The Regulators

According to an interview by the Wall Street Journal with Thomas Lonngren, the outgoing Executive Director of EMEA, pharmaceutical companies must innovate and regulatory agencies have to get together.  From my prismatic view of the world through the kaleidoscope of antibiotics, this seems easier said than done – especially given the state of affairs at the FDA. 

Innovation in antibiotics has been difficult to say the least. But I see hopeful signs on the horizon.  New classes (at least for human therapy) are being studied by a number of companies, large and small, with a few having reached late stage development.  BC-3781, a pleuromutilin from Nabriva and NXL-104, a non-beta-lactam beta-lactamase inhibitor from Astra-Zeneca-Forest are examples of such compounds in phase II or later.  The siderophore monobactam from Basilea and the siderophore monocarbam from Pfizer are examples of new classes entering early clinical development.  Of course, we are all still waiting for the genomics revolution to hit antibiotics either in terms of antibiotic discovery, choice of patient populations for study or even for non-clinical safety studies.

Although the regulators frequently call for more innovation, it turns out that in many cases it is the regulators themselves that stifle it.  A good example is the conundrum antibiotics developers now face in designing trials in community acquired bacterial pneumonia.  The patient population for analysis must be those who have a documented bacterial infection.  But even in the best of trials, no more than 30% or so of patients enrolled will fit this definition for lack of a bacterial diagnosis at baseline.  The trials remain infeasible just based on the size of the enrollment population at this rate of diagnosis.  The diagnosis rate must be at least 50% for trials to be feasible.  To get there, given the paucity of FDA approved diagnostics available for pneumonia-causing pathogens in human specimens, experimental methods would have to be used.  This would require (1) a diagnostics company to see a potential market in such a diagnostic such that they would develop one (so far no one does) or (2) trail-blazing and risk-taking on the part of the pharmaceutical company sponsor.  I don’t object to this as long as the sponsor has $30 million or more per trial to put at risk.  Here, regulators could help by providing such a pathway and/or sponsoring research that would lead to a path forward.  But to hold companies hostage awaiting a way forward will only lead to more defections from antibiotic discovery and development. 

One wonders if the regulators are following Mr. Lonngren’s advice and speaking to each other about coming together on a feasible path forward for the development of antibiotics for community-acquired pneumonia.  The same could be said for hospital-acquired pneumonia, ventilator associated pneumonia, and skin and skin structure infections where guidelines from the FDA require either infeasible trials or trials that are feasible but insensitive or clinically irrelevant.  These guidelines differ markedly from anything coming from EMEA. 

My hope would be that EMEA would reject the FDA guidelines and simultaneously try and bring the FDA to a more rational stance. After all, EMEA has stated publicly on numerous occasions that the development of new antibiotics for resistant infections is their highest priority.  This laudable stance seems the polar opposite to that of the FDA. 

So – will EMEA follow Mr. Lonngren’s direction and both stand up to the FDA and try and bring the FDA along on some more reasonable (read feasible) path or not?  We all await the results of the scientific advisory group that they will convene sometime soon. 

And by the way - Happy New Year to all of you out in antibiotic land. 

Related articles

• Drug Regulator Urges Innovation (online.wsj.com)

Timeout!

At this time of year, my thoughts turn to others – one in particular.  No – its not cholera in Haiti. 

Many years ago, when infectious diseases physicians could still perform and read their own Gram’s stains, examine their patients’ cultures and susceptibility tests, I was training with Manny Wolinsky of non-tuberculous mycobacteria fame.  At my side, was Michael Lederman.  For reasons I could never understand, Michael decided that he would go into immunology and ended up being on the front lines of the HIV epidemic.  I finally realized that he did this because he was smarter and more prescient than me.  After all – how many companies who started in antibiotics are still carrying out research in the area?  For HIV – most companies who started out there are still in the fight. 

