WHO Workshop on Assessment of Bioequivalence Data Addis Ababa, 31. August – 3. September 2010
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Transcript of WHO Workshop on Assessment of Bioequivalence Data Addis Ababa, 31. August – 3. September 2010
WHO Workshop on Assessment of Bioequivalence Data
Addis Ababa, 31. August – 3. September 2010
Selection of comparators
Compiled by Jan Welink
WHO Workshop on Assessment of Bioequivalence Data ,31 .August - 3.September 2010, Addis Ababa
WHO Workshop on Assessment of Bioequivalence Data31. August – 3. September 2010, Addis Ababa2 |
Introduction
Quality of generics:
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Comparator
Introducing the comparator:
* a pharmaceutical product with which the multi-source product is intended to be interchangeable in clinical practice.
* the selection of the comparator product is usually made at the national level by the drug regulatory authority.
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Comparator
Introducing the comparator:
innovator product, approved on full documentation:
- established safety and efficacy
Quality
Pre-clinical
Clinical
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Physically:
WHAT IS THE DIFFERENCE BETWEEN INNOVATOR AND GENERIC?
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Scientifically:
INNOVATOR GENERIC
BE
WHAT IS THE RELATION BETWEEN INNOVATOR AND GENERIC?
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Choice of the comparator:
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Comparator
Selection by the DRA:
select national granted innovator for which quality, safety and efficacy has been established (nationally authorised innovator)
select WHO comparator product from the comparator list (WHO comparator product)
select innovator product from well-regulated country (ICH et al. innovator)
if no innovator can be identified, choice must be justified
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Comparator
Justification if no innovator can be identified:
approval in ICH- and associated countries
pre-qualified by WHO
extensive documented use in clinical trials (reports)
long and unproblematic post-market surveillance
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List A and B
WHO provides a list with comparator products
- information DRA/pharmaceutical companies
List A: WHO model list of Essential Drugs
- ‘best’ innovator products on national markets
List B: Products for which no innovator product could be identified
- no equivalence test can be performed
- quality, safety and efficacy based upon local, national, or regional pharmacopoeia
- innovator products with insufficient information
No innovator, but market leader available!
………………………………
………………………………
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Decision tree
Choosing comparator complex
WHO provides criteria decision tree
YESNO
YES
NO
NO
?
?
?
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Bio-creep
WHO: Annex 11 also written for a single market
cannot be translated in case other countries are at stake
national comparator may be the national market leader
no problem in that market but others?!
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Bio-creep
0204060
80100120
%
Generic 1 Innovator Generic 2 Generic 3 Generic 4
Relative BA
Relative BA
Interchangeable
Not interchangeable
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EMEA (Europe)
Differentiate between use for single market or many countries!
Austria
France
Latvia
Poland
Belgium
Germany
Liechtenstein
Portugal
Cyprus
Greece
Lithuania
Slovak Republic
Czech Republic
Hungary
Luxemburg
Slovenia
Denmark
Iceland
Malta
Spain
Estonia
Ireland
The Netherlands
Sweden
Finland
Italy
Norway
United Kingdom
EMA:
For an abridged application claiming essential similarity to a reference product, application to numerous Member States based on bioequivalence with a a reference product from one Member State can be made.
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Prequalification project
List of acceptable reference products for the prequalification project for reproductive health
List of acceptable reference products for the prequalification project for reproductive health
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Guidance documents
Recommended comparator products: Reproductive Health medicines
Comparator products should be obtained from a well regulated market with stringent regulatory authority i.e., from countries participating in
the International Conference on Harmonization (ICH)
Countries officially participating in ICH are the ICH members European Union, Japan and USA; and the ICH observers Canada and Switzerland .
