David's New Book

Wednesday, April 27, 2016

Australia, Antibiotics, Head in Sand


A recent news article from Australia that quoted my friend and colleague Matt Cooper caught my attention. The article notes the potential for an onslaught of antibiotic resistant superbug infections and talks about ways to counter this threat.  One topic discussed was addressing the market failure for supporting antibiotic R&D. That is, the market size remains too small for pharmaceutical companies to invest in antibiotic research.  Hence the pipeline of new antibiotics active against these resistant pathogens is nowhere near what it needs to be. Matt is quoted as saying that Australia needs to be paying into a sort of insurance fund that will go towards providing government support for an improved antibiotic marketplace. 
 
I wrote Matt to ask him what was happening in Australia. I noted my skepticism.  My doubts are based on Australia’s long history of fighting the pharmaceutical industry tooth and nail over pricing and patent exclusivity.  Australia has one of the shortest patent exclusivity periods for new drugs in the world.  It also requires companies to accept exceedingly low prices to be allowed to market their drugs in Australia.  Now the latter depends on how innovative a drug might be – but my experience is that now matter how active a new antibiotic is against resistant pathogens, it is never innovative enough to garner a reasonable price in Australia. Is a lower frequency of dosing for an antibiotic innovative enough? How about an expanded spectrum of activity including resistant superbugs?  Would a safer antibiotic be innovative enough?  In Australia – not necessarily. With a population of only 23 million, many companies are happy to walk away from the Australian market with their low prices and short exclusivity periods.

Back to the article in question. Given the threat of new and more resistant superbugs, what is the Australian government willing to do? The answer can be found in their strategy – here. Like most other government authorities, antimicrobial stewardship, surveillance for resistance and other such measures figure prominently in the Australian plan. Australia would also like to increase research funding for Universities and basic research – but Matt informs me that has not really happened yet. What is missing from the report is the very sort of incentives that the rest of the world, especially Europe, is considering seriously.  That is, providing incentive payments to those companies that do bring needed new antibiotics or other therapies to market that successfully combat superbug infections. Europe is looking at plans to provide payments of around $2 billion or so to companies who succeed as a way of guaranteeing that they will have a market.  The idea is to incentivize companies already in antibiotic R&D to continue, to provide a motivation for those who gave up antibiotic R&D to come back and to provide impetus to investors to support new company entrants to the field.


Whether Europe plans to do this on its own or whether they will be seeking other global partners is not totally clear yet. But - will Australia be participating?  As a country that has a long history of being part of the problem, it seems unlikely it will become part of the solution.

Tuesday, April 12, 2016

Urinary Tract Infection and the FDA

This week, as a result of a casual conversation with another antibiotic developer, I took a look at the FDA’s Guidance on developing antibiotics for urinary tract infection that was released last year.  Being retired, I no longer follow all this as closely as I did when I was consulting. I was surprised to find one particular change in the description of the required analysis population fort these trials.

      The microbiological intent-to-treat population (micro-ITT population): All randomized patients who have a baseline bacterial pathogen on culture of urine or blood that causes cUTI against which the investigational drug and control drug have antibacterial activity. . .

What does this mean?  You are carrying out a clinical trial of a new antibiotic compared to an older one in the treatment of urinary tract infection. During this trial, it will probably take 2-3 days before you get your microbiology results from the lab.  During this time, any given patient will have been treated with either the older antibiotic or the newer one on a randomized and blinded basis.  IF the pathogen happens to be resistant to either drug, you must exclude the patient from the analysis population. Hopefully, since the new drug is, in fact, new, you will be unlikely to see resistance to it.  But, for any older antibiotic, you may see resistance. If the lab result comes back and says you have a resistant strain – what should the physician do? Obviously, if the patient has not responded to therapy – the patient is removed from the study and therapy is changed.  If the patient is responding to therapy, the physician can either decide remove them from the study or not – why not?  The clinician does not know which drug the patient is receiving.  At the end of the study, it is likely that those in this situation will have failed therapy more often than those where the pathogen was fully susceptible.  Surprise.  But – that’s the real world, folks. But – if all these patients must be removed from analysis at the end of the study, the numbers of patients required for study will increase based on the rate of resistance to the antibiotics used in the study.

So what? Well – if the trial is for a drug that can only be used intravenously, you could use a comparator older antibiotic where resistance is less likely to occur like the carbapenems. Even there, you may see a few cases of resistance.  But, if your drug can be taken orally, you would like to use a comparator that can also be taken orally.  The only, or at least the main, alternative out there is levofloxacin. In areas where we run these trials today, Eastern Europe, the Middle East, Russia, South America, levofloxacin resistance rates are elevated.  Therefore, you will pay a price (having to study more patients) for innovating a desperately needed orally available drug to treat Gram-negative superbug infections because the resistance you want to fight actually exists.

Why did the FDA make this change?  I asked – they’re not talking. So I speculate on what they might be thinking.

This will “level the field.” My response – in the real world, the field is anything but level.

“We don’t want to see studies claiming superiority of new antibiotics against comparators where the pathogens studied are resistant.”  Ahem.  Excuse me. The entire basis of the PK/PD arguments that new antibiotics will work against resistant organisms is that they will work against these strains. The trial that I described and that we had done in the past is merely a clinical demonstration that PK/PD is correct and reflects the world we live in.

“Why are we arguing over 10, 20 or even 30% more patients to study? You can afford it.” I won’t even bother responding to that one – been there before.

From the point of view of companies, one of their greatest challenges is going to be to explain the PK/PD justification for the activity of new antibiotics against pathogens resistant to older antibiotics. I know that for those working in the field and now even for regulators, this concept is an obvious one.  But for the physicians who prescribe antibiotics, most of whom are not infectious diseases specialists, the argument is not easy.  As I noted in a previous blog – this will require a great deal of education. Clinical trials that demonstrate the truth of the argument can only help in this regard.



Monday, March 28, 2016

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.

Thursday, March 17, 2016

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!