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.

A Few Updates

Apparently, the FDA is continuing in its effort to regulate fecal transplants for the treatment of Clostridium difficile diarrhea. I received an email from the IDSA stating that the FDA has announced that an emergency IND will be required to treat patients in this way. What a colossal waste of time and energy!  This will only delay the delivery of effective therapy to patients some of whom require treatment urgently. As I stated in my previous blog – what we need are clinical guidelines, not FDA regulation. 

As recommended by their advisory committee, the FDA has finally approved telavancin for use in nosocomial pneumonia based on exactly the same data used to reject Theravance’s application years earlier.  Further, they state that mortality in the telavancin arm was no different than that in the comparator arm.  So what? Ptients with nosocomial pneumonia frequently die of causes completely unrelated to their infection. Therefore, 28 day mortality is a futile endpoint in a non-inferiority study of nosocomial pneumonia as it drives everything towards the null.  I say this in spite of the retrospective data FDA has used to justify this endpoint.  See my previous writings on this topic.

Finally, BARDA has awarded Basilea, a European biotech, a grant that could be worth up to $89 million to develop its BAL30072 monosulfam antibiotic. This antibiotic has a very spotty spectrum.  Klebsiella are resistant while Acinetobacter are quite susceptible.  Nevertheless, BAL30072 is active against strains bearing metallo-B-lactamases since it is essentially a monobactam like aztreonam. BAL30072 might be a perfect candidate for a pathogen specific approach to clinical development as called for in LPAD.   Go BARDA!

LPAD - The Full Court Press

Limited Population Antibiotic Development (LPAD) is a proposal from the Infectious Diseases Society of America (IDSA) to streamline antibiotic development for patients with “unmet Need” – that is those with antibiotic resistant infections whose choices for therapy are very limited or non-existent.  Recently, Helen Boucher of IDSA has published an opinion piece on CNN where she makes a compelling case for the need for new antibiotics with a moving case example. She notes that the LPAD legislation, which would enshrine this regulatory approach for antibiotics, is currently moving through congress. The New York Times also covered this topic stating that the “administration” was pushing LPAD legislation.  Of interest, the Times article also quoted an opposing voice – that of John Powers – who stated that the limited trials proposed by IDSA would not prove that the new antibiotics were effective and that there would be an increased safety risk because the amount of patients studied would be smaller and therefore the study would be less able to pick up uncommon safety concerns.  While what John says is true, the alternative is to have no new antibiotics in the pipeline.  Which would you rather have; untreatable infections or new antibiotics where the risk benefit ratio might be more like what we currently have for cancer drugs?

Helen believes that this rapid regulatory pathway will entice more pharmaceutical companies into antibiotic research – something that is essential if we are going to bolster our pipeline.  While LPAD is required, it unfortunately will not be sufficient.  We also need to provide companies a return on their R&D investment.  This debate has recently come to the fore with the announcement by Astra-Zeneca that antibiotic R&D would no longer be a priority area for them. The bottom line is that a number of companies do not have confidence in the increased reimbursement that has been discussed for new antibiotics developed under LPAD.  It is clear to me that both things must occur.  We must have a feasible and rapid regulatory pathway to approval for antibiotics for resistant infection and at the same time we must provide companies confidence that their R&D efforts will be financially rewarded. Unfortunately, it is likely that some regulatory reform will come first and confidence in pricing structures will only come later if at all. 

There are aspects of the regulatory discussion that I find disturbing, however. It seems as if all progress towards bringing this pathway forward at FDA has halted while they wait and see if congress will pass the legislation.  The FDA wants the legislation, in my view, because they want congressional cover in the case that one of the new antibiotics approved under this more risky pathway runs into trouble – something I believe is likely to occur.  The FDA does not want to go through another Ketek experience with congress. I do not necessarily disagree that having this legislation would be nice from this point of view.  But I’m not at all convinced that even such legislation will provide the cover they want. In addition, it seems highly controversial whether this legislation is actually required on a statutory basis.  It seems to the non-regulatory-lawyer (me) that is it not. Yet we may have to wait for new guidance while congress dithers.  To me, this is unacceptable.  If passage is imminent – before the summer break – ok.  If not – the FDA should just bite the bullet and get new draft guidance (based on multiple discussions with sponsors and at Brookings) out there.

Without new guidance, the industry is stuck in neutral.  But even with new guidance, we will only get to first gear when the financial issues are clarified.

The FDA and Fecal Transplants

The FDA has recently put the medical community on notice that the use of fecal transplants for the treatment of Clostridium difficile diarrhea constitutes use of an unapproved biologic.  This is another fascinating and discouraging FDA intrusion into medical practice that threatens to set back the use of a clearly beneficial and safe therapy for years. What is wrong with these people?

First, there are a number of studies published on the use of fecal transplants in the treatment of this deadly infection.  C. difficile diarrhea is estimated to kill 14,000 Americans every year and the numbers of fatalities has steadily risen over the last 20 years or so. Although initial therapy is 90% or more efficacious, the relapse rate is as high as 25%.  For those patients who have multiple bouts or whose initial infection is especially severe, fecal transplants offer superior efficacy in every study performed so far. The best review of this topic can be found via this link. In one controlled study (albeit small), the efficacy of fecal transplant in recurrent C diff diarrhea was 81% and that for standard therapy was 31% - a very statistically significant difference. In the studies reported so far – hundreds of patients treated – there have been no important safety signals whatsoever. Therefore, the risk benefit ratio appears to be all benefit and no risk.

In addition, the procedure is not so pleasant.  One obtains stool from a volunteer or volunteers, suspends it in saline and milk, filters it through gauze and administers it to the patient via a nasogastric tube inserted through the nose going to the duodenum.  The patient has to have a bowel cleansing with massive laxative therapy the day before the transplant and has to take a pill to reduce stomach acid prior to receiving the stool transplant.  Sounds like fun for both physician and patient, right? This means that not everyone is going to want to do this and only those with a significant problem will do so.

So – what is the FDA’s problem? First, they are not in control. Beyond that, I suppose they interpret this intervention as doing their job to protect Americans from unsafe and ineffective therapies.  But other than the studies done so far, what do they want?  If they want larger, controlled studies, who will pay for these studies?  How long will they take? Will we have to have a manufacturer that is approved provide a volunteer stool sample within 6 hours so it can be used?  How does that work?

Also – which FDA are we speaking to?  The letter comes from CBER.  But I understood that the use of biologics for therapy would be regulated through the antiinfectives division in CDER . . . ??

This entire approach is reminiscent of the FDA’s disastrous attempt to make antibiotic trials more stringent by making them impossible to perform or impossibly expensive to perform or both.

My recommendation here is that the FDA get together with Gastroenterologists and ID specialists and define a clinical guideline similar to the Cleveland Clinic approach such that physicians are aware of a recommended standard approach to this procedure.  But the FDA should not be regulating this.  This is yet another bridge too far.