Michael is known as Leachem to his friends.  He likes to speak and write backwards.  They say that most brilliant people are quirky!  He experienced a life-threatening type-I aortic dissection this past week.  I understand that he is recovering well.  But I wonder how his interaction with the hospital bureaucracy went given his penchant for speaking and writing backwards.  I’m sure that the main reason he survived is that he made his own diagnosis within milliseconds of experiencing symptoms and was able to prod the surgeons into taking him seriously. Leachem is a spectacular clinician and diagnostician and I am sure that even his own illness would not have interfered with his ability to discern his own diagnosis immediately and correctly. 

Leachem, being an acute ID physician, is more than aware of the dangers of being in the hospital.  When told that the only people washing their hands were the infectious diseases colleagues visiting him, while still on the ventilator, he wrote “____heads!”  on a pad of paper.

I understand Leachem is back at home recovering at this point.  Home is a much safer place than the hospital.   So, I wish him an his family all the best.

Superbugs and NXL-104

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You know there is trouble brewing when the latest superbug hits the New England Journal of Medicine.  That’s just what happened this week with the publication of a perspective on the latest superbug – or super resistance gene – NDM-1 – by Bob Moellering.  NDM-1 stands for New Delhi Metallo-Beta-lactamase.  It is actually a gene encoding an enzyme (beta-lactamase) that chews up our most advanced antibiotics.  Having a metal ion in its active site and not a serine, it is resistant to our usual Beta-lactamase inhibitors including the latest addition to our pipeline for the treatment of serious Gram-negative infections, NXL-104.  Luckily, NDM-1 does not attack one of our antibiotics, aztreonam.  Most of the pathogens that carry NDM-1 also carry other B-lactamases that do hydrolyze aztreonam.  They also carry a host of other resistance genes.  This may be related to the fact that this gene and the plasmid that carries it evolved in India and is widespread on the Indian subcontinent.  In India, there is widespread use of antibiotics without prescription and frequently in low dosage or for only a few days resulting in inadequate therapy perfect for selecting resistant bacteria.

Dr. Moellering cites the Centers for Disease Control as stating that NDM-1 bearing bacteria should respond to the usual infection control measures.  While that may be true, our experience with other new Beta-lactamases, with MRSA and with all the other superbugs has been that once they start to spread, with the exception of a few especially diligent centers, the cat is out of the bag.  NDM-1 has already found its way to the UK and even over here to the US.  It is probably just a matter of time before it becomes even more widespread.

Once again, we will need new antibiotics to fight this infection.

NXL-104 is an inhibitor of Beta-lactamase with serine at their active sites – so not NDM-1.  But it does hit some of the most difficult of these enzymes like those that hydrolyze our most valuable antibiotics like imipenem.  NXL-104 was originally discovered at Aventis (now Sanofi-Aventis) but was spun off into Novexel at the end of 2004.  Novexel took the compound through Phase II trials in combination with ceftazidime, another antibiotic plagued with resistance – but which is susceptible to hydrolysis by NDM-1. Forest is developing NXL-104 in combination with their recently approved antibiotic, ceftaroline. 

Last year at the ICAAC meeting, David Livermore pleaded with industry to combine NXL-104 with aztreonam.  With aztreonam being resistant to NDM-1 and with 104 inhibiting the enzymes that might otherwise hydrolyze aztreonam – NXL-104-aztreonam could clearly be a winner for this particular superbug.  Is there enough of a medical need?  Will there be enough of a medical need in the next five years (when NXL-104 might be launched)?  I don’t know.  But I am sure that these are exactly the questions Astra-Zeneca and Forest are asking themselves.

Astra-Zeneca and Forest acquired Novexel in a complicated deal at the end of 2009 – almost exactly one year ago.  In their annual report from 2009, Astra-Zeneca stated that ceftazidime-104 should enter phase III trials at the end of 2010.  So far (to my knowledge), that has not happened.  So I wonder what happened to NXL-104 and whether the powers that be are seriously considering David Livermore’s suggestion . . . .

Related articles

• "Super superbug" NDM-1 spreads in Europe (reuters.com)

Antibiotics and the FDA - Where are we?

