Reliability of Mesh Aerosol Devices Used During INHALE Trial

In the recent review by Palmer and Smaldone,⁽¹⁾ the authors provide a review of trials associated with used treatment of ventilator-associated infections, making a creditable case for early prophylaxis and treatment of tracheobronchitis. Although the complexities of treatment of pulmonary infections are well presented, their emphasis on the “possible” but unsubstantiated claims of mesh aerosol device variability undermining the success of the INHALE or IASIS trial seem out of context and inappropriate.^(2–4)

The issues raised about mesh nebulizer reliability are not based on identified adverse events or reports of failure of the aerosol devices used, but rather on author's experience with mesh nebulizers that were not used in either trial. The author's analysis should be based on the devices that were actually used in these specific trials.

The authors' assertion that “The INHALE trial used Aerogen technology…” is misleading and is factually inaccurate and incorrect. The Pulmonary Drug Delivery System (PDDS) used in the phase 2 AMIKACIN studies was indeed developed by Aerogen Ltd., Galway, Ireland. However, the system used in the INHALE pivotal trial was developed by Nektar Therapeutics for Bayer (not Aerogen Ltd.). In the years before the INHALE trial the study sponsor made major changes to the PDDS device, including mesh production and aerosol generator architecture, mesh atomizer configuration, modified reservoir, different cables, and redesigned controller. The similarities with the phase 2 device were largely particle size distribution of the emitted aerosol and a breath synchronization algorithm.

The FDA requirements for drug/device Investigational New Drugs (INDs) include extensive testing for consistent drug/device performance. The sponsor did not enter phase 3 pivotal trials without extensive life and performance testing of devices to assure proper and consistent performance in the precise conditions of use, including dose uniformity. Aerosol device failures would have been reported as adverse events per the clinical protocol and the absence of reports of device failures or inconsistent performance suggest that the failure of the INHALE trial to meet its clinical endpoints was not related to device failures. This lack of device failures was confirmed by the study coordinator (personal communication). Furthermore, a published report of the performance of the device that was actually used in the trial suggests consistently high inhaled doses were achieved.⁽⁴⁾ Based on this, it is extremely unlikely that aerosol device failure was the “cause” or significant contributing factor of the INHALE trials failure to meet its clinical endpoints.

Despite the absence of reports of device failures or inconsistent performance in the trial, the authors take considerable pains to describe their experience with a vibrating mesh nebulizer that was not used in the trial. At last count there were >30 marketed vibrating mesh aerosol devices, each with different meshes, core design, reservoirs, and controllers. Inconsistent performance has not been widely reported with these devices either. Justifying concerns of trial integrity based on limited non-GMP testing of a vibrating mesh nebulizer that was not used in either study is neither relevant nor appropriate in an otherwise sound review and acts to distract from the more crucial question of why the INHALE study failed to meet endpoints.