importance:
2. Guideline for registration of fixed-dose combination medicinal products
(WHO Technical Report Series No. 929, 2005)
Artemisinin combined medicines, Kampala, February 200910 |
Prequalification Requirements for Finished Pharmaceutical Products (FPPs)
Prequalification Requirements for Finished Pharmaceutical Products (FPPs)
Website WHO: (http://www.who.int/prequal/default.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 WHO Technical Report 937: WHO EXPERT COMMITTEE ON SPECIFICATIONS FOR PHARMACEUTICAL PREPARATIONS TRS 937
• Innovator: „What data and information needs to be submitted in a dossier for an innovator product?“
Artemisinin combined medicines, Kampala, February 200911 |
Artemisinin - Innovators?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 Artemisinin-FPP for which Expression of Interest was invited
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Use of GuidelinesUse of Guidelines
Guidelines are guidances, no law
But: – It should be apparent that the relevant guidelines are known– deviations from guidelines should be based on scientific
justification
Guidelines make „life“ easier– especially for applicants
Artemisinin combined medicines, Kampala, February 200913 |
Use of GuidelinesUse of Guidelines
No presentation, no training course can help to avoid the thorough study of guidelines
To find all relevant guidelines is - to some degree - an art
WHO website provides an excellent starting point
Artemisinin combined medicines, Kampala, February 200914 |
Where to Find GuidelinesWhere to Find Guidelines
In previous and following presentations some references to guidelines are given
in distributed material (CD) many more are included or referenced
see also the presentations of a previous workshop (Kiev, 2005) for many additional references in particular relevant for bioequivalence studies
Artemisinin combined medicines, Kampala, February 200915 |
Other Useful DocumentsOther Useful Documents
In distributed papers or CD is a complete and detailed „Table of Contents“ (TOC) for a bioequivalence study report
In my opinion, a very valuable help for scientists intending to conduct such a study
also useful for other study reports to give an idea about the detailedness of a „Full Study Report“
Artemisinin combined medicines, Kampala, February 200916 |
Other Useful DocumentsOther Useful Documents
Also in distributed material: Annex 7 (a template):
Presentation of bioequivalence trial information
Together with the TOC, these documents should, if properly populated, help to avoid >90% of currently encountered deficits in submitted bioequivalence trials
Artemisinin combined medicines, Kampala, February 200917 |
Other Useful DocumentsOther Useful Documents
WHO Guidelines for registration of fixed-dose combination medicinal products !!! (see distributed material)
Sample analysis for a comparative bioavailability study (see distributed material, and general hint: If questions about BE-studies arise, the website of the Canadian health authority should be one of the first places to look at)
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Difficulties in understandingDifficulties in understanding
Delays in prequalification by lack of mutual understanding
Not only language problems, but– same words have different meanings for people with different
previous experience e.g.A „full study report“ is obviously something different for an European assessor and for an employee of a Chinese company. This doesn‘t mean that one is right and the other not!!!
Artemisinin combined medicines, Kampala, February 200919 |
Difficulties in understandingDifficulties in understanding
Talking and asking helps a lot, therefore one of our intentions for this workshop:
Less presentations about something which is better read anyway
More time for discussion in and about case studies
Artemisinin combined medicines, Kampala, February 200920 |
Finally: The bare necessitiesFinally: 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 (which may, in very exceptional cases be only in vitro bioequivalence studies) for „multi-source“ products
no Finished Pharmaceutical Product will pass the prequalification.
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