Janeen Interlandi just published an interesting article in Newsweek where she explores the perfect storm we are facing over the future of antibiotics.  She concludes that we need a new way of thinking about antibiotics, but offers precious little in terms of direction. I guess she is just as confused as the rest of us.

I continue to believe that one way forward will be for the industry and the FDA together to devise FEASIBLE trial designs for antibiotics such that they can be developed and approved in the US.  The other option – I think of it as the nuclear option – is to declare the US antibiotic market irrelevant and inaccessible and to focus on Europe and, more importantly, the emerging markets like Brazil, Russia, China, India, Mexico and Turkey (BRCIMT).

But since the US is still a relevant, even important, market, lets examine what we have left in terms of a path forward for antibiotics and lets contrast that with where we need antibiotics the most.  The table below shows that those indications where the medical need, at least in the US, is the greatest for new antibiotics are either not so attractive markets or, in the case of hospital-acquired pneumonia and ventilator associated pneumonia, are indications where the FDA-required trials are simply infeasible.  The other message from this table is that there are precious few indications left in which new antibiotics will be marketed.

So, the choices we have are:

1.  A process that allows industry and FDA to actually come together and agree on FEASIBLE trial designs (the FNIH seems to be the same people saying the same things but in private).
2.  Incentives that will work (but we still need feasible trial designs for indications where there is clear medical need).
3.  Further loss of pharmaceutical companies from antibiotics research.
4. The nuclear option.

Under number 1 above, and in line with Ms. Interlandi’s article, I favor a new approach.  Lets take the current FDA team and all its consultants out of the room and replace them with FDA top management and their consultants.  Lets get an entirely different team of statisticians.  Lets get industry and IDSA to present their best and most innovative designs and strategies. Lets lock the room for about 3 months and make them come up with something FEASIBLE for antibiotic development.

If we can’t make this work, we’re left with the nuclear option.  Option 3 will probably occur anyway.

Related articles

• Are We Running Out of Antibiotics? (newsweek.com)

Paul Ambrose on the FDA's Skin Infection Guidance

This is a post submitted by Paul Ambrose (with a few comments by yours truly).

Ambrose et. al. suggested to the FDA an others that there was an alternative pharmacometric-based method to using historical data to estimate the magnitude of antibiotic treatment effect. The pharmacometric-based method overcomes the numerous limitations inherent in the interpretation of historical data and is based upon contemporary data and clinical endpoints.   Better yet, the methods would utilize authenticated clinical data that was part of recent NDAs.  The method relies upon the construct exposure-response or pharmacokinetic-pharmacodynamic relationships, which are typically evaluated as part of modern-day drug development.    
The upper and lower regions of exposure-response relationships for efficacy provide estimates of drug effect as exposure increases toward maximal-treatment effect or as exposure decreases toward no-treatment effect (Figure 1).  The difference between the patient response rates at the upper and lower asymptotes closely approximates the treatment effect (i.e., the maximal benefit of therapy in a given patient population).  Such an estimate provides the critical missing data needed to design non-inferiority studies with appropriate statistical power, which in turn obviates the need for superiority study designs.  Moreover, these data make it possible to estimate the no-treatment response rate without exposing patients to any risk (mortality or mortality) incurred by conducting superiority studies that are placebo-controlled or which utilize suboptimal dose ranges or comparator regimens).
 

Comments from Antibiotics – The Perfect Storm - For those of you not in the know – Paul is simply proposing to take the various drug exposures that might occur across a large clinical trial and extrapolate them to zero as a way of estimating the “no treatment”effect.  The treatment effect is then defined by the difference between that and, I suppose the mean or maximal drug exposure for the group of treated patients.

Paul and his collaborators have a number of other comments and critiques of the FDA’s stance. I refer you to their FDA Docket submission for more details.
 

More Bad News from Neverland. The FDA Guidance on Nosocomial Pneumonia.

