Groundhog Day - Urinary Tract Infection at the FDA

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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  Yesterday, their new Draft Guidance - Complicated Urinary Tract Infections: Developing Drugs for Treatment - was published.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!

Antibiotic Breakpoints, FDA, CLSI, EUCAST etc.

One of the most important issues in the development and marketing of a new antibiotic is the breakpoint that is ultimately assigned by the regulatory authorities.  For the uninitiated out there, this is the way clinical laboratories determine whether a given bacterial pathogen identified in some clinical specimen (urine, blood, sputum, etc) is actually susceptible to an antibiotic or not.  This determines whether the antibiotic is likely to work for a given patient’s specific infection.  It also determines, for each pathogen, how many such infections will be “covered” by the new antibiotic and therefore how useful it might be for physicians and their patients suffering from infections caused by that pathogen.  It makes no sense, for example, to study an antibiotic for infections where only 50% of those infected are likely to be covered unless no other antibiotic covers the infection at all.

So – how does this work?  Each pathogen is assigned a breakpoint corresponding to susceptible or resistant (and sometimes intermediate) for a given susceptibility testing method – and there are a few out there.  Mainly it is a zone of inhibition of growth of the bacteria around a disk placed on an agar plate.  It may also be inhibition of growth in panels containing wells where the antibiotic is diluted stepwise. The level at which the cutoffs for inhibition zones or for concentrations that inhibit growth correspond to susceptible are determined by the regulatory authorities – the FDA for the US and EMA for Europe - mainly.  How do they do this?

For the most part, the regulatory authorities rely on the susceptibility of organisms studied in the clinical trials provided by the sponsor.  For example, if you determine that all the staph strains in the world are inhibited by your antibiotic at a concentration of 10 micrograms per ml, if your clinical trial only enrolls patients whose staph strains are all inhibited at 1 ug per ml, your susceptibility breakpoint will be 1 ug/ml assuming that these patients were actually cured in your trial. That means, even though your antibiotic may actually work against strains with much greater levels of resistance, no one will use it to treat such strains since they will be labeled by the microbiology laboratory as resistant based on the cutoffs assigned by the regulatory authorities.

Of course, because we know so much about how antibiotics work based on animal models and based on modeling of how the antibiotic works in people, we can frequently predict with great accuracy that we can actually predict that patients with pathogens requiring 10 ug/ml of antibiotic to inhibit growth would actually be cured in clinical trials.  But – if you haven’t shown this, it is very hard to get the regulators to agree that this is a reasonable cutoff.

This is a terribly important point since it might mean the difference between being able to market your drug to 50% of patients with a given infection or 90%. But it amazes me that we really pay so little attention to this in the early days of developing a new antibiotic.  We need to consider how to get patients likely to have organisms with higher levels of resistance into trials (both for the comparator and for the new drug) to justify higher breakpoints.  But the regulatory authorities need to pay more attention to our predictive powers using pharmacometrics to help establish higher breakpoints than might be justified by the patients re3cruited into our trials.  Although both Europe and the US pay lip service to this concept, it is practiced more in the breach than the observance.

Complicating the picture further are the roles played by the Clinical Laboratory Standards Institute in the US and EUCAST in Europe.  EUCAST analyzes all the relevant information and makes a determination of both a breakpoint to be used in epidemiological reporting – to survey for emerging resistance – and a separate breakpoint for clinical therapy.  The EUCAST breakpoints become the breakpoints for the EMA in Europe.  In the US, the situation is more complicated – or maybe less so depending on your point of view.  The Clinical Laboratory Standards Institute (CLSI) determines breakpoints for susceptibility, but these have, in a way, little meaning since the only breakpoints the manufacturers can use are those provided by the FDA. If a given hospital or laboratory wants to alter their breakpoints, for those antibiotics and pathogens where the FDA and CLSI disagree, they must do so on their own responsibility.  But as long as the device allows for this to happen, the individual hospitals or laboratories can initiate this change.

Finally, when I asked one of the testing device manufacturers whether they had any skin in this game, the response was, “no.”  They will sell their devices and kits regardless of FDA, CLSI, EUCAST and EMA pronouncements on breakpoints or even regardless of whether a new antibiotic is approved or not or whether the new antibiotic is used or not.

I will follow this up with more details on specific EUCAST, FDA and CLSI viewpoints in future blogs. In the meantime – I hope you are all as confused as I am. 

