guilin, 9-13, january 2006 1 prequalification of antimalarial drug products hans kemmler consultant...

Guilin, 9-13, January 2006 1

PREQUALIFICATION OF PREQUALIFICATION OF ANTIMALARIAANTIMALARIALL DRUG DRUG

PRODUCTSPRODUCTS

Hans Kemmler

Consultant to WHO

Guilin, 11.Jan. 2006

Frequently Encountered Deficits in Expression of Interest for

Originators


OverviewOverview

Prequalification Requirements for

Finished Pharmaceutical Products

(FPPs)

Clinical issues

The „basic requirements“

Results of evaluation

Conclusions


Artemisinin-Generics for Malaria?Artemisinin-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)


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 FPP for which Expression of Interest was invited


The main deficiencyThe main deficiency

Insufficient reporting of the

evidence about the clinical efficacy

and safety.....

– No fully documented trial reports– No full evaluation of published

literature


Clear deficiencies in many Clear deficiencies in many submissions received:submissions received:

No characterisation of pharmacokinetic

properties of FPP: For innovators and

generics as well unacceptable

General statements: – No interaction known -> clearly not true– No (or minimal) adverse events: information

has to be provided through literature survey

Too broad efficacy claims


Clear deficiencies:Clear deficiencies:

Galenical development history not provided -> 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


Clear deficiencies: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 60:54-57, 1994. 353. Ziffer H, Highet RJ, Klayman DL: Artemisinin: an endoperoxidic

antimalarial from Artemisia annua L. Fortschr Chem Org Naturst 72:121-124, 1997.


Toxicological dataToxicological 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


Lessons learned during Lessons learned during assessmentassessment

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


Note to applicants....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 product’s 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


Note to applicants....Note to applicants....2. Provide direct evidence in support of the

product’s 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


Basic requirements 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 (see°1.)

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


Basic requirements Basic requirements IaIa

1. 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).


Basic requirements Basic requirements IbIb

1.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.


Basic requirements Basic requirements IIII

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

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.


Basic requirements Basic requirements IIIIII

3. 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/bioavailability 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


Basic requirements Basic requirements IVIV

4. 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 )


Basic requirements Basic requirements VV

5. 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


Basic requirements:Basic requirements:

Consequences for assessment 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.


Results of Results of evaluationevaluation

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


Conclusions PastConclusions 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


Conclusions: Presence Conclusions: Presence and Futureand 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


And finally: The bare And finally: The bare necessitiesnecessities

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.

guilin, 9-13, january 2006 1 prequalification of antimalarial drug products hans kemmler consultant...

Documents

guilin pharma slide

artemisinin innovators

fpp specific data

toxicological data

specific fpp

clear deficiencies

clinical efficacy

literature survey