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The FDA has just released its new Draft guidance on clinical trial design for antibacterial drugs in the treatment of hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP).  As anticipated, they call for an endpoint of 28 day all cause mortality.  But the devil is in the details.  The FDA suggests that patients at high risk of dying (those with APACHE scores of 15 or greater) be enrolled to allow for a treated mortality rate of around 20%.  That would allow for a non-inferiority margin of 10%.  BUT – the analysis population is the microbiology intent to treat (MITT) population – that is, those patients enrolled and treated who have an identified bacterial pathogen at study entry. 

Once again, in the appendix to the guidance, the FDA has gone to extraordinary and unscientific lengths to discount the treatment effect of antibiotics in VAP such that they arrive at an infeasible trial design. They demonstrate that inappropriate therapy for VAP is associated with a 62% mortality and that appropriate therapy is associated with a 20% mortality.  The treatment effect of appropriate vs. inappropriate therapy is, therefore, 42%.  Of course, inappropriate therapy is not no therapy, and 42% as a treatment effect is therefore already conservative.  But, the FDA is not satisfied with that.  They go on to apply their 95/95 rule using the upper bound of the 95% confidence interval for treatment effect of inappropriate therapy and the lower bound for appropriate therapy yielding a treatment effect of 29% instead of 42%. They then discount the treatment effect of 29% by an additional 30% for good measure. The FDA justifies their additional 30% discount by claiming that this is necessary to correct for “uncertainties” of the historical database.  This brings the treatment effect or M1 down to 20%.  How convenient!  They now take 50% of that and call that a justified non-inferiority margin of 10%. (Is 10% starting to sound like a familiar number?)  But since the margin simply has to be smaller than the treatment effect, the margin could just as easily have been 19%. But of course the entire discounting argument is overly conservative and irrational.

So, as an amateur developer, I’ve been trying to understand the practical consequences of this design.  Lets take VAP since the FDA seems to focus on VAP in their guidance. In my calculations I have made the following assumptions:

Cure rate = 80% (20% mortality). 

Evaluability – as far as I can tell, in modern trials, the MITT population is about 45% of the enrolled population.

NI margin = 10%

90% power (to exclude the chance of falsely concluding inferiority as much as possible).

I calculate that one would need to enroll over 1200 patients per trial.  That would be at least 2400 patients in two trials.

I believe that the largest HAP/VAP trials ever performed were the ATTAIN-1 and -2 trials by Theravance/Astellas. They enrolled 1518 patients over about 28 months.  I don’t know how many centers were used. They powered their trials to show a 20% non-inferiority for treatment of MRSA infection compared to vancomycin.  Non-inferiority margins of 15-20% used to be common for VAP trials since these patients are so hard and so slow to enroll and since the trials are so expensive to run.  Those were the days when we actually considered feasibility of trial designs before we issued guidance. Two trials at 1200 patients per trial in VAP is, once again, totally infeasible.  Even just in terms of the time that would be required to complete such a trial.

I calculate, based on recent enrollment rates as cited by Steve Barriere of Theravance, that such a trial could take anywhere from 5 to 50 years to complete. In the current FDA guideline, the suggested severity of illness (APACHE score > 15) will slow enrollment.   The number of centers participating in the trial and, as a corollary, the number of competing trials will all affect enrollment rates and costs.  After even 5 years, the trial design and comparator might already be obsolete.

In terms of cost, VAP trials are probably the most expensive trials we currently undertake.  I’m guess that costs now are in the order of $30-50,000 or more per enrolled patient.  If the analysis population will now be the MITT population, these costs could be even higher.  Frank Tally estimated that in Cubist’s failed (for lack of enrollment) trial of daptomycin in the treament of bacteremia caused by vancomycin-resistant Enterococcus, their costs were $250,000 per evaluable patient.  They spent $20 million before jettisoning the trial.  At $50,000 per enrolled patient, a 2400 patient set of trials in VAP would cost $120 million.  No company, let me repeat that, NO COMPANY will take this on!  The costs rapidly outstrip any return on investment.

What about superiority trials as a solution?  We’ll address that in a future blog. 

Have a great day!

