who training course on prequalification introduction efficacy and safety issues hans kemmler...

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.


OverviewOverview

Defining efficacy and safety of a medicine (finished pharmaceutical product = FPP)

Dossier requirements

Use of guidelines

Difficulties in understanding


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


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


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.


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.


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


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)


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?“

http://www.who.int/medicines/library/qsm/


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


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


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


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


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“



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



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)


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!!!


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


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.

Thank you For inviting usFor listeningFor active participation in the case studies

who training course on prequalification introduction efficacy and safety issues hans kemmler...

Documents

artemisinin combined

prequalification slide

quality medicines

understanding slide

safety relevant information

medicine efficacy

complete information

safe use