NCHR Testimony on Mannitol Inhalation Powder for Cystic Fibrosis

Stephanie Fox-Rawlings, PhD, National Center for Health Research, May 8, 2019

Thank you for the opportunity to speak today on behalf of the National Center for Health Research. I am Dr. Stephanie Fox-Rawlings. Our Center analyzes scientific and medical data to provide objective health information to patients, health professionals, and policy makers. We do not accept funding from drug and medical device companies, so I have no conflicts of interest.

We all agree that new treatments to improve the lung function and quality of life for patients with cystic fibrosis are needed. It’s equally important that new treatments should have a clear benefit and a well-defined risk profile. Mannitol inhalation powder (Bronchitol) was not approved during its first application due to concerns about safety and efficacy. Even though the new clinical trial addresses some of the issues with the original clinical trials, there are still essential questions that haven’t been answered about both safety and efficacy.

The new clinical trial (study 303) found that patients taking 400mg mannitol had a statistically significant improvement in FEV1 compared to patients taking a subtherapeutic dose. However, this improvement was modest, 51 ML, which was similar to the amount improvement seen in the previously submitted trials. It is unclear if this translates into a meaningful outcome for the patients.

In addition, the secondary efficacy endpoints related to exacerbations [Protocol-Defined Pulmonary Exacerbation] and respiratory symptoms did not support efficacy. Since there was no improvement in functional outcomes, it seems that the small change in FEV1 may not have a meaningful impact on patients’ lives. Furthermore, FDA raised concerns that this modest improvement may decline over time.

In addition to questionable efficacy, mannitol may also increase the risk for serious exacerbations [as determined by clinician; condition aggravated], particularly in US patients. 21% of US patients taking mannitol had a serious exacerbation compared to 11% of US controls or either of the treatment arms outside the US. At least part of this difference could be due to differences in patients and medical practices between the US and other countries. Unfortunately, that means that including the rates of adverse events from all countries may underestimate the risk to patients in the US.

We are concerned that if the subtherapeutic doses of mannitol used by the control group has an increased the risk for adverse events such as exacerbations in the control group, it would also bias the results to make the risks of the drug seem lower than it really is.

In summary, it is uncertain if the benefits outweigh the risks based on the data discussed today. However,  there should be sufficient evidence of both safety and efficacy before approval. Postapproval regulatory methods would be insufficient to determine if the benefits outweigh the risks. Perhaps mannitol would be a good option for a subset of patients, but if so, this should be determined prior to approval and specified in the indication on the label. However, if mannitol is approved, we agree that the label should require a  mannitol tolerance test prior to starting treatment.

Thank you for your time.

The Pulmonary-Allergy Drugs Advisory Committee was split on whether the benefits outweighed the risks for mannitol inhalation powder to improve lung function in adults with cystic fibrosis; 9 voted for the drug and 7 voted against. You can read more about the meeting here.