It is interesting to see how often a discussion of study results moves from microbiology to clinical significance to statistical analysis details. When an antibiotic is not evaluated on the basis of its antimicrobial activity but on its ability to change a clinically relevant measure (the “feel, function, survive” mantra popularized by FDA’s statistical advisor Tom Fleming), we run into one major difficulty: There is only a very indirect relationship between microbial eradication and clinical outcome.
Statistics to the rescue: For non-life-threatening conditions, mortality is obviously not a good outcome measure of efficacy. Then “feeling better earlier” becomes the all-important test criterium. It may not be a big deal on the outside but being symptom-free faster is desirable when you are a patient, trust me. It was sufficient for the approval of our HSV and influenza medications which– on average – result in 1 day faster resolution of symptoms. Hence, “feeling better”, “functioning better” matters to patients and regulators alike.
Several development projects have tried to prove that ‘Antibiotic A’ leads to faster symptom relief than ‘Antibiotic B’. They all failed to prove the point: while occasionally a benefit was seen, this could not be replicated in subsequent confirmatory trials (see trials on recurrence of exacerbations for COPD).
Pulmaquin is a mixture of liposomal and non-encapsulated ciprofloxacin
The Aradigm ORBIT trials are different: here inhalational ciprofloxacin is compared to placebo in an attempt to show that reduction in bacterial CFU count matters clinically. The primary efficacy endpoint chosen was “median time to first exacerbation” in patients with non-CF bronchiectasis. Clearly, it becomes of critical importance to define “exacerbation”, to understand how bacterial load correlates with “exacerbation”, and what triggers an “exacerbation” other than bacteria and the quantitative parameter called bacterial load. This all needs to further related to P. aeruginosa, as this was the key targeted organism. Not an easy task – something for trail blazers.
From the results of similar trials, we can confidently state that inhalational ciprofloxacin will reduce bacterial density in sputum including P. aeruginosa. We also are fairly confident that the drug delivery to bronchiectatic spaces should be adequate, assuming aeration. We are less confident that the condition under study, i.e., BE, is sensitive to study drug effect and that recurrence time to next exacerbation is the best primary efficacy endpoint.
Here the data so far:
In Phase 2, ORBIT-2 showed a significant reduction in “median days to first exacerbation”.
In Phase 3, ORBIT-3 clearly missed the significance threshold (p=0.8488), and ORBIT-4 just barely made it (p=0.0462). As complete reports from either Phase 3 trial are unavailable, we refrain from further analysis. The company’s press release  makes the excellent point that using a different statistical methodology would have shown significance. Yes, sure. Where did we hear that argument last time?
Good to see that Pulmaquin prolonged the time to exacerbation (by approx. 2-3 months) in some patients. However, unlike CF trials, pulmonary function did not improve in BE patients which may explain the unconvincing results. But let’s not quibble about statistics: it is clear already now that the well-designed  ORBIT studies will improve our knowledge of of the natural history of BE in a highly significant manner!
CF cystic fibrosis
 Aradigm Press Release Dec 1, 2016, http://files.shareholder.com/downloads/ARDM/3585942206x0x919507/2B7D67AE-6002-494D-9453-0AE73CB290F2/ARDM_News_2016_12_1_General_Releases.pdf
 A O’Donnell. ATS Internat’l Conference 2016, San Francisco, Poster #A1775