Congress, FDA and Antibiotics

I hope everyone had a happy Easter holiday.  Its raining here today, and under these depressing conditions, I find myself thinking back to the Ketek scandal of 2006 and wondering about the continued meddling of Congress under the influence of Public Citizen in antibiotic trial design issues. What am I talking about? See my book chapter on the FDA. (I apologize, but they still charge $29 for the chapter download).  Basically, in 2006, after a few cases of serious liver toxicity caused by Ketek, a new antibiotic active against resistant bacterial pathogens, the FDA was threatened with congressional investigations on the antibiotic trial designs that led to the Ketek approval.  The FDA went into defense mode, people were fired or transferred and antibiotic development went from slow to non-existent for the next six years.

Fast forward to 2016.  The FDA rebooted its antibiotic development program in 2012 and since then we have seen a flurry of antibiotic approvals including two new antibiotics for the treatment of serious Gram-negative infections.  One of these, ceftazidime-avibactam (near and dear to me), was approved mainly based on phase II data (even though it met a 15% NI margin and top line data from one phase III trial was available). This was a historic first for the FDA.  

In its reboot process, the FDA released a guidance for the development of antibiotics for patients with unmet medical needs. This guidance calls for streamlined trial designs to get needed antibiotics to the patients who need them quickly. It was under this guidance that ceftazidime-avibactam was approved based on a smaller data set than any other antibiotic in modern times.  I now find that the designs embodied in this guidance document that would allow these streamlined approaches are threatened once again by Public Citizen and its congressional meddlers. This time, I don’t know who it is in congress that is involved. But the stream of questions from congresspersons and veiled threats of congressional investigations harken back to the dark days of the Ketek scandal and the FDA once again may respond by ducking back into its shell. And when that happens, you can forget about new trial designs for rare infections, pathogen specific antibiotics and other needed new approaches to antimicrobial therapy.

The PATH act is currently in mark-up in the senate. It is sponsored by Orin Hatch of unregulated supplements fame (probably not a good thing). There are many moving parts here including LPAD, ADAPT etc – but PATH has the language I think the FDA wants and I like it better. It provides congressional authority by law for the FDA to carry out much of what is already outlined in the FDA’s unmet need guidance.  The FDA believes (in my opinion) that this will protect them from congressional meddling and threats of investigation for their decisions regarding antibiotic development and approval. I am not at all convinced that this is the case.  I also believe that the FDA already has the statutory authority to do what the PATH act outlines.  But – the FDA wants this – and – at this point, if it helps them, it helps us. So – write your congressional representatives. At the same time, please ask them to leave the FDA alone on antibiotic development issues and ask them to ask their colleagues to do the same.

Antibiotic Trial Designs - Rex, Shlaes Part 2

See my previous blog.  Today, I want to look at other ways to skin this cat. These ideas are mostly mine – but again, John Rex was my sounding board.

As  background, I highly recommend viewing the video of the presentation by Ellenberg presented at an NIH conference on trial designs for emerging infectious diseases.  It is very informative. The statistical problems for such trials are numerous but hinge on the following assumption that we must try and meet/validate – that the distribution of patients with good vs. poor prognoses are the same in the experimental and control groups. This is a key basis for preferring a randomized trial. In designing trials to address rare infections, rare pathogens, and pathogen-specific indications, the patient numbers may not be able to support a randomized design. We might not even be able to achieve statistical inference with an externally controlled design – but, in my view, this is where we will have to go. According to the paper by Byar (requires subscription) and later Elllenberg, an externally controlled trial design can be justified if the following conditions can be met . .

·      A randomized trial is infeasible because of the rarity of the condition under study.

·      There must be sufficient experience to ensure that patients not receiving therapy will have a uniformly poor prognosis.

·      The therapy must not be expected to have substantial side effects.

·      There must be a justifiable expectation that the potential benefit to the patient will be sufficiently large to make interpretation of the results of a non-randomized trial unambiguous.

·      The scientific rationale for the treatment must be sufficiently strong that a positive result would be widely expected.

I would argue that a new antibiotic expected to be active against resistant pathogens would meet these criteria assuming it had been shown to be safe in a sufficient number of volunteers/patients.  The data supporting a lack of efficacy of antibiotics where the exposure (drug levels) obtained are not high enough for the MIC (“susceptibility”) of the pathogen are clear and overwhelming.

Most of the failures of externally controlled trials to provide reliable results have resulted from inadequate controls.

·      Controls had been derived from a different time such that control therapy had changed by the time the actual trial was conducted;

·      Or supportive care had changed altering prognosis for controls.

·      Effect size in controls had simply been underestimated for other reasons.

How can we overcome these obstacles for antibacterial drugs?

• ·Get your PK/PD house in order. If you buy the UDR vs. XDR argument from the previous blog, then we can use PK/PD to show that pathogens resistant to comparator agents will be effectively treated by our experimental drug. .
• o   Have clearly and adequately designed PK/PD targets.

o Make sure you have adequate PK in the population you intend to treat (possibly studying the PK of the new antibiotic PK as an add-on to the SOC or comparator to be used as a control  in your proposed study).

·      Consider a small, open label phase II study to help convince physicians and regulators that your new antibiotic will, in fact, benefit patients as you expect based on PK/PD considerations. This will also bolster your PK/PD argument and may even provide an early look at efficacy.

·      Define your inclusion/exclusion criteria early.  I would advise being expansive rather than constrictive here – you don’t want a lot of amendments in the middle of your pivotal trial – this is not non-inferiority.

·      Carry out a retrospective (within the previous year or two) observational study of the key patient population treated with SOC or with comparator drug to define control level of response.  This should be done in centers likely to participate in the trial to remove center-to-center bias as much as possible.

