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Multisource (generic) products and Interchangeability . Training Workshop on Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceutical Classification System. Hotel Bratislava 1 Malyshko Street Kyiv, Ukraine Date: 25 to 27 June 2007.

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slide1

Multisource (generic) products and Interchangeability

Training Workshop on Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceutical Classification System.

Hotel Bratislava

1 Malyshko Street

Kyiv, Ukraine

Date: 25 to 27 June 2007

slide2
Training Workshop on Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceutical Classification System.

WHO guidance:

Choice of comparator product for establishing bioequivalence

Presenter: Drs. J. Welink

Senior pharmacokineticist

Medicines Evaluation Board, NL

WHO adviser

E-mail: j.welink@cbg-meb.nl

guidance documents4
Guidance documents

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

* Note to applicants on the choice of comparator products for the prequalification project

* Guideline on generics

- Annex 7 (Multisource (generic) pharm. products: guidelines on registration requirements to establish interchangeability)

- Annex 11 (Guidance on the selection of comparator pharm. products for equivalence assessment of interchangeable multisource (generic) products)

introduction
Introduction

* Note to applicants ….... the prequalification project

generics

QUALITY

introduction6
Introduction

Incorrect

ingredient

16%

Incorrect

amount

17%

No active

ingredient

Other errors

60%

7%

Quality problem?!!

Percentage breakdown of data on 325 cases of substandard drugs - reported from around the world to WHO database

introduction7
Introduction

Daily mail……

dare thinking off day, am got as talked you changed did? Certified OnlinePharmacyGenuine Quality Ingredient &All Countries Shipping

introduction8
Introduction

Multi-source (generic) drug products must satisfy the same standards as those applicable to the originator’s product. In addition, reasonable assurance must be provided that they are, as intended, clinically interchangeable with nominally equivalent market products.

comparator
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.

comparator10
Comparator

Quality

Clinical

Pre-clinical

Introducing the comparator:

innovator product, approved on full documentation:

- established safety and efficacy

comparator11
Comparator

Choice of the comparator:

comparator12
Comparator

Selection by the DRA:

  • choose national granted innovator for which quality, safety and efficacy has been established (nationally authorised innovator)
  • choose WHO comparator product from the comparator list (WHO comparator product)
  • choose innovator product from well-regulated country (ICH et al. innovator)
  • if no innovator can be identified, choice must be justified
comparator13
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
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
Decision tree

Choosing comparator complex

WHO provides criteria decision tree

NO

YES

?

?

YES

NO

NO

?

decision tree16
Decision tree

Comparator pharmaceutical product of known quality, safety and efficacy

Innovator product known?

Consider innovator product as comparator

Consider obtaining innovator: List A

Innovator product available?

Available on local market?

Consider innovator product as comparator

Consider market leader product

+

+

-

+

-

decision tree17
Decision tree

Comparator pharmaceutical product of known quality, safety and efficacy

Innovator product known?

Present on List B?

Follow compendial standard approach

Acceptable results?

Quality market leader known?

Consider market leader product as comparator

Consider market leader product

Conduct comparative compendial tests on multisource and market leader products

Consider second market leader product

Consider market leader product as comparator

-

-

+

-

+

+

-

bio creep
Bio-creep

Annex 11 also written for a single market

WHO:

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 creep19
Bio-creep

Interchangeable

Not Interchangeable

slide20
EMEA

Differentiate between use for single market or many countries!

EMEA:

EMEA:

For an abridged application claiming essential similarity to a reference product, application to numerous Member States based on bioequivalence with a reference product from one Member State can be made.

slide21
EMEA

The various immediate-release oral pharmaceutical forms shall be considered to be one and the same pharmaceutical form with respect to the legal basis of the application.

However, ‘appropriate bioequivalence data’ means that for the national reference products bioequivalence has to be demonstrated. Where the reference product has the same pharmaceutical form in all Member States normally one bioequivalence study is sufficient. When there are different pharmaceutical forms of oral immediate-release formulations it is the responsibility of the applicant to demonstrate bioequivalence of his product with the different pharmaceutical formulations in the Member States.

slide22
EMEA

Whether an additional bioequivalence study or additional dissolution data are needed has to be decided on a case by case basis. For each Member State bioequivalence of the generic medicinal product and reference product has to be demonstrated because generics and reference products are considered to be interchangeable.

Capsules and immediate release tablets differ considerably in composition and properties and in accordance with the Guideline on bioavailability, a bioequivalence study is required for each pharmaceutical form unless the applicant can justify otherwise that the reference product is bioequivalent with all pharmaceutical formulations in the Concerned Member States.

innovator bio creep
Innovator bio-creep

Line extension of innovator

bioequivalent

bioequivalent

Test: generic

Innovator

innovator bio creep24
Innovator bio-creep

Line extension of innovator

bioequivalent

bioequivalent

bioequivalent

Test: generic

Test: generic

Innovator

?

prequalification project
Prequalification project

List of acceptable reference products for the prequalification project for reproductive health

example
Example

Fixed dose combination (FDC):

Comparator:

Combination of the acceptable reference products with only one drug!

WHY?

example27
Example
  • Bioequivalence study, 1999, accepted in EU, Switzerland and by WHO:  

Rimstar 4-FDC®

versus

Rimactane ® + Isozid ® + Rolab Pyrazinamide ® + Myambutol®

example28
Example

Rimstar 4-FDC® (Rifampicin 150, Isoniazid 75, Pyrazinamide 400, Ethambutol 275mg) 4 tablets given in a single dose

versus

Rimactane ® (Novartis, Switzerland*) 4 capsules each containing 150mg rifampicin

Isozid ® (Fatol, Germany) 3 tablets each containing 100 mg isoniazid

Rolab Pyrazinamide ® (Rolab, South Africa) 3 tablets each containing 500 mg Pyrazinamide

Myambutol® (Lederle Arzneimittel GmbH & Co) 2 tablets containing 400mg and 3 tablets containing 100mg ethambutol

BIOEQVALENCE PROVEN

example29
Example
  • Such FDC’s should normally not be used as comparators – even if approved by ICH countries (bio-creep phenomenon)
  • Instead again the individual components should be used as comparators.
  • However, there are also some fixed-dose-combinations which were used as such extensively in clinical trials, thus direct, “own” evidence for their efficacy and safety is available. These can be used !!!
conclusion
Conclusion

- Let quality rules

- Comparators helps you into quality

- Do not fall in the bio-creep

conclusion31
Conclusion

Thank you for your attention