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HYATTSVILLE, MD – A Food and Drug Administration advisory panel voted against recommending Linhaliq, ciprofloxacin dispersion for inhalation, to treat adult non-cystic fibrosis bronchiectasis (NCFBE) patients who have chronic lung infections with Pseudomonas aeruginosa.
“Two trials that have two very different outcomes – and no matter how we try and explain what the difference was, there was something really missing there,” said advisory committee member Peter Weina, MD, chief of the department of research programs at Walter Reed National Military Medical Center, Bethesda, Md.
NCFBE is often treated with antibacterial drugs, which temporarily reduce inflammation and bacterial load. One of the most common colonizing bacteria in NCFBE infections is P. aeruginosa, which is often associated with increased risk of death and hospital admission.
Prior studies involving inhaled bacterial drugs such as gentamicin and colistin to treat NCFBE have yielded mixed results, and none has been approved for that indication by the FDA.
The FDA granted cipro DI orphan drug status in June 2011 and fast-track approval in August 2014. Cipro DI’s developer, Aradigm, conducted two phase 3 clinical trials to support inhaled ciprofloxacin for the NCFBE indication.
The two phase 3 clinical trials, ORBIT-3 and ORBIT-4, were nearly identical in design. Patients in both were randomized 2:1 to receive cipro DI or placebo once daily for six cycles of 56 days each.
The efficacy results of the ORBIT-3 and ORBIT-4 trials were mixed. In ORBIT-3, there was very little difference between the treatment and placebo arms, with a median difference of 78 days for the primary endpoint of time to first pulmonary exacerbation (PE) (hazard ratio, 0.99; P = .974). ORBIT-3 also showed no difference between treatment and placebo in the frequency of PEs by week 48 of the study (incidence ratio, 0.852).
In contrast, a marginal treatment effect was observed in ORBIT-4, with a median time difference to first PE of 72 days between the placebo and treatment arms (HR, 0.71; P = .032). ORBIT-4 also demonstrated an ability to reduce the number of PEs (incidence ratio, 0.631) by approximately 36.9% by week 48.
Adverse events were the most common reason leading to patient discontinuation in both studies, accounting for 13.1% and 5.3% in the treatment arms of ORBIT-3 and ORBIT-4, respectively.
Despite some of the positive findings in ORBIT-4, FDA presenter LaRee Tracy, PhD, of the FDA’s office of biostatistics, voiced concerns about the trial data – specifically, the failure to reach the primary endpoint in ORBIT-3.
“If I were to be a [statistically speaking] ‘strict’ person, I wouldn’t be looking at the frequency of the [secondary] endpoints, because the primary [endpoint] failed,” Dr. Tracy noted. She also voiced concerns about a re-analysis Aradigm conducted after the trial data were unblinded, stating that the changes made to the original analysis plan “lend a lot of concerns for me.”
Both ORBIT-3 and ORBIT-4 presented uncertainties related to the long-term use of cipro DI. The durability of efficacy and safety findings did not extend beyond a year, leaving some committee members wondering about the development of antibiotic resistance in cipro DI-treated patients. In addition, members were concerned that long-term use of cipro DI could limit the utility of systemic fluoroquinolones to treat severe bacterial and pneumonia infections in NCFBE patients.
The FDA usually follows the recommendations of its advisory panels, which are not binding.
This article was updated 1/11/18.
HYATTSVILLE, MD – A Food and Drug Administration advisory panel voted against recommending Linhaliq, ciprofloxacin dispersion for inhalation, to treat adult non-cystic fibrosis bronchiectasis (NCFBE) patients who have chronic lung infections with Pseudomonas aeruginosa.
“Two trials that have two very different outcomes – and no matter how we try and explain what the difference was, there was something really missing there,” said advisory committee member Peter Weina, MD, chief of the department of research programs at Walter Reed National Military Medical Center, Bethesda, Md.
NCFBE is often treated with antibacterial drugs, which temporarily reduce inflammation and bacterial load. One of the most common colonizing bacteria in NCFBE infections is P. aeruginosa, which is often associated with increased risk of death and hospital admission.
Prior studies involving inhaled bacterial drugs such as gentamicin and colistin to treat NCFBE have yielded mixed results, and none has been approved for that indication by the FDA.
The FDA granted cipro DI orphan drug status in June 2011 and fast-track approval in August 2014. Cipro DI’s developer, Aradigm, conducted two phase 3 clinical trials to support inhaled ciprofloxacin for the NCFBE indication.
The two phase 3 clinical trials, ORBIT-3 and ORBIT-4, were nearly identical in design. Patients in both were randomized 2:1 to receive cipro DI or placebo once daily for six cycles of 56 days each.
The efficacy results of the ORBIT-3 and ORBIT-4 trials were mixed. In ORBIT-3, there was very little difference between the treatment and placebo arms, with a median difference of 78 days for the primary endpoint of time to first pulmonary exacerbation (PE) (hazard ratio, 0.99; P = .974). ORBIT-3 also showed no difference between treatment and placebo in the frequency of PEs by week 48 of the study (incidence ratio, 0.852).
