In the EU, guidelines for the clinical development of inhaled products first came into existence in 1999, wherein the document was made available by the agency for the authorisation of drugs used to treat chronic obstructive pulmonary diseases. In 2002, a guidance document for the development of asthma products was made available. In 2004, a detailed document CPMP/EWP/4151/00 was released by the EU agency highlighting points to be considered on the Requirements for Clinical Documentation for Orally Inhaled Products. Especially directed at the replacement of chlorofluorocarbons (CFCs) with the hydofluoroalkanes (HFAs), this guidance described how to demonstrate therapeutic equivalence for the inhaled products.
This guidance advised that potential marketing authorisation applicants also refer to the guideline on clinical requirements for locally acting products (CPMP/EWP/239/95) which mentions that the demonstration of therapeutic equivalence in clinical trials is, in principle, necessary. So while the abridged application for known active was possible with demonstration of in vitro equivalence, it did, on the other hand, indicate the need for a clinical programme with minimal role of bioequivalence studies.
In 2009, the revised guidance CPMP/EWP/4151/00 Rev. 1 came into effect for clinical documentation of orally inhaled products. It clarifies the requirements for clinical documentation for abridged applications for orally inhaled formulations and variations/extensions to a marketing authorisation, including both single active substance products and combination products, in respect of the demonstration of therapeutic equivalence between two inhaled products for use in the management and treatment of asthma and chronic obstructive pulmonary disease in adults, and the management and treatment of asthma in children and adolescents. Products containing a new active substance are required to undergo a full clinical programme regardless of the type of inhalation device. However, in case of a known active substance, this guidance describes a three step approach: in vitro comparability, pharmacokinetic study with and without charcoal blockade, and therapeutic equivalence study. If the product does not satisfy all of the pharmaceutical criteria for equivalence, in vivo studies should be performed to substantiate equivalence. Whilst for abridged applications, satisfying the 9-point criteria to meet in vitro comparability with the innovator drug product is a real tough challenge; it is equally or even more difficult to match drug pharmacokinetics with the reference products, with variability in the inhalation technique playing a key role.
If the bioequivalence is demonstrated for a particular generic inhaled product then again there is hardly any precedent of approval solely based on the PK approach for an abridged application. So in the case of multiple country filing and with the need for further harmonisation amongst different EU member states, the granting of marketing authorisation can be delayed and sometimes impossible.
Failure to show bioequivalence and need for therapeutic equivalence study using assay sensitive study design is a Herculean task; more so when innovators have not managed to show statistical dose response in certain instances, especially in the case of inhaled steroids.
Additionally, paediatric and spacer studies are also warranted as appropriate to support the label claim, all making this project a hard nut to crack. However, a face-to-face dialogue with the regulators at an early stage of drug development is beneficial in understanding true clinical requirements for such complex generics and obtaining successful registrations at the end of quite a long product development journey.
Dr Siddharth Chachad is the head of global clinical development and medical affairs at pan-European regulatory affairs organisation ELC Group.