The most intense discussions of Day 2 of RDD Europe occurred during an afternoon session on LABA and LABA/ICS postmarket trial design in which industry representatives differed with each other and with regulators over the usefulness of LABA safety trials such as those now demanded by the FDA. The afternoon culminated with a panel discussion that featured fairly blunt statements of dissatisfaction aimed at the sole FDA regulator in attendance.
The day started off on a less controversial note with a session titled “Science in Product Development: Advances in Processing, Formulation, and Characterization.” The morning papers ranged from discussions of the effects of electrostatic charge on cascade impaction to an explanation of why some MDIs fail to hold their prime under temperature cycling conditions, with several other talks focused on various types of particle manufacturing for stability, performance, and features such as controlled release.
After lunch, the “Posters on the Podium” session highlighted posters by (mostly) young researchers, although Richard Dalby acknowledged that the selection committee had broken its “no gray hair” rule in one case. Posters selected for this special recognition included:
Influence of L-Leucine Coating on Drug Dissolution from Carrier-free Powders, Janne Raula, Teicos Pharma,
Evaluation of Delivery Efficiency from Valved Holding Chambers with Facemasks under Simulated Use Conditions, Wenchi Hsu, University of Maryland,
Materials Compatility Testing of Honeywell’s New Low Global Warming Potential Propellants, Segolene Sarrailh, Aptar Pharma,
Biodegradable Particles For Local And Prolonged Delivery Of An Oligonucleotide Decoy To Nuclear Factor-KB In The Lung, Francesca Ungaro, University of Naples,
and Imaging Particle and Drug Deposition in Airways of Laboratory Animals, Anthony S. Wexler, University of California at Davis.
The LABA postmarket trials session began with a talk by session chair Ian Hall of the University of Nottingham, who discussed some of the difficulties that have been observed in getting reliable results in past safety studies of LABAs and noted that “conflicting agendas often get in the way of teasing out the objective truth” when safety issues are involved.
Hall took an informal survey of attendees, asking how many thought that LABAs are safe for all patients, for a majority of patients, for a minority of patients, or not safe at all. Most of the hands in the room went up for “a majority of patients,” with a handful voting for “all patients,” and no one expressing the opinion that LABAs are more unsafe than safe.
Hall was followed by Badrul Chowdhury, Director, Division of Pulmonary, Allergy, and Rheumatology Products at the Center for Drug Evaluation and Research of the FDA. After explaining that he was presenting his own opinions and not the official position of the FDA, he reviewed last year’s directives on reducing the use of LABAs and the new requirements for postmarket studies. He also explained the derivation of the FDA’s legal authority to order the trials.
Asserting that the FDA had consensus for requiring manufacturers to conduct large safety studies for Advair, Symbicort, Dulera, and Foradil, Chowdury presented the parameters of the trials that had been selected: the four studies will take 6 months each and will require a total of nearly 60,000 patients taking fixed doses of ICS to determine definitively whether the addition of LABAs to ICS increases risk of adverse outcomes.
Peter Byron then stepped in for GSK’s Steven Pascoe, who was ill and unable to attend, to present a position from GSK’s point of view, using a presentation he compiled from GSK slides from previous meetings. Allison Cave of the UK Medicines and Healthcare Products Regulatory Agency (MHRA) contrasted the use of LABAs in COPD and asthma, with an emphasis on the current lack of good information about LABA safety.
The last speaker, Donald Stanski of Novartis, refuted assertions that COPD patients show no evidence of dose response to LABAs by using sophisticated model-based dose analysis techniques to demonstrate that dose response is currently getting lost due to low signal to noise ratio in FEV1 but that 3-D plots show that dose response curves do exist and depend on severity of disease. Stanski pointed out that a better understanding of dose response would provide a great deal of help in understanding safety issues.
Once all of the speakers were seated as a panel, a number of questions arose regarding the validity of the proposed postmarket trials, with questions about the implications of confounding factors and different phenotypes, how to identify whether there is a subset of patients that do worse on LABAs, the financial consequences of spending billions on the trials instead of on development of more effective products, and even the legal consequences of a failure to conduct the studies. A number of people questioned the design of the study and whether it could produce any useful data, while Chowdhury stood by his position that the data produced would be useful to patients.
Peter Byron also directly challenged Chowdhury’s assertion that there is consensus for the LABA postmarket safety studies, pointing out that no one currently in the room was at the FDA meeting last year and asking whether people were simply being polite in not objecting vociferously. Chowdhury responded that the advisory committee meeting was open to the public and that everyone had the opportunity to attend; furthermore, he said, an editorial in the New England Journal of Medicine had come out in support of randomized controlled trials.
The session came to an end with the vast majority of the audience still seemingly unconvinced.
