Thank you for the opportunity to speak today. My name is Dr. Megan Polanin, and I am a Senior Fellow at the National Center for Health Research. I trained at Johns Hopkins before joining our research center, which analyzes scientific and medical data and provides objective health information to patients, providers, and policymakers. We do not accept funding from the pharmaceutical or medical device industries, so I have no conflicts of interest.
We strongly support efforts to improve antibiotic use and drug safety. However, we have serious concerns about the efficacy, safety, and potential for antibiotic resistance of this drug.
Based on available clinical data, this drug has not been shown to be effective. Across both studies and treatment regimens, researchers only found a significant treatment effect in one instance. The Cipro 14-day regimen achieved a statistically significant improvement in the time to the 1st pulmonary exacerbation (TFE), the primary endpoint, in the RESPIRE 1 clinical trial. However, in the RESPIRE 2 trial, the Cipro 14-day regimen did not achieve a statistically significant improvement in TFE. The 28-day regimen did not demonstrate improvement in either study. These results indicate that the first finding was likely due to chance.
In addition, we have methodological concerns about the clinical trials. We agree with the FDA that it is unclear whether the chosen primary endpoint, studied for only 48 weeks, translates into a clinically meaningful benefit for patients who would likely be taking this drug for life. Moreover, studies have shown that sputum color cannot be judged reliably and is therefore not a well-defined marker for the primary endpoint. One 2009 study illustrated the importance of utilizing disease-specific patient-derived and reported symptoms tools to measure outcomes for new treatments.
We also urge caution with the comparison to the inhaled placebo. As the FDA noted, it is quite possible that the inhaled placebo exacerbated symptoms, which could make symptoms worse for patients. This comparison also makes it difficult to evaluate risks of the inhaled drug.
Regarding safety, we know quinolones can have very dangerous side effects, including arrhythmias; tendon ruptures; kidney problems; changes in blood sugar levels; neuropathy; and central nervous system problems. This drug resulted in serious adverse events, including bronchospasm, hemoptysis, tendinopathies and ligament disorders, and the occurrence of non-tuberculous mycobacteria. This condition is more common in older adults, particularly those 75 and older, so this population should be adequately represented and assessed for side effects, including kidney issues, neuropathy, and tendinopathy. Unfortunately, these studies do not provide enough data to generalize to this group. Given these serious risks without evidence of efficacy, how can we approve this drug for patients?
While quinolones can be life-saving drugs for certain types of infections, we must be extremely cautious about their safety and efficacy to ensure that benefits outweigh harms for any new indication or any new version. Fluoroquinolones should be taken only when needed and for the appropriate amount of time. Patients should not be given the drug for longer than necessary or for conditions where the use of another drug is more appropriate. In fact, in May 2016, the FDA encouraged physicians and other health care providers to avoid prescription of quinolones for respiratory and urinary tract infections unless other antibiotics have been tried and were unsuccessful.
We applaud the FDA for recommending that two adequate and well-controlled trials be conducted to support this drug’s non-cystic fibrosis bronchiectasis proposed indication, particularly as this is a new treatment indication and route of administration for ciprofloxacin. The sponsor provided the recommended data, but unfortunately, the data indicate that this drug’s benefits do not outweigh its potential risks.
Finally, we are concerned that the potential for antibiotic resistance is high for any patients taking it for a long period of time. The two clinical trials provided by the sponsors show that this concern is valid. In both trials, a higher proportion of participants taking the active treatment had resistant bacteria (mostly for the P. aeruginosa bacteria) compared to those taking placebo. Thus, we simply cannot rule out that prolonged use of this drug will result in increased resistance. This is especially problematic because patients will likely potentially remain on this drug for the rest of their lives.
Will there be additional safety issues and a decrease in efficacy due to bacterial resistance over time? None of us know the answer to this question. The question for you today is: Do we know enough to approve this drug for people who really need it? We respectfully urge you to consider the inadequacy of the current data.
We recommend further study of this drug with clinically meaningful primary endpoints, such as severity of exacerbation, overall lung function, and patient-reported outcomes to directly assess patients’ symptoms such as cough, wheezing, and sputum production. We also recommend comparing the drug to a non-powder to ensure that the method of use does not worsen symptoms and including more patients 75 and older.
Thank you for the opportunity to share our views.
The Antimicrobial Drugs Advisory Committee voted 6-9 and 1-14 that there was not substantial evidence of the safety and efficacy in delaying the time to first exacerbation after after starting treatment for the ciprofloxacin 14-day and 28-day regimens, respectively. Read more about the meeting here.