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:


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.


Comparator

Introducing the comparator:

innovator product, approved on full documentation:

- established safety and efficacy

Quality

Pre-clinical

Clinical


Physically:

WHAT IS THE DIFFERENCE BETWEEN INNOVATOR AND GENERIC?


Scientifically:

INNOVATOR GENERIC

BE

WHAT IS THE RELATION BETWEEN INNOVATOR AND GENERIC?


Choice of the comparator:


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


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


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!

………………………………

………………………………


Decision tree

Choosing comparator complex

WHO provides criteria decision tree

YESNO

YES

NO

NO

?

?

?


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?!


Bio-creep

0204060

80100120

%

Generic 1 Innovator Generic 2 Generic 3 Generic 4

Relative BA

Relative BA

Interchangeable

Not interchangeable


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.


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


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 .


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)


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)


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.


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


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)


Guidance documents


* 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


Guidance documents


* 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.”


Guidance documents


* 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.”


Conclusion

-Let quality rules

-Comparators helps you into quality

-Do not fall in the bio-creep


End

Thank you for your attention

Documents

WHO Workshop on Assessment of Bioequivalence Data Addis Ababa, 31. August – 3. September 2010