NCHR Testimony at the FDA about Antibiotic for Inhalation, Cipro DI

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 strongly support efforts to improve antibiotic use and drug safety.

It is important that any drugs should clearly demonstrate efficacy and a good long-term safety profile before they are approved. That is especially true for Cipro, which has known risks, and for an indication that involves use for years or even decades. Cipro DI has clearly not yet met that standard.

There are questions about whether the primary endpoint of time to first exacerbation is clinically meaningful. Since patients would be treated with repeated courses of this drug for years or decades, the relevance of a one time event is unclear. The secondary efficacy endpoints are more pertinent: frequency of exacerbations, number of severe exacerbations and quality of life.

The data provided can help generate hypotheses that the sponsor can test in future studies, but they are not adequate as a basis for approval. In addition to questions about the clinical relevance of the selected primary endpoint, the primary and some secondary endpoints were met in only one out of the two phase-3 trials. Overall, these improvements are small, and it is not clear that they would be clinically meaningful for many patients.

The value of conducting two clinical trials is to show that the results can be replicated. While we could hope that ORBIT-3 was not successful due to random circumstances, it is also quite possible that the success of the ORBIT-4 trial was the fluke or that Cipro DI is only effective for a specific subgroup of patients that hasn’t yet been defined. For example, the trials differed in the number of patients from various countries and patients differed in their baseline lung function prior to participation in the study.

This drug has serious risks, so it is crucial to identify if the drug is effective and for whom prior to approval, and to ensure the indication is clearly defined. These risks are inherent in the fact that patients would be expected to take Cipro DI for years or decades and there will be subtherapeutic levels of drug throughout the body during each course.

We agree with the FDA’s concerns that long-term exposure would increase the risk of developing antibiotic resistant bacteria.  Over time, the effectiveness of the drug may decrease, while the harms to the individual patients and the population would increase.

Fluoroquinolones in general and Cipro in particular have risks for serious adverse events involving the heart, brain, and tendons. It seems reasonable to assume that the risk of adverse events is lower when a drug acts locally rather than systematically. But expecting that it should be safer is not the same as proving it is safer.  Long-term exposure may result in unexpected adverse events, which could be difficult to recognize are due to this drug.

 The clinical trials did not study enough patients or evaluate them for a long enough period of time to adequately evaluate the risk for resistance or long-term adverse events. They cannot predict the extent to which Cipro DI would maintain effectiveness beyond the 1-year mark.