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Guidance documents
Invited medicinal products Recommended comparator product (Strength, Manufacturer)
Oral hormonal contraceptives
Ethinyl estradiol + levonorgestrel 30 μg + 150 µg tablet
Microgynon 30 (Schering AG) Seasonale (Duramed, US)1 Nordette-28 (Duramed, US) 1 The 3 products above are combined oral contra-ceptives (ethinylestradiol 30 μg and levonorgestrel 150 µg tablet)
Levonorgestrel 30 µg tablet
Microlut (levonorgestrel 30 µg tablet, Schering AG)
Levonorgestrel 750 µg tablet (pack of two)
Postinor-2 (two tablets each containing 750 µg levonorgestrel, Gedeon Richter) Plan B (two tablets each containing 750 µg levonorgestrel, Duramed, US) 1
Levonorgestrel 1.5 mg tablet (pack of one)
Postinor-1 (levonorgestrel 1.5 mg tablet, Gedeon Richter)
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Guidance documents
Injectable hormonal contraceptives
Medroxyprogesterone acetate (DMPA), depot injection 150 mg/ml
Depo-Provera (medroxyprogesterone acetate, depot inj 150 mg/ml, Pharmacia/Pfizer)
Medroxyprogesterone acetate (DMPA) + estradiol cypionate, injection 25 mg + 5 mg
Cyclofemina (medroxyprogesterone acetate 25 mg + estradiol cypionate 5 mg inj, Millet Roux Ltd, Brazil)2
Implantable contraceptives
Two rod levonorgestrel-releasing implant; each rod containing 75 mg of levonorgestrel
Jadelle (two-rod levonorgestrel implant, each rod containing 75 mg of levonorgestrel, Bayer Schering Pharma)
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Guidance documents
Oxytocics
Oxytocin, injection 10 IU
Syntocinon (oxytocin 5 IU/ml inj, Novartis)
Mifepristone + misoprostol, co-packaged mifepristone 200 mg tablet + 4 tablets of misoprostol 200µg
Mifegyne (mifepristone 200 mg tablet, Exelgyn SA) + Cytotec (misoprostol 200 µg tablet, Searle/Pfizer) Mifeprex (mifepristone 200 mg tablet, Danco Labs, US)1 + Cytotec (misoprostol 200µg tablet, Searle/Pfizer)
Prevention and treatment of eclampsia
Magnesium sulphate, injection 500 mg/ml --3
1 The recommended comparator product is approved by US FDA and may not be available outside US. 2 Not available in ICH (associated) countries; product should be obtained from Brazil. 3 Solution for injection; no specific comparator product selected. Demonstration of pharmaceutical quality needed only.
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Guidance documents
Information Requirements Within the submitted dossier, the country of origin of the comparator product should be reported together with lot number and expiry date, as well as results of pharmaceutical analysis to prove pharmaceutical equivalence. Further, in order to prove the origin of the comparator product the applicant must present all of the following documents: 1. Copy of the comparator product labelling. The name of the product, name and address of the
manufacturer, batch number, and expiry date should be clearly visible on the labelling. 2. Copy of the invoice from the distributor or company from which the comparator product was
purchased. The address of the distributor must be clearly visible on the invoice. 3. Documentation verifying the method of shipment and storage conditions of the comparator
product from the time of purchase to the time of study initiation. 4. A signed statement certifying the authenticity of the above documents and that the comparator product was purchased from the specified national market. The certification should be signed by the company executive or equivalent responsible for the application to the Prequalification Programme
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Guidance documents
http://apps.who.int/prequal/
* Note to applicants on the choice of comparator products for the prequalification project
* Guideline on generics
- WHO TRS 937 Annex 7 (Multisource (generic) pharm. products: guidelines on registration requirements to establish
interchangeability)
- WHO TRS 902 Annex 11 (Guidance on the selection of comparator pharm. products for equivalence assessment of interchangeable multisource (generic) products)
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Guidance documents
http://apps.who.int/prequal/
* updated documents on the choice of comparator products for the prequalification project
Comparator for anti-tuberculosis medicines
Comparator for anti-malarial medicines
Comparator for Influenza-specific antiviral medicines
Comparator for medicines for HIV/AIDS and related diseases
Comparator for reproductive health products
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Guidance documents
http://apps.who.int/prequal/
* a word on Dose Equivalence
“In case the invited product has a different dose compared to the available acceptable comparator product, it is not always necessary to carry out a bioequivalence study at the same dose level; if the active substance shows linear pharmacokinetics, extrapolation between similar doses may be applied by dose normalisation.”
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Guidance documents
http://apps.who.int/prequal/
* a word on Fixed-dose Combination Products
“The bioequivalence of fixed-dose combination (FDC) product should be established following the same general principles. The submitted FDC product should be compared with the respective innovator FDC product as listed above. In cases where a FDC comparator product is not listed above, individual component products administered in loose combination should be used as a comparator. The principles of dose normalization as mentioned above are applicable.”
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Conclusion
-Let quality rules
-Comparators helps you into quality
-Do not fall in the bio-creep
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End
Thank you for your attention