Speaking of Antibiotic Task Forces

In my last blog I reviewed a number of committees and taskforces on antibiotics and antibiotic resistance in which I have participated in one way or another.  But one that I left out is the Antimicrobial Availability Taskforce (AATF) of the Infectious Diseases Society of America (IDSA).  The IDSA (and its sister societies) is probably the most prestigious and well-respected group in the world when it comes to infectious diseases.  A number of years ago, they began to take a keen interest in the declining antibiotic pipeline, its potentially catastrophic implications for patients and physicians and the role of the US as a society and our regulatory agency, the FDA, in this emerging public health threat.  In response to this, the IDSA put together this task force which included a number of experts from a variety of different disciplines from antibiotic discovery scientists to practicing clinicians to clinical trial and regulatory experts. They asked me to participate as well.  At the time, I was becoming frustrated with the Forum on Emerging Infections of the Institute of Medicine (IOM) because I felt that in spite of all our work and our various publications, we were not able to push requisite changes at any level.  IDSA is able to lobby congress while the IOM cannot. I immediately left the Forum of the IOM and joined the IDSA effort.  The immediate result of this effort was the now well-known white paper, Bad Bugs, No Drugs that was released in 2004.  I am very proud of this paper and the Society for bringing this issue into the public eye with greater force than anyone previously.

With this white paper, the IDSA embarked on a campaign to bring about the changes necessary to improve our pipeline.  They carefully update their pipeline assessment and note their progress every year.  Since 2004, they have worked hard on all relevant fronts in this battle.  They push for antimicrobial stewardship in every health care setting, they have an initiative on limiting unnecessary use of antibiotics in agriculture, they provide information on resistance in the US, and they have initiated a campaign they call 10 x 20.  The 10x20 campaign challenges the world to come up with 10 new antibiotics active against resistant bacteria by 2020.  (I actually believe that we will achieve this goal, although probably not in the US unless something drastically changes at FDA). 

The AATF of the IDSA has really focused on two key areas to achieve their goal.  One is regulatory reform at the FDA and the other is incentives for industry through legislative efforts. And I believe they have been effective on both fronts.  The FDA is slowly beginning to see that releasing guidance documents requiring infeasible designs only takes us backwards.  The IDSA has been essential in getting the FDA as far as they have come – but we are still a long way from where we need to be.  They have accomplished this through a series of public workshops with FDA and with many meetings both in person and over the telephone.  They have also been instrumental in participating and leading the Foundation for the National Institute of Health Biomarkers Consortium effort to help the FDA at least define feasible endpoints for their new trial designs. Once again – the question is why are we stuck with these endpoints anyway and why can’t we define feasible non-inferiority margins for infectious disease indications.

On the incentives side, I think the IDSA can take much credit for the GAIN act that is shuffling through congress.  The problem is that I don’t think the GAIN act will actually incentivize the companies that we need to target with incentives.  And, personally, I am now questioning whether the markets in emerging economies will not provide enough of an incentive without government intervention.  Nevertheless, that the IDSA has come as far as they have is an accomplishment that we all have to recognize with gratitude.

So, even though I don’t always (infrequently?) agree with the specific directions the IDSA takes, and even though I remain frustrated with the amount of time this is all taking, the IDSA deserves many kudos and much recognition for what they are doing.  My advice to the IDSA on the regulatory front – where I think they can make the most impact – is – get aggressive!  No more Mr/Ms nice guy!

Another Taskforce Bites the Dust!

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I don’t know how I missed this, but the Transatlantic Taskforce on Antimicrobial Resistance published its long-awaited report in September last year.  I was disappointed but not surprised.  I have been involved in a number of such efforts going back to the mid-1980s.  Back then a number of us engaged in research on antimicrobial resistance began to suscpect that there was an active bias against funding such research within NIH.  We carried out an investigation of the previous 25 years or so of funding and found that the record of NIH funding for such research was absolutely appalling.  We suggested as a key step forward that the NIH establish a new study section peopled with experts capable of reviewing grant applications in this area.  In 2006, 20 years after our original suggestion, they did just that.  And that was the most successful such effort in which I have participated.

In the early 1990s, the US government established an interagency taskforce on antimicrobial resistance.  I was a member of the first group of advisors for this taskforce.  At the time, I was very concerned about the US research agenda.  Virtually all of the recommendations from our section were ignored.

In 1994, the ASM convened a similar taskforce in which I also participated.  This report called for more funding for surveillance and for more research to better understand the role of antibiotics used in farming and aquaculture.  While some of the recommendations were followed to one extent or another, basic research on antimicrobial resistance in the US still had to await the formation of the new study section for the NIH in 2006.

