Groundhog Day - Urinary Tract Infection at the FDA

Cover via Amazon

Image via Wikipedia

Its Groundhog Day at the FDA!  Urinary tract infections and intraabdominal infections are key indications allowing entry into the therapy of Gram-negative infections – our area of highest medical need currently and for the foreseeable future. In spite of multiple conversations and blogs exhorting the agency not to release guidance documents for complicated urinary tract infection and complicated intraabdomninal infection before their ideas can be vetted for their feasibility in the real world, the FDA has done just that.  Yesterday, their new Draft Guidance - Complicated Urinary Tract Infections: Developing Drugs for Treatment - was published.  Once again, it is detailed and comes with a detailed appendix to calculate a required non-inferiority margin of – guess what – 10%.  

But lets take things one at a time.  As is often the case, there are some good things in this guidance.  These include the willingness of the FDA to discuss superiority designs that seem reasonable for those patients with “unmet need” – that is those suffering from infections caused by multiply-resistant or pan-resistant pathogens where the new therapy offers the possibility of cure.  They offer several design suggestions and note that they are open to discussion on other approaches.  Yaayyy!!!

Another positive aspect of the guidance is the recognition that IV therapy for the duration of total dosing (usually 10-14 days) will be impossible.  They allow for the continuation of therapy as an oral drug other than the investigational drug or its comparator for a period of time. This will be essential for the study of IV drugs for which no oral formulation is available.   They do want an evaluation for clinical and microbiological response at the end of IV therapy as well as clear criteria for the switch to oral therapy – OK.

They also encourage sponsors to study shorter durations of therapy – consistent with current clinical practice.  Bravo.

The inclusion and exclusion criteria they suggest seem reasonable except for one key item.  And now the fun starts.  They preclude any previous antibiotic therapy for the 48 hours preceding entry into the trial with a drug that has activity in the treatment of urinary tract infection. In the face of a positive urine culture at the time of entry, or perhaps better, a positive urine culture with an organism resistant to the antibiotic used previously. This stance will rule out the entry of the vast majority of patients with cUTI both in the US and the rest of the developed world.  Once again, one might question the ethics of withholding therapy for a patient with pyelonephritis who is suffering from pain, fever and possibly has bacteremia while they wait for all the procedures required to get them enrolled into a trial so they can start therapy. This issue was raised during the discussion of community acquired pneumonia at the last FDA advisory committee meeting – but apparently, the agency has been unable to extrapolate that message to UTI.

The other major issue with the guidance, once again, is the magical NI margin of 10%.  It is amazing that no matter how extensive the treatment effect is for a given infection, we always end up with a margin of 10%. In its extensive appendix, which must have taken a team of people many months to assemble at the FDA, the agency goes through their justification for a 10% margin.   Here we’re back to the preantibiotic era publications.  These involved very small numbers of patients where, frequently, the organism was called the colon bacillus.  We presume that is E. coli – but who knows? Their review suggests that an average of 26% had spontaneous resolution of symptoms and microbiological clearance without specific therapy.  They then go through a number of recent trials for cUTI demonstrating a 73% average clinical plus microbiological success rate.  I get that that results in a 47% treatment effect.  Next, they look at clinical and microbiological success at End of Treatment – or on day 5 of therapy.  In the FDA’s view – not an unreasonable one really – an assessment at the end of IV therapy is required if you are going to switch to an oral antibiotic different from the investigational drug or comparator as would be the case for an IV drug with no oral formulation available. That gets you down to a 69% clinical and microbiological response rate – for a treatment effect that is still 43%.  But then, once again, the FDA performs its discounting magic. Based on taking the lower bound of the 95% confidence interval and via other discounting measures, the 43% suddenly becomes 23%. That gets us to a justified NI margin of 10%.  Isn’t that convenient? My view of this is that it would be easy to justify a 15-20% NI based on the data they presented. 

The FDA then goes on to provide trial size calculations for us.  Based on 90% for each of two trials, and assuming an 80% microbiological evaluable rate, they calculate that 495 patients are required per arm for an astounding 1000 patients per trial.  A total of two trials are required giving us 2000 patients enrolled. 

These two provisions, the proscription against any prior antibiotic and the 10% NI margin on the microbiologically evaluable population once again render the design totally infeasible and possibly even unethical. I have personally studied two IV drugs that had no oral formulation in cUTI.  The most recent was Novexel’s, now Astra-Zeneca’s ceftazidime-avibactam.  In our phase II trial in cUTI, we allowed a single dose of an active antibiotic within 48 hours of enrollment. Our microbiological evaluable rate was 45%. These numbers gives me 1604 patients per trial or 3200 patients for two trials.

I can tell you that running a trial in cUTI with an IV only drug and requiring 5 days of IV therapy is an unbelievable challenge and won’t happen here in the US.  In our most recent such phase II trial, we went to Guatemala, India, Jordan and Lebanon to enroll patients.

So – FDA – can we start over?  I hope you are not actually requiring companies to comply with this guidance.  If you are – good luck to those folks!