Footnote: As far as I can tell, Theravance never published the full results of their trials.  I can only find abstracts and a very brief and incomplete summary of their results on clintrials.gov. Now that it is clear what the FDA wants – will Theravance be able to provide it?

Ear Infections - Round 2

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A recent article appeared in the Journal of the American Medical Association regarding the treatment of infections of the middle ear of children (acute otitis media or AOM).  The article caused a stir because the authors concluded that antibiotics have a limited benefit, that there was little difference among antibiotics, and that antibiotics also had side effects.  They seemed to indicate that expectant therapy would be a reasonable recommendation for dealing with these ear infections.   While I don’t argue with this conclusion, I think that it would be good to be clear on exactly which patients we are talking about and at what time we decide whether patients have benefited or not. 

First, the article in JAMA was a meta-analysis.  That is, it just reviewed results from previously published studies and kind of pooled the data.  For the antibiotic therapy of AOM, they chose studies that looked at clinical response to treatment after 14 days.  At 14 days, they showed that amoxicillin had a success rate of about 73% compared with 60% for placebo – a 13% treatment effect.  The antibiotics also had side effects like rash and diarrhea.  No other time points were examined.  A variety of antibiotics had similar results at 2 weeks.  Many news services picked up on these results to indicate that the use of antibiotics to treat ear infections is usually unnecessary and could represent an abuse of antibiotics that might, in turn, select for antibiotic resistance.

The meta-analysis published in JAMA was picked up by a number of news services including The Boston Globe, CNN, and others. They all echoed the authors’ conclusions that antibiotic treatment is of only modest benefit and is associated with side effects.

The studies that were reviewed did not use a standardized method of diagnosis of middle ear infection. One thing we have learned over the years is that a definitive diagnosis is important and can be easily made simply by looking at the eardrum through an otoscope, seeing that the drum is red, swollen, and immobile when you blow a little air on it. That has a 95% chance of correctly diagnosing a bacterial infection of the middle ear.  Thus, if some patients who did not actually have bacterial otitis media were admitted to the studies, the antibiotic effect would be lessened. 

On the other hand, the researchers who recently reported their results on clintrials.gov as I noted in my previous blog on otitis, carefully documented the presence of middle ear infection in each case.  They also looked at responses while patients were still on therapy (within 72 hours) and at 7 day endpoints for their trial. In the results from their study, which should probably be considered the definitive study, 23% of placebo treated patients were clinical failures compared to 3% of antibiotic treated subjects at the on therapy visit (within 72 hours).   16% of antibiotic-treated patients and 51% of placebo patients were failures at end of therapy (7 days).  These data establish a treatment effect of 11% during the first 72 hours and 35% during the 7 days of therapy.  This treatment effect being more than twice what was seen in the meta-analysis published in JAMA might be explained by the heterogeneity in the population studied and the 14 day endpoint used by these studies.

To conclude that antibiotics do not work well and are not justified in light of these most recent data seems premature. 

The Infectious Diseases Society Sounds Off on the FDA and Skin Infections

Well, boys and girls, it looks like at long last, the Infectious Diseases Society of America (IDSA) has taken off the gloves.  I guess they are now as frustrated as the rest of us with the FDA’s inability to provide a clear and feasible path forward for antibiotic development.  Their frustration takes the form of comments (you have to scroll down to the IDSA Comments section in this link) to the FDA’s latest guidance on clinical trial design for studies of acute bacterial infections of the skin and skin structures.  This is ironic, because I was just relieved that we finally had guidance that proposed, at least, a feasible design.  But the IDSA has a number of critical comments.

First, they note that in their view, “ There is no doubt that the lack of clear and feasible FDA guidances has contributed in a significant way to the growing crisis (of our poor antibiotic pipeline in the face of growing resistance).”  Their first specific criticism is of the crazy estimate of the treatment effect (M1) of antibiotics for skin infections of 12%.  As I explained in a previous blog, they use excessively conservative estimates and pseudoscientific discounting to arrive at this preposterous figure. Luckily, in discussions with sponsors, they have been ignoring their own calculations, probably because trials based on the assumption of a 12% treatment effect would still be infeasible. 

