Clinical trial rethink needed to address unmet needs in severe asthma

A major rethink is needed on how clinical trials are conducted in severe asthma, leading respiratory physicians say.

Innovation in trial design, effective partnerships with patient groups and multi-national trials consortia are urgently needed to tackle “significant and major” unmet needs in the treatment of patients with severe asthma, according to a perspective article published in the American Journal of Respiratory and Critical Care.

The group led by Salman Siddiqui, Professor of airway disease and respiratory medicine at the NIHR Respiratory Biomedical Research Centre, Leicester University, UK, says the need for better biomarker identification in severe asthma makes it difficult to conduct effective clinical trials. And the proliferation of therapeutic choice for severe asthma may complicate the design and treatment choice in future clinical trials.

“Future challenges in the delivery of severe asthma clinical trials may be predicted by drawing analogies to cancer therapeutics where [the] pharmacopeia has outstripped the capacity to test new drugs,” the group said.

“This issue when coupled with two additional factors, (i) the proliferation of competing compounds targeting the same biological pathways (e.g. immunotherapies targeting PD-1 in a range of solid organ cancers) and (ii) the limited number of patients seen at clinical centres that can conduct such sophisticated trials, are likely to make testing the next generation of severe asthma therapies far more complex without novel approaches to study design and collaborations.”

The experts suggest a potential response to these challenges is the implementation of standardised international severe asthma registries that systematically capture clinical care in severe asthma to better understand the implications of regional and national variations in care. Such registries would ideally require alignment of data capture to allow curation of data across countries.

“In addition, development of a standardised clinical care pathway framework for severe asthma, outlining the key baseline assessment for accurate diagnosis, evaluation of adherence, optimisation of comorbidities and ultimately the position of monoclonal therapies, would facilitate the development of a ‘standard of care arm’ in pragmatic severe asthma trials,” they said.

An ideal care pathway would be a live and iterative document with periodic revisions as evidence becomes available from clinical trials and disease registries, they added.

According to the group, the delivery of pragmatic trials requires the development of robust early stopping rules when biologics are deemed to be failing, with future advances likely to require parallel advances in identifying theragnostic biomarkers of treatment response or failure.

They note that the development of reproducible biomarkers requires considerable efforts to harmonise protocols across severe asthma trials, and efforts to allow sample sharing across consortia with appropriate ethics committees’ approval are required at the inception stage of clinical protocols.

Discussing the importance of a collaborative approach, the group said there are current transatlantic opportunities to conduct clinical trials that could facilitate the development of common trial platforms to maximise overall efficiency and move the field of severe asthma forward.

They also flagged the importance of patient participation for successful next generation severe asthma trials.

“The development of severe asthma trial networks focusing on pragmatic platform trials should enable patients with severe asthma to receive therapies under a clinical trial indication even when they do not meet the criteria for a licensed monoclonal or trials of sequential monoclonal antibodies.

“An optimal model of care would be to embed clinical trials within the severe asthma treatment pathway with seamless integration such that all patients are offered participation in a clinical trial,” they said.

Such trials may include personalised approaches to treatment selection, non-pharmacological measures such as dietary modifications, interventions to optimise patient adherence and systematic approaches to addressing comorbid factors before considering biologics, they added.

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