Masterstudiengang "Drug Regulatory Affairs"
Regulatory requirements related to the registration of generic orally inhaled drug products in the EU and US - A comparison of the European "stepwise approach" and US "weight of evidence approach" ***
Carina Schunk (Abschlußjahr: 2019)
The regulatory approval of generic or rather hybrid orally inhaled products stands out by an intricate relationship of different regulatory and scientific key aspects in contrast to traditional pharmaceutical dosage forms, such as orally administered drug products.
With focus on the ICH regions EU and US the detailed comparison of their rather complex approaches is striking that they share basic principles for demonstration of bioequivalence of two OIPs. Both regulatory approaches generally require in vitro tests covering device similarity and in vivo PK and PD studies. However, acceptance criteria, on which bioequivalence is established, or the study designs of in vivo studies may vary in some respect.
CHMP advocates a stepwise approach with in vitro studies as starting point, which enables the demonstration of equivalence at each level (in vitro, PK studies, PD studies). Consequently, in case of insufficient in vitro data in vivo PK or PD studies have a higher priority in the bioequivalence decision making. This strategy leaves a certain margin for the applicant with respect to timing and costs of each OIP individually based on the outcome at each "step" for demonstration of bioequivalence. On the other hand, FDA requires by its weight of evidence approach the entire "study program", i.e. in vitro studies including device similarity and in vivo PK, and PD studies, right from the start. This leads to the conclusion that in contrast to the EU all acceptance criteria have to be fulfilled, which covers in vitro data as well as in vivo study results. Otherwise regulatory approval in the US is rather unlikely.
Despite the different approaches, both CHMP and FDA may accept the claim for a biowaiver. In the EU no in vivo data are required in case certain criteria are satisfied at in vitro level. In addition, equivalence for solutions for nebulisation may rely on in vitro data only in case of the same qualitatively and quantitatively composition of the drug product. The US on the other hand supports a similar approval strategy for suspensions for nebulisation containing budesonide.
Partial biowaiver claims for multiple strengths products are feasible in the EU in the event of in vitro dose linearity and linear PK, so that PK or PD studies, if required, need to be conducted with one dose strength only.
FDA in turn accepts reduced investigations in this respect only for PD studies, where the lowest dose strength should be chosen.
With respect to available guidance documents, CHMP provides one universal guideline applicable for all "generic" OIPs, in particular for drug products for the treatment of asthma and COPD. In contrast, FDA published very detailed product-specific guidance documents that should lead the applicant through the pharmaceutical and clinical development of the respective OIP.
Eventually, it seems from the outside that the approach envisaged by the US is more conservative towards the approval of those rather complex drug products. This might stem from the different scientific and regulatory views concerning the previous absence of an adequate IVIVC, though EU as well as the US acknowledges this issue as an overall challenge. Therefore, it could be advisable for an applicant who intends to file in the EU and US in parallel to seek close dialogue with both authorities already during early development.
Harmonisation of both regulatory approaches towards global consistency is a desirable objective. However, different attitudes towards the relevance of data required for the demonstration of bioequivalence of two OIPs make this a major challenge. Consequently, this will call for separate development plans for each ICH region at the present time. That is already evident with regard to the choice of originator product as both authorities require the reference product to be authorised in their own region. Furthermore, bridging in vitro or in vivo data generated with a reference product, e.g. from the EU with the one of the US, is not foreseen in either jurisdictions.
Pages: 73, Annex: I, pages: 15