For seven years I participated in the Forum on Emerging Infections at the national Academy of Science led by Josh Lederberg following his landmark book on emerging infections.  During those years, I tried to focus on the impending disaster in our antibiotic pipeline.  1999 saw the first of the large pharmaceutical companies to abandon the area of antibiotic R&D and the continuing consolidation with the industry was also taking its toll.  My own focus became more and more the regulatory environment in the US.  In 2001, an entire chapter in the Forum’s report on Biological Threats and Terrorism was devoted to this topic. And where are we with US regulation for antibiotics and biothreats today?

The report from the transatlantic taskforce is disappointing but for a different reason.  It’s recommendations regarding strategies for improving the pipeline aside from the discussion on incentives are so weak as to be inconsequential.  With a report like this, we are going nowhere. The key recommendations from improving the pipeline are as follows:

Incentives to stimulate the development of new antibacterial drugs in human medicine	Policymakers should strongly consider the establishment of significant incentives to stimulate antibacterial drug development
Research to support the development of new antibacterials	Increase communication between US and EU research agencies to identify common scientific challenges that may represent opportunities for collaboration
Publicise funding opportunities to EU, US research communities
Regulatory approaches for antibacterial products	FDA and EMA intend to discuss ways to facilitate the use of the same clinical development programme to satisfy regulatory submissions to both Agencies
Establish regular meetings between FDA and EMA to discuss common issues in antibacterial drug development and regulation
Exchange information on possible approaches to drug development for bacterial diseases where limited drugs are available

For the FDA and EMA to exchange information and establish regular meetings – come one!  What outcomes are desired from these exchanges that will impact our pipeline?

I’m sorry – but I guess my expectations for this taskforce, as low as they were, were still too high. 

Community Antibiotics - Juice vs. Squeeze?

Here it is Sunday, and I have been obsessing on the following conundrum.  (I need therapy)! 

I have been railing against the current regulatory policies in the US and Europe requiring placebo-controlled trials for approval of antibiotics to treat otitis media, acute bacterial sinusitis and acute bacterial exacerbations of chronic obstructive lung disease.  A quick search of the clintrials.gov website reveals that there are currently no new antibiotics being studied in either phase II or phase III trials for any of these indications.  Otitis media is a key entry indication for pediatrics – but it remains off the table. Of course, this is no surprise since the placebo-controlled design required by the regulatory authorities is probably infeasible.  An example of a current dilemma for clinicians is – the severely penicillin and cephalosporin allergic pediatric patient where macrolide resistant pneumococcus is a likely pathogen. The only choice left is a fluroquinolone, that many pediatricians use in spite of the safety warnings against use in pediatric patients. A new ketolide or other alternative would be a welcome product for these patients – but it is not to be.

But here is the sudden thought that got me thinking.  Does the pharmaceutical industry care?  I admit that I don’t have the precise numbers at my fingertips, but I daresay that these three indications still account for some huge percentage of all antibiotic prescriptions worldwide.  These indications at one time accounted for a large bulk of the total dollar volume of the antibiotics business. Most of the antibiotics used for these indications are generic and cheap, and physicians and patients still believe, regulatory authorities aside, that antibiotics are beneficial in shortening the duration of illness even for these “mild and self-resolving” infections.

Twenty years later – the world has changed.  When these indications drove the antibiotics business, each prescription had to be sold to each physician and each patient.  It was a marketing war out there. But now, payers are as much the target audience as physicians and their patients.  If one can justify a new antibiotic to the payer, half the battle is already won. Nevertheless, to get to that point with an antibiotic for otitis, sinusitis or bronchitis, what will it take?  Will it take placebo-controlled trials to prove value?  Will it actually take a superiority study to show an advantage over an existing regimen? If so, we are lost since those trials will probably never take place. And even if a more feasible non-inferiority design would work for payers and physicians, does the industry have the stomach for the marketing spend that will still be required to sell in the community market?  I’m not so sure.

So I wonder if we are not finding ourselves at a curious coalescence of views between the regulators and the markets.  The regulators insist on infeasible designs and at the same time, these same designs might be what the payers will require.  Yet the market spend required, even if the trials were feasible, might also work to dissuade companies from thinking about these indications at least for now.

This means that for physicians and patients, we had better be able to live with the antibiotics we have now because nothing new is going to be approved for these indications for a very long time!  This seems unfortunate because a number of drugs are in late stage development that could address future medical needs (presumably driven by resistance) in these infections.  The list includes, CEM-101, a ketolide from Cempra, BC-3781, a pleuromutilin from Nabriva, PTK-0796 and TP-434, tetracyclines from Paratek and Tetraphase, and perhaps others. As it stands now, none of these are being developed for use in otitis, sinusitis or bronchitis. 

