RDD Europe 2013 — Day 2

On Day 2 of RDD Europe 2013, the focus was primarily on regulatory issues. Prior to sessions titled “Weighing the Evidence in Support of Bioequivalence,” “Orphan Drugs: Opportunities and Regulatory and Clinical Challenges,” and “Harmonizing the Clinical Requirements for LABA/ICS Combinations in the USA and Europe,” however, the day opened with a “Posters on the Podium” session with five poster submissions selected by the organizers for presentation to the full audience.

Participants included:

• Mehra Haghi of the University of Sydney, “Uptake of Salmeterol Xinafoate and Fluticasone Propionate from Single and Combination Dry Powder Inhalers After Deposition on Calu-3 Respiratory Epithelia”
• David Fergenson of Livermore Instruments, “Real-Time Determination of Aerodynamic Particle Size Profiles and the Presence/Co-Presence of Active Ingredients in Inhalational Pharmaceutical Products Using a SPAMS 3.0”
• Ekaterina Zevak of Novosibirsk State University, ”Salbutamol-Glycine Composite Microballs for Pulmonary Drug Delivery”
• Robert Winkler of Boehringer Ingelheim, “Dose Range of a Propellant Driven High-Dose Dry Powder Inhaler”
• Regina Scherließ of Christian Albrecht University, “Evaluation of Impact of Nasal Dry Powder Vaccine Formulations on Uptake and Activation by Dendritic Cells”

In the session on bioequivalence, Stephanie Kim of the FDA participated by phone call from the US, where it was 4:30 a.m. Presenting”An Assessment of the FDA’s Dose-Scaling Approach to Evaluate Pharmacodynamic Bioequivalence,” she described the FDA’s dose scale method for evaluating equivalence, which is described in the guidance on Orlistat and called for in the recently issued guidance on albuterol. She also described an FDA-sponsored PD study to evaluate exhaled NO as a biomarker in demonstrating ICS dose response using Flovent HFA that failed to demonstrate dose response.

In response to a question from Peter Byron, who noted that “Obviously, we’re well away from having a PD test for ICS,” Kim said that the Office of Generic Drugs would weigh PK and in vitro results more heavily and would view a PD study as more “confirmatory.”

In the remaining presentations of that session, Jan de Backer of FluidDA described the possibilities for BE testing using functional respiratory imaging (FRI), and Byron compared a variety of mouth/throat models available for in vitro testing, including the VCU realistic mouth/throat models, the OPC consortium models, and the Alberta idealized throat.

The final session concluded with a panel discussion on differences in requirements for ICS/LABA combinations between FDA and EMA with the presenters, most of them regulators, including Badrul Chowdhury of the US Food and Drug Administration (FDA), Sanjeeva Dissanayke of Mundipharma, David Lyons of the Irish Medicines Board and David Wright of the UK Medicines and Healthcare Products Regulatory Agency (MHRA), David Lyons of the Irish Medicines Board, a member of CHMP, and moderator Leslie Hendeles of the University of Florida.

Over the course of the session, the presenters delineated a number of contentious issues for ICS/LABA approval that have caused dilemmas for sponsors submitting applications to both the FDA and EMA, including the inclusion of placebos and LABA only arms in studies for the US and the inclusion of EU-approved comparator drugs for EU submissions.

In general, panel members agreed that the process has been complicated by submissions where one or more of the component drugs has not previously been approved. David Wright expressed frustration with pressure to quickly review submissions for combinations that include currently unapproved drugs, saying, “i know there are commercial reasons for pressing ahead, but it isn’t necessarily a win-win situation to do that.”

The panel also agreed that the lack of harmonization is causing problems and that the FDA and EMA may need to work together, and both Chowdhury and Wright indicated willingness to be flexible with requirements and to consult with each other but warned that time considerations might limit the number of parallel advice cases that the regulators could take on, even if ICS/LABA combinations could be added to the parallel advice procedure.