The IDSA then takes aim at the proposed endpoint of cessation of spread of the lesion at 72 hours arguing that since even the sulfonamides worked 99% of the time, such an endpoint would not discriminate among different therapies. They also note that for the practicing physician, this is a completely irrelevant endpoint.  The IDSA proposes a much more rational endpoint of clinical cure encompassing mortality at 28 days.

They also take issue with the lesion size requirement (>75 cm²) since that has never been validated anywhere. The IDSA takes the FDA to task in a number of other specific areas of the guidance as well.  They take aim at the use of the Snodgrass trial comparing sulfonamides to UV light from the 1930s as the modern totem to which all trials must compare. 

As I noted, this is the most aggressive stance I have seen by the IDSA vis a vis the FDA.  I guess that I have become so numb over the years that I was just grateful to have a trial that I thought industry could actually accomplish.  But the IDSA wants more.  They want the FDA to withdraw from the guidance their crazy stance on margins even though the FDA accepts margins larger than what they propose.  I suspect that the FDA’s proposal was more for political consumption than for sponsors.  See my blog on Markey and Grassley.

IDSA – Kudos!  And welcome to my world of fantasyland where science and the rational approach to solving problems disappears in the face of politics and pseudoscience. I only ask that as you and the FDA continue to work on issues of guidance for the study of antibiotics, you keep one concept in mind above all – feasibility.

FDA – these are the US physician experts in infectious diseases laying down the gauntlet. They are telling you that your approach to regulation of antibiotics has been misguided and inappropriate.  What are you going to do about it?

Next on this blog – Otitis and Antibiotics – Round 2.

Antibiotics, Incentives and Disincentives - continued.

Going back to that article by Andy Pollack in the NY Times, he includes a graphic from the FDA showing a substantial increase in the number of new antibiotics entering clinical development over the last few years. I think it is worth taking just a few minutes to put this in perspective.  It is absolutely true that the number of antibiotics entering the pipeline is increasing – especially in 2008 when a record 14 new molecules entered development in the US.  But, having looked at the same data from the FDA, I note the following.  The average for the decade between 1990-1999 was 4 new antibiotics entering clinical development per year.  For the last decade (2000-2009), it was 5.7 molecules per year – a 42% increase.  The worst period was the years between 1996 and 2003 when only 3.25 molecules entered development per year.  In general, only 1 in 5 of such molecules will make it all the way to the marketplace, and it takes say 7-10 years to get there once clinical trials start. So, for the next decade, at best, we can expect new antibiotic approvals to still be in the range of about 1 per year.  This is still 3-4 fold worse than during the 1980s.

The other point I wanted to emphasize is that these molecules are mostly entering at the earliest stage of development, Phase I.  A few are entering already at a later stage, Phase II.  But neither of these stages is really expensive.  So most are coming from biotech companies who will not have the means to develop the molecules beyond Phase II.  Phase II trials cost, say, $6-10 million.  Phase III trials, and you have to run two of these for each approved indication you want (with a few exceptions), cost on the order of $35 million when all is said and done.  Biotech investors cannot support this level of spend. Phase III trials must be funded either by public markets or by large pharmaceutical companies.  The former is still essentially non-existent.  The latter is a rapidly dwindling resource, especially for antibiotics.  So, incentives for both large and small companies are still needed, even if there are encouraging signs that the number of new antibiotics entering clinical development in the US is increasing.

