Transcript Document 7116593

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 Data
Hans Kemmler
Swissmedic, Switzerland
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.
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Overview

Defining efficacy and safety of a
medicine (finished pharmaceutical
product = FPP)

Dossier requirements

Use of guidelines

Overview results for HIV-drugs
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Defining Efficacy and Safety
The “Clinical Quality”
of a Medicine
Efficacy and safety
of the active
ingredient
Information on the
appropriate and
safe use
Galenical
formulation
All aspects are assessed during prequalification
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Efficacy and Safety of the Active
Ingredient

Investigated and documented in
preclinical and clinical trials of
– possibly – different galenic
formulations
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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.
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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.
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Dossier 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://mednet3.who.int/prequal/
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Dossier requirements
Particulars for HIV/AIDS FPP containing more than
one active ingredient:
 Guideline for registration of fixeddose combination medicinal products
(WHO Technical Report Series No. 929, 2005)
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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
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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
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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
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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“
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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
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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
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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/ )
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Summary of Submissions for
HIV/AIDS-Drugs

Antibacterials
56

Antimycotics
24

Antiprotozoals
7

other Antivirals
18

Anticancer

Nucleosid RTI
86

NRTI Combi
34

Non-Nucleosid RTI
18

Prot.Inhibitors
18
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Distribution of submissions
Antibacterials
Antimycotics
Antiprotozoals
18
18
other Antivirals
56
Anticancer
34
Nuclosid RTI
24
7
18
86
NRTI Combi
Non-Nucleosid RTI
Prot.I
10
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Distribution of prequalifiedAntibacterials
Antimycotics
products (appr. 80)
Antiprotozoals
10
other Antivirals
8
Anticancer
6
Nucleosid RTI
5
2
4
4
2
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NRTI Combi
Non-Nucleosid
RTI
Prot.I
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Update, status Dec. 2005

316 submissions

73 under active assessment

142 cancelled

85 products prequalified
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NRTI prequalified
Nucleoside RTI prequalified
14
12
10
8
6
4
2
0
Abacavir
Didanosine
Lamivudine
Lam-comb
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Stavudine
Zalcitabine
Zidovudine
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Nucleoside RTI prequalified
Innovators
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Update to last slide, status
December 2005

6 Lamivudine combinations added

+ 2 Lamivudine mono

+ 3 Zidovudine mono
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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
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Prequalification Results of
Protease Inhibitors
All prequalified PI are from
innovator companies, none
is a generic
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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
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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
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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
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Conclusion in Project

Some problems arise again and again,
from many applicants
More
And
advice needed !!
is possible !
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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
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