Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

In vitro equivalence criteria of orally inhaled products (OIPs) and role of in vitro data in the overall therapeutic equivalence program - A comparison between Europe, Canada and the U.S. ***

Dr. Edda Ballweber (Abschlußjahr: 2008)

Language: English

The incidence of respiratory diseases worldwide is increasing in both morbidity and mortality driving the need for fast and straightforward development and authorisation process of orally inhaled drug products (OIPs). During the development process of new and generic products and variations of medicinal products demonstration of therapeutic equivalence to a reference product is often necessary and represents one of the most important and crucial milestones, which must be passed for obtaining a marketing authorisation.

In this thesis the regulatory requirements for demonstration of in vitro equivalence of OIPs (MDI/DPI) in Europe, Canada and the U.S. are presented and compared. The role of in vitro data in the overall therapeutic equivalence program, which generally consists of in vitro and in vivo studies are elaborated and evaluated. Based on this information the extent of regulatory disharmony in the three jurisdictions is ascertained and the possibility to perform one global development process for authorisation in Europe, Canada and the U.S. is evaluated.

Regulatory information on this issue is collected from currently effective and draft OIP specific guidelines and interpreted. Since no OIP specific guideline exists in the U.S. OIP requirements were derived from drafted requirements for nasal products. This is sound because the basic regulatory principles are valid for both types of products.

A close inspection of the regulatory guidances indicates that the in vitro equivalence criteria in the three regions are only the same in basic aspects, which are partially stipulated in the region specific law. These include the active substance, which must be qualitatively and quantitatively the same and possess the same physicochemical attributes as the active substance in the reference product. Identical requirements are also imposed for the same dosage form, same instructions for use of the inhalation device and same delivered dose and dose uniformity. The main different aspects concern the qualitative and quantitative composition of excipients, the extent of physicochemical characterisation of the active substance, the necessity to demonstrate the same physical attributes and operating characteristics of the delivery device, and different characterisation requirements on the final formulation and the aerosol cloud. One important regulatory deficiency in all three regions with high impact on the evaluation of in vitro data are the lack of regulation on statistical in vitro approaches. For many criteria the acceptance limits are also missing.
In vitro data obtained from comparative equivalence testing represent an essential part in the overall therapeutic equivalence documentation and must be submitted in each region. The role of the comparative in vitro data in the overall therapeutic equivalence program however is different.

This fact can be attributed to different regulations concerning the necessity to demonstrate equivalence and not only comparability and to the different regulations on biowaivers.
In Europe the possibility exists to demonstrate therapeutic equivalence on in vivo data solely, if in vitro equivalence fails. Such a scenario is not allowed in Canada and the U.S., which demand both in vitro and in vivo equivalence. Thus in vitro equivalence is one essential prerequisite in Canada and the U.S. but not in Europe for achieving a marketing authorisation.
The role of in vitro data in an European application attains high importance if they show equivalence. In such a case a biowaiver can be applied for and therapeutic equivalence argumentation is based on in vitro data solely. Such a scenario is also described for solution formulations in the U.S., but not for suspension formulations. Biowaivers for OIPs are not regulated in Canada at this time.

In vitro data in Europe seem to gain also a high importance, if they cover certain clinical aspects, which can be subjected to a partial biowaiver according to the recommendations in the new European draft guideline. This guideline establishes high implications of in vitro studies in the therapeutic equivalence program to replace in vivo testing with regard to e. g. further strengths, indications for futher diseases, patient populations and spacer use. In vitro data can also be supportive, if critical clinical aspects need confirmation through in vitro tests. Such a high regulatory implication of in vitro studies in the overall therapeutic equivalence program is unique and can only be found in this extent in the new European draft guideline but not in Canadian or U.S. regulations. Paediatric indication and spacer use are two aspects which claim high importance in the European draft guideline, but these are not addressed in the Canadian and U.S. guidances.

In principle a full therapeutic equivalence package consists of in vitro studies and in vivo efficacy and safety studies. Due to the fact that the regulation of biowaivers and the recommendation of the required type of clinical studies (lung deposition, PD, PK or clinical studies) are not consistent the overall therapeutic equivalence program in the three jurisdictions is also different.

The marked disharmony in equivalence testing of OIPs entails high limitations concerning global development and global marketing of generic OIPs. As the differences demonstrate, not only equivalence tests and the resulting documentation could differ but also the developed product itself, even if the reference product is a global marketed product and in consequence identical in all three regions.

Harmonised regulatory requirements for therapeutic equivalence testing would ensure economical
use of resources and avoid an unnecessary delay in global development and availability of new and generic medicine. The CHMP guideline on the pharmaceutical quality of inhalation and nasal products has been jointly developed by the CHMP and Health Canada and is the first and only harmonised guideline for OIPs. This guideline could serve as a starting point for future harmonisation activities on in vitro equivalence criteria and in a further step in harmonisation of in vivo equivalence programs. Due to the high diversity of OIPs with regard to e. g. the delivery device, handling of the delivery device and the diverse substance classes with their diverse physiological ways of action the development of product specific guidelines as partially realised by Health Canada should be taken into consideration.

Pages: 58