The FDA Reboot of Antibiotic Development Begins!

Hang on to your hats ladies and gentlemen!  The FDA has just released a NEW GUIDANCE ON THE DEVELOPMENT OF ANTIBIOTICS FOR PATIENTS WITH UNMET NEED IN THE TREATMENT OF SERIOUS INFECTIONS!!  This is the formal beginning of the reboot that we have all been anxiously awaiting for the last 14 months.  As I will explain, I think this is a very positive step forward and demonstrates that we are dealing with a new, rebooted FDA.  I have been seeing signs of this in my dealings with the FDA (mostly through clients) during the last year – but here is the first concrete public disclosure of the new face of antibiotics at FDA.   This guidance allays my fears that we would have to wait for new LPAD legislation before seeing the reboot.

The new guidance is a very European style document.  It is written in a question and answer style to provide insight into the latest FDA thinking rather than a great deal of specifics. It leaves lots of room for discussion.  Many will complain that there is not enough detail here in terms of designing new trials for antibiotics active against highly resistant pathogens.  But I don’t agree with this stance.  Every other paragraph contains a plea for sponsors to come to FDA and present plans and designs.

Because these drugs will be developed to treat infections in patients who have few or no treatment options, they are likely to be drugs that: (1) act via new mechanisms of action; (2) have an added inhibitor that neutralizes a mechanism of resistance; or (3) have an alteration in the structure of the molecule that makes the drug no longer susceptible to the mechanism of resistance to existing drugs. Due to the paucity of available therapies for many patients with bacterial infections, antibacterial drugs that are intended to treat patients with intolerance or allergy to currently available drugs are also likely to be considered to address an unmet medical need.

A drug that treats a single genus and species of bacteria causing a serious bacterial disease also is a possible candidate for a streamlined development program, particularly when intended to treat patients with unmet medical need. For an antibacterial drug active against only a single genus and species, the clinical trial design should be discussed with the FDA (e.g., pathogen-focused antibacterial drug development). Sponsors should consider the following factors:
 The frequency with which the genus and species of interest causes serious infections

 The ability to identify patients with the bacterial pathogen of interest; standard culture and in vitro susceptibility testing often take 2 days or more to identify the bacterial pathogen of interest

 The potential of rapid diagnostic tests to identify patients with the bacterial pathogen of interest for prompt enrollment into a clinical trial of a pathogen-focused antibacterial drug

 The availability of rapid diagnostics to detect the genus and species of interest, which could be essential to the study of the drug for the demonstration of clinical benefit.

The FDA lists possible approaches to development but states that sponsors could use parts or combinations of approaches.  They do state that all approaches would require strong non-clinical support data –

 The in vitro activity of the investigational drug

 The mechanism of action of the drug and whether mechanisms of resistance to other drugs affect the investigational drug’s activity

 The evaluation of pharmacokinetic/pharmacodynamic (PK/PD) relationships from animal models of infection

 Activity of the investigational drug in animal models of infection; these studies may provide important information evaluating the activity of an investigational antibacterial drug at particular body sites (e.g., pneumonia)

The approaches listed include statistically powered active control superiority trials in either one indication or patients with varying sites of infection.  I feel these are unlikely to be feasible given the expected patient numbers available for study.  Non-inferiority trials with a nested superiority component are also discussed.  But most importantly (at least for me) is a discussion of externally controlled or historically controlled trials.

A clinical trial design that relies on a historical or external control may be acceptable to evaluate efficacy in a patient population with an unmet need, in particular a patient population in which standard-of-care therapy is suboptimal and the investigational drug shows activity in nonclinical and early clinical development such that withholding the investigational drug may be considered unethical. This trial design type generally is acceptable when the untreated morbidity is high and does not vary widely in the patient population enrolled in the trial, and the effect of the investigational drug is expected, based upon early clinical or nonclinical data, to be large compared to historical experience. The outcomes among patients with unmet medical need who received the investigational drug should be compared to the outcomes in an external control group, and should be expected to show a large treatment benefit for the investigational drug, because of concerns regarding potential bias from cross-study comparisons. The information needed to evaluate the historical control response rate is fairly similar to what is needed to support a noninferiority margin in an active-controlled trial, although the goal of the trial is different. In a noninferiority trial, one is seeking similarity to the best-available therapy (i.e, ruling out an unacceptable difference). In the case of the historical control trial, one is seeking an advantage over what is essentially no treatment.

 

 Sponsors considering a trial design that relies on a historical control based on a retrospective review should characterize the proportion of patients with the clinical outcome of interest when given no therapy or inadequate therapy. Current antibacterial drug development guidances contain information on retrospective reviews of outcomes when patients were given no therapy or inadequate therapy in specific disease conditions.

Efficacy endpoints – to be discussed (YES!!!).  Hopefully we can give up on mortality.  I am even hoping for pharmacometric controls and clinical endpoints.  Even surrogate endpoints are up for discussion – but whether the usual FDA evaluation of such will be required is not stated.  I wonder if they will decide that clinical outcome is a surrogate for mortality.??? 

Premarket safety database – as small as 300 patients!

Although with the old FDA – I would say you never know.  With the rebooted FDA – I am encouraged enough to say that discussions of streamlined approaches to approval of antibiotics active against resistant pathogens is definitely on the table and that they will be sensitive to feasibility. (Always the optimistic pessimist).

What is left unsaid is when the FDA will retract their previously released and completely infeasible guidances for more traditional development. But even here – since they are no longer following their own guidance and since they seem to have learned that they actually have to stick to their words to a great extent, I am optimistic.