Antibiotics, Big Pharma and Deals

There is a good deal of speculation in the trade press that large pharmaceutical companies are looking for deals – especially ex-US.   The pressures that drive them to deals are manifold and include; failed late stage trials, failure of internal R&D to deliver, generic intrusion, rapidly growing markets in emerging economy countries and a large cache of cash in spite of stock buyback programs to keep shareholders happy.

At the same time, these same pressures are conspiring to make antibiotics attractive once again.  Generic intrusion into the statins and anti-depressant markets combined with the failure to deliver new drugs for these indications are decreasing the potential for multi-billion dollar blockbusters in these indications.  While many companies still dream of big breakthroughs for Alzheimer’s disease they remain elusive. So the average NPV of antibiotics is starting to look competitive once again in the context of a hospital portfolio. 

From my view on the ground, though, I must say that I am not impressed with the number of large pharma companies banging on my door or the doors of my clients searching for antibiotic biotech deals. It remains a buyers’ market out there. 

One interesting speculation though revolves around Astellas and Basilea.  Astellas, as reported in a recent blog, recently returned the rights to telavancin to Theravance.  At the same time, they have a deal with Basilea for their antifungal drug, isavuconazole.  Basilea is now trying to re-apply for marketing approval via the EMA at least and the FDA if possible for ceftibiprole, their anti-MRSA cephalosporin that would then compete with ceftaroline from Forest.  Given that these two products probably account for the vast majority of the value of Basilea, an acquisition by Astellas is certainly not out of the question.

Even if this all comes to pass, Astellas would have to outperform Forest considerably given the slow uptake of ceftaroline in the US. Forest’s net sales of ceftaroline (Teflaro) were $6.5 million in the 3^rd Q last year. Forest, though, remains very optimistic on the potential for Teflaro given the early patient numbers, the ex-US market is still to come and the fact that the respiratory season had not started until after the 3^rd Q.

As always, I await further developments with great interest.  But if the situation for antibiotic biotechs does not improve soon, even this source of new antibiotics will be an endangered species.

Antibiotic Development - EU vs. US.

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The European Medicines Agency has now released its new guidance on the development of antibacterial drugs.  This document demonstrates how advanced they are in their thinking compared to the US FDA.  I will highlight a few key points that differentiate their approach from that of the FDA below.

The EMA notes that a number of patient types will not have elevated temperatures or white blood cell counts at the time of enrollment.  They therefore do not require these as inclusion criteria. 

In Europe, it is clear that clinical outcome at test of cure is the preferred primary endpoint for studies of antibacterial agents.  This is completely in line with the desires of most physicians and in complete disagreement with the FDA. The EMA would treat the test of cure in the all treated and the clinically evaluable populations as co-primary – again in distinction to the FDA.

The EMA does not specify the non-inferiority margin to be used.  They indicate that one must have reason to believe that the treatment effect of the comparator drug would be superior to placebo and that the non-inferiority margin would conserve at least some of that effect.  But no specific margins are specified and it seems like the determination of the margin for any given study of any given indication could be discussed on a case-by-case basis. 

In this regard, Europe suggests that the historical database of so-called placebo-controlled trials is inadequate for the justification of treatment effect in modern trials.  They therefore encourage the use of pharmacometric analysis of modern trials for this purpose. The FDA is about to makes its first exploration of the value of pharmacometrics (hopefully) this year.  

Europe also provides a discussion of alternative trial designs in their guidance document that clearly shows they are thinking about difficult clinical development issues that could impede our ability to bring new therapeutic options to the sickest patients with the greatest medical need.  This is an area the FDA is just beginning to consider.  The EMA devotes an entire section of their guidance to this.  They discuss the study of rare infections such as endocarditis and meningitis.  They discuss adaptive designs implying they would be willing to discuss a Bayesian approach.  In this case the EMA clearly wants to be part of a detailed and careful discussion before agreeing – but at least they are open to the discussion. Although they clearly state that a randomized active control trial is always preferable, they clearly recognize that in some circumstances, an active control may not be feasible and a historical control might be necessary.  Again, such an approach would require considerable discussion with the EMA.

The EMA clearly states their preferences, but recognizes that it must be open to innovative approaches if we are ever to deliver the kind of targeted therapy we want to those patients with the greatest medical need. This openness, this willingness to discuss new approaches provides a breath of fresh air when compared to similar discussions at FDA who do not even seem to be sure where to start.  I suggest they start by looking at the EMA guidance and actually embarking on a serious harmonization process with the EMA.

When comparing guidance documents for antibacterial drugs, there is no comparison. For those of you with antibacterial products in development where you are struggling with innovative design options – go to Europe. At least you will get an open and considered hearing.