In contrast, a marginal treatment effect was observed in ORBIT-4, with a median time difference to first PE of 72 days between the placebo and treatment arms (HR, 0.71; P = .032). ORBIT-4 also demonstrated an ability to reduce the number of PEs (incidence ratio, 0.631) by approximately 36.9% by week 48.
Adverse events were the most common reason leading to patient discontinuation in both studies, accounting for 13.1% and 5.3% in the treatment arms of ORBIT-3 and ORBIT-4, respectively.
Despite some of the positive findings in ORBIT-4, FDA presenter LaRee Tracy, PhD, of the FDA’s office of biostatistics, voiced concerns about the trial data – specifically, the failure to reach the primary endpoint in ORBIT-3.
“If I were to be a [statistically speaking] ‘strict’ person, I wouldn’t be looking at the frequency of the [secondary] endpoints, because the primary [endpoint] failed,” Dr. Tracy noted. She also voiced concerns about a re-analysis Aradigm conducted after the trial data were unblinded, stating that the changes made to the original analysis plan “lend a lot of concerns for me.”
Both ORBIT-3 and ORBIT-4 presented uncertainties related to the long-term use of cipro DI. The durability of efficacy and safety findings did not extend beyond a year, leaving some committee members wondering about the development of antibiotic resistance in cipro DI-treated patients. In addition, members were concerned that long-term use of cipro DI could limit the utility of systemic fluoroquinolones to treat severe bacterial and pneumonia infections in NCFBE patients.
The FDA usually follows the recommendations of its advisory panels, which are not binding.
This article was updated 1/11/18.
HYATTSVILLE, MD – A Food and Drug Administration advisory panel voted against recommending Linhaliq, ciprofloxacin dispersion for inhalation, to treat adult non-cystic fibrosis bronchiectasis (NCFBE) patients who have chronic lung infections with Pseudomonas aeruginosa.
“Two trials that have two very different outcomes – and no matter how we try and explain what the difference was, there was something really missing there,” said advisory committee member Peter Weina, MD, chief of the department of research programs at Walter Reed National Military Medical Center, Bethesda, Md.
NCFBE is often treated with antibacterial drugs, which temporarily reduce inflammation and bacterial load. One of the most common colonizing bacteria in NCFBE infections is P. aeruginosa, which is often associated with increased risk of death and hospital admission.
Prior studies involving inhaled bacterial drugs such as gentamicin and colistin to treat NCFBE have yielded mixed results, and none has been approved for that indication by the FDA.
The FDA granted cipro DI orphan drug status in June 2011 and fast-track approval in August 2014. Cipro DI’s developer, Aradigm, conducted two phase 3 clinical trials to support inhaled ciprofloxacin for the NCFBE indication.
The two phase 3 clinical trials, ORBIT-3 and ORBIT-4, were nearly identical in design. Patients in both were randomized 2:1 to receive cipro DI or placebo once daily for six cycles of 56 days each.
The efficacy results of the ORBIT-3 and ORBIT-4 trials were mixed. In ORBIT-3, there was very little difference between the treatment and placebo arms, with a median difference of 78 days for the primary endpoint of time to first pulmonary exacerbation (PE) (hazard ratio, 0.99; P = .974). ORBIT-3 also showed no difference between treatment and placebo in the frequency of PEs by week 48 of the study (incidence ratio, 0.852).
In contrast, a marginal treatment effect was observed in ORBIT-4, with a median time difference to first PE of 72 days between the placebo and treatment arms (HR, 0.71; P = .032). ORBIT-4 also demonstrated an ability to reduce the number of PEs (incidence ratio, 0.631) by approximately 36.9% by week 48.
Adverse events were the most common reason leading to patient discontinuation in both studies, accounting for 13.1% and 5.3% in the treatment arms of ORBIT-3 and ORBIT-4, respectively.
Despite some of the positive findings in ORBIT-4, FDA presenter LaRee Tracy, PhD, of the FDA’s office of biostatistics, voiced concerns about the trial data – specifically, the failure to reach the primary endpoint in ORBIT-3.
“If I were to be a [statistically speaking] ‘strict’ person, I wouldn’t be looking at the frequency of the [secondary] endpoints, because the primary [endpoint] failed,” Dr. Tracy noted. She also voiced concerns about a re-analysis Aradigm conducted after the trial data were unblinded, stating that the changes made to the original analysis plan “lend a lot of concerns for me.”
Both ORBIT-3 and ORBIT-4 presented uncertainties related to the long-term use of cipro DI. The durability of efficacy and safety findings did not extend beyond a year, leaving some committee members wondering about the development of antibiotic resistance in cipro DI-treated patients. In addition, members were concerned that long-term use of cipro DI could limit the utility of systemic fluoroquinolones to treat severe bacterial and pneumonia infections in NCFBE patients.
The FDA usually follows the recommendations of its advisory panels, which are not binding.
This article was updated 1/11/18.
REPORTING FROM AN FDA ADVISORY COMMITTEE MEETING