An Op-Ed in a recent Boston Globe calls for an incentive combined with a sort of disincentive.  I have been unable to read the full article (since they actually want to charge me money!), but I think I understand what Drs. Kesselhem and Outterson are getting at.  What they claim is that pharmaceutical companies inappropriately market, or at best fail to appropriately market antibiotics such that abuse is encouraged to feed their bottom lines.  They argue that antibiotics are underpriced relative to their value to society.  I have one word from Drs. Kesselheim and Outterson – Zyvox.  Zyvox is an antibiotic that is priced to reflect its high value in the fight against MRSA and also to tie it to use only when an MRSA infection has been documented or at least is highly suspected.  Otherwise, no one would pay the price they charge.  The same is true for a number of antibiotics used in hospitals that are only available intravenously.  The argument that antibiotics are cheap usually refers to those used for infections in outpatients in indications that are, essentially, no longer considered valuable by the FDA – ear infections, bacterial bronchitis and acute bacterial sinusitis. In those infections, there is no longer a question of price since it is not feasible to develop antibiotics to treat them at the present time.

The idea of providing a disincentive, though, to pharmaceutical companies who abandon antibiotic discovery and development is not new.  Dr. Louis Rice suggested this a number of years ago.  He calls it both an antibiotic abuse tax – to make companies pay for the years they allowed patients and physicians to abuse antibiotics by using them when they were not necessary – and a disincentive for abandoning the field.  In this way, companies who continue to try and discovery and develop antibiotics would be exempt from the tax.  Combining this kind of disincentive with the kinds of incentives the London School of Economics has proposed for antibiotic discovery and development would be reasonable.  Although I think the incentive alone would be enough, the tax would help pay for the incentive – making it more palatable politically.  Then again, didn’t we just elect a very anti-tax congress?

Antibiotics and Incentives

A recent article by Andrew Pollack in the New York Times discussed the idea of incentives for the pharmaceutical industry to encourage them to develop new antibiotics. Mr. Pollack points out that while antibiotic resistance is rising, the antibiotic pipeline remains dismal with only two new antibiotics approved by the FDA in the last two years. On a more optimistic note, he also shows data from the FDA that the number of antibiotics in clinical trials has soared since 2003.  Some of these trials are being carried out by large pharmaceutical companies and will likely lead to marketed new drugs.  These include ceftazidime + NXL-104 and ceftaroline-NXL104 trials now being driven by Astra-Zeneca and Forest/Cerexa and Calixa-tazobactam from Cubist (a mid-sized company).  Unfortunately, many of the trials cited by the FDA data are early stage trials being funded by privately held, venture-capital-based biotechs.  These small companies will, probably, be unable to afford the phase III trials that will be required to register a new antibiotic.  They will therefore be dependent on one of two sources of funding; (1) the public markets or (2) large pharmaceutical companies.  But the public markets are virtually non-existent at least for now.  Trius’ public offering resulted in a vastly lowered share price compared to what the company had envisioned.  It is still not clear to me how they will actually pay for the two phase III trials required to register their drug, torezolid. Large pharmaceutical companies that are still interested in antibiotics is a rapidly disappearing species with only 5 of the 13 largest companies in the US and Europe still in the business of discovering antibiotics.  And when companies abandon the field, they lose their expertise.  They become unable to appropriately evaluate new opportunities.  This leads them either to make poor decisions or simply leads them away from in-licensing antibiotics. 

The Infectious Diseases Society of America has proposed a number of incentives for industry.  They also strongly support enactment of The STAAR Act (STRATEGIES TO ADDRESS ANTIMICROBIAL RESISTANCE ACT).  The STAAR Act, while an important step forward, does not really address key incentives to the industry for the development of new antibiotics active against resistant pathogens. Incentives supported by the IDSA do not really include those most likely to work, in my opinion.  The incentives that I think are most likely to work include (1) the wild card patent exclusivity, (2) the push-pull mechanism from the London School of Economics report and, perhaps most importantly, (3) a feasible path forward for new antibiotic development from the FDA and EMEA.  Although the latter might not be formally considered an “incentive”, we will have no antibiotics without it.  The wild card patent exclusivity would allow a company like Pfizer to obtain an additional 6 months to two years of patent exclusivity for a drug like Lipitor in return for marketing a new antibiotic active against resistant pathogens.  This has been shown by Spellberg and coworkers  to be cost effective given the societal costs of antibiotic-resistant infections.  The push-pull mechanism would provide support for development, say for the phase III trials required for registration, plus a guaranteed initial government purchase of a new antibiotic for resistant infections.  This would reduce the company’s risk and at the same time provide an initial sales spurt that would more than offset launch costs and provide an immediate return on investment for the company.  In my view, this is superior to the wild card option in that the costs to taxpayers would be less, but the incentive would still work quite well.

