US FDA reviewers skeptical of Novartis' easier-to-use tobramycin

Although Novartis' inhalation powder form of tobramycin, dubbed TIP, is faster, simpler and more portable to use for patients with cystic fibrosis (CF) infected with the bacterium Pseudomonas aeruginosa, US FDA drug reviewers were skeptical it works as well as the company's already approved inhalation solution form of the medicine, known as TOBI.

The FDA plans to seek the advice of its Anti-Infective Drugs Advisory on 5 September to help the agency decide whether to approve the newer drug, an inhalation powder hard-capsule formulation of tobramycin administered with a hand-held, manually-operated, breath-activated dry-powder inhaler, known as T-326, which has a proposed trade name of Podhaler.

The active ingredient in TIP, tobramycin, an aminoglycoside antibiotic, is identical to that in TOBI, which was approved in the US in 1997 and has become a standard-of-care treatment for CF patients with P aeruginosa.

But because TOBI is a nebulized product which takes up to 20 minutes to administer – twice each day – with an added 15 minutes or so to prepare the dose, assemble and disassemble the nebulizer and compressor and clean and disinfect the nebulizer, treatment adherence often is poor.

In contrast, TIP can be administered in about 5 minutes, with no added time for assembling, cleaning and disinfecting equipment – saving patients several hours each treatment cycle, reducing their treatment burden, Novartis argued.

TIP's treatment cycle for P aeruginosa in CF is the same as TOBI's – 28 days on drug and 28 days off.

But the FDA raised concerns about Novartis’ studies of TIP.

While the primary analysis of Novartis' study C2301, a double-blind randomized study of TIP versus placebo in CF patients 6-21 years, showed significant relative improvements in forced expiratory volume in one second (FEV-1) percent predicted from baseline to day 28 in both parametric and non-parametric tests, with or without control for covariates, the FDA found limitations with the trial.

Notably, the positive findings were primarily driven by patients in Europe who experienced substantially larger relative changes, versus patients in North America, FDA's drug reviewers said in briefing documents posted online on 31 August ahead of the advisory committee meeting.

A major limitation of study C2301, which was conducted to demonstrate superior efficacy of TIP to placebo in FEV1, is that the primary analysis excluded 41% of the randomized population, regulators said.

They said the analysis of C2301 based on 59% of the original intent-to-treat (ITT) population, or 61 of 102 patients, was "seriously limited," because the "patients who dropped out could be informative," the FDA's reviewers said, insisting such a limitation could introduce potential biases.

The FDA reviewer's sensitivity analysis based on all randomized patients receiving treatment showed a smaller magnitude of treatment effect.

Although both TIP and placebo patients who crossed over to treatment had improvements in FEV1% predicted following their first course of therapy, improvements in both groups diminished by the following 56-day cycle for both mean and median changes, regulators said.

"The sustainability of improvements in FEV1% predicted found in study C2301 may raise concern regarding the clinical significance of these findings," the reviewers said.

Improvements in FEV1% predicted in study C2301 were not correlated with improvements for other important clinical outcomes, such as reductions in antipseudomonal antibacterial drug usage and reduction in respiratory hospitalizations, they said.

Supportive analyses in the trial were limited as a result of using a sample size that was substantially smaller than the planned sample size of 140 participants, and the study protocol was also amended such that there would be no formal testing of any secondary outcome measure, such as all secondary outcomes were considered to be exploratory, the FDA's reviewers said.

Study C2301 was conducted in patients with no prior exposure to inhaled antipseudomonal antibiotics for at least 4 months for 1 cycle – 28 days on and 28 days off treatment – followed by additional two cycles of open-label TIP treatment.

In a similar double-blind randomized study, known as C2303, TIP was tested against placebo in CF patients 6-21 years with no prior exposure to inhaled antipseudomonal antibiotics for at least four months for only one cycle.

Study C2303, however, did not accrue the projected sample size and it failed to meet its primary endpoint. Additional sensitivity and supportive analyses of the trial also failed to show significance, regulator pointed out.

"Although there is a weak suggestion of a benefit from TIP therapy in terms of FEV1% predicted improvements based on numeric comparisons and graphical representations, the level of evidence presented from the primary analysis is not acceptable for drawing valid statistical inferences, since the possibility of chance findings cannot be ruled out," FDA's reviewers said.

Novartis also conducted an open-label extension study, known as study C2302, in CF patients 6 years or older with no prior exposure to inhaled antipseudomonal antibiotics for one month were randomized to TIP or TOBI across three cycles.

In that trial, a larger percentage of discontinuations were observed in the TIP arm and a greater proportion of discontinuations were attributed to adverse events – 13% TIP versus 8.1% in TOBI, with FEV1% predicted comparisons generally favoring the latter drug, regulators said.

They noted that at the end of cycle 2, or week 25, the treatment difference favored TOBI and bordered on statistical significance in the reviewer's analyses using the Wilcoxon Rank Sum test, with a p-value of 0.055.

That outcome was supported by findings of rates of new use of antipseudomonal antibacterial drugs where treatment differences were significantly favored TOBI over TIP, regulators pointed out.

The FDA's reviewers also noted that, for both TIP and TOBI, improvements from baseline in FEV1% predicted were "modest" during the on-therapy period and were substantially reduced during the off-therapy period.

In TIP patients, both mean and median FEV1% predicted measurements dropped below their baseline levels following the first cycle of on/off therapy.

The reviewers also said the evaluation of the sustainability of improvements was limited by high rates of missing data, which varied across visits and tended to be greater in TIP patients, and differences in study conduct across visits.

"Differences in rates of missing data made treatment comparisons challenging," regulators said.

While study C2302 did not demonstrate improved compliance for TIP versus TOBI, there was statistically higher patient satisfaction assessed by questionnaire for TIP, regulators said.

The reviewers noted that the risks associated with TIP use are anticipated to be similar to TOBI.

The FDA wants its panel of outside advisers at the 5 September meeting to vote on whether Novartis has demonstrated adequate evidence of efficacy and safety to support the use of TIP in the managing CF patients infected with P aeruginosa or if additional data are needed.

The agency wants the committee to discuss, but not vote, on whether TIP should be approved.

The FDA also wants to hear about any implications of the changes in minimum inhibitory concentrations seen after treatment with TIP versus TOBI.