INTER CHANGEABILITY and EQUIVALENCE. Where we are and what we still have to determine!

Size: px
Start display at page:

Download "INTER CHANGEABILITY and EQUIVALENCE. Where we are and what we still have to determine!"

Transcription

1 INTER CHANGEABILITY and EQUIVALENCE Where we are and what we still have to determine!

2 Acknowledgement Joint presentation UNICEF/MSF/ICRC Cecile Mace Jean Michel Caudron Birgit Schmauser

3 What do we mean with equivalence? Pharmaceutical equivalence Bio-equivalence

4 Pharmaceutical equivalence Same amount of the same active pharmaceutical ingredient Salts, esters Same dosage form Comparable dosage forms e.g., tablet vs. capsule Same route of administration Is pharmaceutical equivalence enough?

5 Sometimes pharmaceutical equivalence is enough Aqueous solutions Intravenous solutions Intramuscular, subcutaneous Oral solutions Otic or ophthalmic solutions Topical preparations Solutions for nasal administration Powders for reconstitution as solution Gases

6 Sometimes it is not enough Pharmaceutical equivalence by itself does not necessarily imply therapeutic equivalence

7 Pharmaceutical Equivalents Test Possible Differences Drug particle size Excipients Manufacturing Equipment or Process Site of manufacture Reference Could lead to differences in product performance in vivo

8 Therapeutic Equivalence : Pharmaceutically equivalent Same safety and efficacy profiles after administration of same dose: bioequivalent Meaning the bioavailabilities (both rate and extent) after administration in the same molar dose are similar to such a degree that their effects can be expected to be essentially the same

9 from a procurement perspective

10 When are bioequivalence studies employed? Multisource product vs. Innovative product Pre-approval changes Bridging studies Post-approval changes Additional strengths of existing product

11 Multisource pharmaceutical products need to conform to the same appropriate standards of quality, efficacy and safety as those required of the innovator s (comparator) product. In addition, reasonable assurance must be provided that the multisource product is therapeutically equivalent and interchangeable with the comparator product. WHO Technical Report Series, N 937, 2006

12 Two WHO publications: Multisource (generic) products: guidelines on registration requirements to establish interchangeability Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate release, solid oral dosage forms WHO Technical Report Series, N 937, 2006

13 The decision to grant a biowaiver is based upon - The Biopharmaceutical Classification System (BCS) - The dissolution characteristics - The nature of the excipients - The Therapeutic Index

14 The Biopharmaceutical Classification System concept: created in 1995 by the US FDA (department of Human Health) First aim: granting biowaivers for Scale-Up and Post-Approval Changes (SUPAC). A simple dissolution test (comparison) could be accepted as surrogate Second aim: more recently, extension of the BCS concept for approval of oral generic products.

15 Eligibility criteria for biowaiver 1. BCS classification of the API: solubility and permeability 2. Dissolution characteristics: very rapidly and rapidly dissolving 3. Risk assessment: To be performed only if an incorrect biowaiver decision is likely to create a risk for the patient 4. Excipients: may influence motility and/or permeability in the gastrointestinal tract. A list of usual and acceptable excipients available at: 5. Formulation: product not designed to be absorbed from the oral cavity

16 According to the BCS, drug substances are classified as follow: Class 1 Highly permeable Highly soluble Class 2 Highly permeable Poorly soluble Class 3 Poorly permeable Highly soluble Class 4 Poorly permeable Poorly soluble

17 Class 1 Highly permeable Highly soluble According to the WHO experts: A biowaiver can be granted, and at the moment these waivers are considered on a case by case basis especially if the therapeutic window is narrow

18 Class 2 Highly permeable Poorly soluble According to the WHO experts: Eligible only if dose: solubility ratio of 250ml or lower at ph 6.8

19 Class 3 Poorly permeable Highly soluble According to the WHO experts: A biowaiver can be granted if the product is very rapidly dissolving

20 Class 4 Poorly permeable Poorly soluble Class 4 API s are not eligible for a biowaiver

21 Products submitted to the Prequalification Programme are usually multisource (generic) products. In such cases, therapeutic equivalence (i.e. efficacy and safety) are generally demonstrated by performing a bioequivalence study

22 Multisource essential drugs market The situation: Very few NDRA s in developing countries require a demonstration of therapeutic equivalence for non ARV-ACT-TB drugs The major donors do not put their contractors under pressure to provide a proof of interchangeability for the purchase of non ARV-ACT-TB drugs. A consensus on the selection of the originator product can be difficult to obtain, specially for old products. Competition on prices is very tough Producers are not encouraged to adhere to the WHO requirements

23 UNICEF MSF ICRC expectations The demonstration of the interchangeability of a multisource product is a key element of the evaluation of its efficacy and safety. For old multisource products The demonstration of therapeutic equivalence will be considered as a plus in the evaluation of the product dossier. For new dossiers The in vivo or in vitro requirements to assure the interchangeability of the product will be clearly expressed to the manufacturers.

24 The UNICEF, MSF and the ICRC share a common aim to supply quality medicine to the patients UNICEF MSF ICRC commitment Commercial offers are not only considered by the cost factor but also by the quality guarantees that the company may offer on their products