·      Early in the trial, carry out a prospective study of SOC or comparator to validate the assumptions you have made about controls during your retrospective SOC – obviously this is done in centers actually participating (and contributing patients to) in the ongoing trial.

The alternatives discussed by Ellenberg such as cluster-controlled trials and adaptive allocation randomization designs all require more patients than we will ever have available to study.

If, in fact, we observe a large treatment effect early, I would wonder - is it still ethical to continue the trial? -  even if statistical inference has not yet been achieved?

Based on my previous discussions with FDA, and John Rex’s feedback, it is possible if not likely that the FDA will balk at externally controlled trials even though these would be allowed in the context of their unmet needs guidance. (Then, of course, that section should be removed). The FDA needs to see -“Substantial evidence of efficacy through adequate and well-controlled investigations . . .” and they may consider that the approach I have outlined above will not meet that criteria.  (Since those adjectives [subtantial, adequate, well-controlled] are not so well defined – I’m not sure how they get to that particular place.)

Alternatives that might be more palatable to FDA might include a non-inferiority trial with wide margins.  For example, a trial powered at 80% with a margin of 25%, even with only 60% evaluable, will only require 67 patients per arm or 134 patients total.  Obviously, one would still need a 300 patient safety database . . .

Another possibility might be an altered randomization ratio like 2:1, 3:1 or even 4:1.  But here – one might consider approval based on a P value of 0.1 – what is so magical about P=.05?

Based on these thoughts, for the right drug, where the population to be studied will be highly restricted, I recommend negotiating a design with Europe, carrying out your trials and then presenting it to FDA as a fait accompli.

Finally, I plea once again for congress to stay out of the way!

Talking with John Rex - New Approaches for Antibiotic Trials

My source of information for this blog comes from John Rex who has been instrumental in the thinking leading to these considerations.  I did not participate in any of the relevant meetings. We don’t agree on everything...

An email to the FDA (Ed Cox) inquiring about this has gone unanswered.

By way of context, there have been a number of conversations over recent years about the potential value of a clinical network for antibacterial development. This idea was discussed at some length, for example, during a July 2014 NIH-NIAID-FDA workshop where examples of this work in other areas (e.g., oncology) were discussed.

But, the challenge of designing trials focused on MDR and XDR pathogens are formidable and recent efforts (e.g Achaogen) have shown us how hard this can be. Indeed, enrolling patients with MDR and XDR infections is hard for lots of good reasons – indeed, we want these infections to be rare.

But, we also know that infection prevention will never be perfect and we definitely need new drugs.

As a strategy for circumventing this problem, a recent Request for Information from BARDA suggests a very different approach. In brief, the RFI proposes creation of a network that is focused on pathogens that are susceptible to least one reasonably available drug.

Here’s where John Rex comes in. Along with his several of his colleagues, he’s proposed a new acronym for us to consider along with the well-known acronyms MDR and XDR:

·      UDR: Usual Resistance

·      MDR: Multi-drug resistance

·      XDR: Extensive multi-drug resistance

Importantly, UDR is not the same as wild-type. Rather, UDR speaks to the ease of selection of therapy and by extension, ease of selection of a comparator for a global trial:

·      UDR: Many easy choices. Easy to choose a single global comparator.

·      MDR: Harder – may need 2nd-line drug. Single comparator is harder

·      XDR: Needs a difficult or unusual drug. Comparator must be ad hoc.

The core notion that a network could be built out of studies of UDR isolates. Indeed, John points out, the BARDA RFI proposes creation of 3 networks designed to run for up to 10 years. There would be one network for each of the three major Gram-negative infections (cUTI, cIAI, and HABP/VABP). The network would be constantly running clinical trial that would permit investigational drugs to rotate in and out efficiently. A picture is really helpful … here’s the graphic from the BARDA RFI.

Imagine Control #1 as a carbapenem and you begin to see how the UDR idea works — basically the network could be established at a collection of hospitals and most patients with cIAI would (probably) be eligible. Indeed, patients known to be infected with something NOT susceptible to a carbapenem would be ineligible.

The sponsor is still free to pursue MDR or XDR pathogens in parallel studies, but putting a drug through this network is a low-risk way to get a good clean trial run against a high-end comparator and hence build a solid foundation for registration.

The success of this strategy depends also, in part, on being able to make a strong PK/PD (pharmacokinetic/pharmacodynamic) argument that if the drug works against UDR organisms, it will also work against highly resistant ones IF the resistant ones are “susceptible” to the new drug. 

That means that the dose used must achieve adequate systemic levels of the drug over an adequate time period such that the infection can be cleared even if caused by organisms resistant to many other antibiotics.  For this to occur, the growth of the organism in question must be inhibited by a concentration of the new antibiotic previously shown in test tubes (MICs) to indicate that the antibiotic will work in systemic therapy. 

Both regulatory authorities, I am told by John, support the UDR approach to approving drugs.  The label might read – “shown to be efficacious in the treatment of cUTI (for e.g.) due to susceptible strains of X,Y and Z bacteria.” And this makes wonderful sense and shows that the FDA in particular agrees that PK/PD arguments are valid.

Companies, though, are concerned that even if the FDA and EMA will approve new antibiotics under these circumstances, physicians still want to see controlled trial data showing convincing activity against these resistant pathogens.  The “community” apparently is not ready for the PK/PD argument yet. Or at least, that is the concern of some companies.  My view is that this is a matter of education.  PK/PD rules! So I completely support the UDR stance.

Notice that all of the above considerations work for non-inferiority trials of relatively broad spectrum agents. For rare diseases, rare pathogens or pathogen specific antibiotics, these designs will probably not be feasible. But – I believe that there are other ways to skin this cat. For further discussion with John see the next blog.