Document 7116593
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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
32
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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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PQ generic
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22
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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