WHO Procurement, Quality and Sourcing Project: Access to HIV/AIDS Drugs and Diagnostics of Acceptable Quality Experience from the Evaluation of Drug Dossiers

WHO Procurement, Quality and Sourcing Project:

Access to HIV/AIDS Drugs and Diagnostics of Acceptable Quality

Experience from the Evaluation of

Drug Dossiers with Respect to

Bioequivalence DataHans Kemmler

Swissmedic, Switzerland

Hanoi, 2006-01-19, H.Kemmler 2

The Prequalification Project

The Prequalification project, set up in

2001, is a service provided by the

WHO to facilitate access to medicines

that meet unified standards of quality,

safety and efficacy for HIV/AIDS,

malaria and tuberculosis.


Overview

Defining efficacy and safety of a

medicine (finished pharmaceutical

product = FPP)

Dossier requirements

Use of guidelines

Overview results for HIV-drugs


Defining 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 Ingredient

Investigated and documented in

preclinical and clinical trials of

– possibly – different galenic

formulations


Galenic 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 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.



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 GuidelinesGuidelines available:

http://mednet3.who.int/prequal/



Particulars for HIV/AIDS FPP containing more than one active ingredient:

Guideline for registration of fixed-dose combination medicinal products (WHO Technical Report Series No. 929, 2005)


Use 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 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 Guidelines

In previous and following presentations

some references to guidelines are given

in distributed material many more are

included or referenced

see also the presentations of the previous

workshop (Kiev, 2005) for many additional

references in particular relevant for bioequivalence studies


Other Useful Documents

In distributed papers 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“


Other 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


Invited Generic Products

Expressions of Interest were invited for Nucleoside Reverse Transcriptase Inhibitors

– 7: Zidovudine, Didanosine, Lamivudine etc.

Non-nucleoside Reverse Transcriptase Inhibitors– 3 : Nevirapine, Efavirenz, Delarvidine

Protease Inhibitors– 6 : Amprenavir, Saquinavir, Ritonavir etc.

Other Anti-infective drugs:Antibacterials, Antimycotics, Antiprotozoals, other Antivirals, Anti-cancer drugs


Submitted Generic Products

Of the appr. 280 Expressions of Interest were 34 files for solutions for

injection requiring no BE study

222 files for tablets/capsules/oral suspensions requiring BE study

19 submissions for oral solutions

About 80 products up to now have been found acceptable, in principle, for procurement by UN

agencies (included in list available : http://mednet3.who.int/prequal/ )


Summary of Submissions for HIV/AIDS-Drugs

Antibacterials 56

Antimycotics 24

Antiprotozoals 7

other Antivirals 18

Anticancer 6

Nucleosid RTI 86

NRTI Combi 34

Non-Nucleosid RTI 18

Prot.Inhibitors 18


Distribution of submissions

56

24

7

18

1086

34

18

18

Antibacterials

Antimycotics

Antiprotozoals

other Antivirals

Anticancer

Nuclosid RTI

NRTI Combi

Non-Nucleosid RTI

Prot.I


Distribution of prequalified products (appr. 80)

8

6

2

4

2

32

4

5

10

Antibacterials

Antimycotics

Antiprotozoals

other Antivirals

Anticancer

Nucleosid RTI

NRTI Combi

Non-NucleosidRTIProt.I


Update, status Dec. 2005

316 submissions

73 under active assessment

142 cancelled

85 products prequalified


Nucleoside RTI prequalified

0

2

4

6

8

10

12

14

Abacavir Didanosine Lamivudine Lam-comb Stavudine Zalcitabine Zidovudine

NRTI prequalified


Nucleoside RTI prequalified

0

24

68

1012

14

PQ generic Innovators


Update to last slide, status December 2005

6 Lamivudine combinations added

+ 2 Lamivudine mono

+ 3 Zidovudine mono


Prequalification results of NRTI

120 submissions for NRTI and combinations with NRTI

36 prequalified

Of 36 NRTI prequalified, only 14 are generics

Of 98 submissions for generic NRTI, 84 not (yet) prequalified


Prequalification Results of Protease Inhibitors

All prequalified PI are from

innovator companies, none

is a generic


WHY?Deficiencies in BE Studies ? YES

About 50% of initial submissions

without bioequivalence study

Of submitted studies:– About 50% with inadequate method validation

– ~ 50% without verification that test product is exactly same as applied-for-product

– ~ 35% without basic statistical evaluation


Other Identified Deficiencies in BE studies

Minor deficiencies (information not presented,

but easily accessible)

Individual pharmacokinetic parameters not

submitted

Pharmacokinetic and statistical calculations not

submitted

Detailed description of study design not

submitted


Identified Deficiencies in BE studies

Minor deficiencies (cont.)

No information on batch size of test product

Certificate of Analysis of test batch not

submitted

In-vitro dissolution profiles not submitted– for test product– for reference product– for different strengths of the same product


Conclusion in Project

Some problems arise again and again,

from many applicants

More advice needed !!

And is possible !


Two New Documents are now available

Note to Applicants on Choice of Comparator Products in the Prequalification Project

Annex 7: Presentation of bioequivalence trial information

BIOEQUIVALENCE TRIAL INFORMATION FORM (BTIF)

link