But all this remains a dream. So far, no one except me and the IDSA, supports giving money to pharmaceutical companies and we still do not have the kind of regulatory path forward that we need to even consider developing needed new antibiotics.  Somewhere, over the rainbow . . . 

Related articles

• Anti-antibiotics: Bugs, drugs and bureaucrats (newscientist.com)

Ear Infection - Antibiotics Work!

The data are in!  The NIH funded placebo-controlled trial of augmentin vs. placebo in children ages 6 months to two years with well documented otitis media (AOM) shows that antibiotics work at some cost of increased adverse events.  In this study, careful tympanography (assessing the swelling, redness and lack of movement of the tympanic membrane) was carried out to document that patients had acute otitis media usually caused by bacterial pathogens and not the confusing, and usually non-bacterially caused serous otitis.  A drawback of the study was that ear punctures were not performed – but even as it was, it took three years to complete enrollment.

The study enrolled 291 patients of whom 284 completed therapy. The only serious adverse events in the trial included one case of mastoiditis and one of pneumonia in the placebo arm. There was an increased incidence of diarrhea, diaper rash and thrush in the antibiotic treated group. Although the overall protocol-defined time to resolution of symptoms did not differ between groups, the antibiotic group did have a significantly faster rate of durable resolution of symptoms (symptoms resolved over two questioning periods = 24 hours) than the placebo group.  23% of placebo treated patients were clinical failures compared to 3% of antibiotic treated subjects at the on therapy visit (within 72 hours).   16% of antibiotic-treated patients and 51% of placebo patients were failures at end of therapy (7 days).  These data establish a treatment effect of 11% during the first 72 hours and 35% during the 7 days of therapy. The latter number should establish a reasonable NI margin for non-inferiority trials in otitis media with an endpoint of 7 days. Although not powered for this result, it is possible if not likely that antibiotics would prevent complications such as mastoiditis and pneumonia in patients with AOM. Since this study is contemporary, there is little justification for the usual discounting in defining the NI margin for a non-inferiority trial as usually practiced by the FDA. A 10% margin seems justified and reasonable.

Hopefully, this should be the last placebo-controlled trial needed for acute otitis media in young children.  The data show that when this diagnosis is established carefully, even in the absence of clear microbiological culture confirmation (which would have required puncture of the ear drum for culture), antibiotic therapy is superior to placebo.  It also confirms what most parents already knew – that symptoms resolve more quickly and completely when antibiotics are given than when they are withheld.  One plausible and likely explanation for the failure of previous trials to show a difference between antibiotic therapy and placebo in acute otitis media is the lack of a clear and consistent diagnosis using tympanography.

The current FDA and EMEA guidances require that placebo controlled trials be used to study the efficacy of antibiotics in acute otitis media.  The data provided by this NIH-sponsored trial belie the basis for the regulatory guidance by demonstrating a clear antibiotic effect.  Where do we go from here?  Is there a sponsor out there who would like to rediscuss phase 3 trial design with the FDA or EMEA?  Sanofi-Aventis?

More on FDA Thinking

In the Oct. 14 issue of the New England Journal, Dr. Susan Okie writes about Drs. Hamburg and Sharfstein’s efforts to “revive” the FDA (an interesting choice of words, don’t you think?).   In this article, Dr. Okie covers the FDA on rosiglitazone, medical devices, food safety, facility inspections and the tension within CDER between their Office of Surveillance and Epidemiology and their Office of New Drugs.  The surveillance folks claim that the new products folks are too focused on approving new drugs to pay sufficient attention to safety risks.  The new drugs folks feel that the surveillance office is too focused on safety to the detriment of valuable new products. Although Dr. Okie cites rosiglitazone as the contemporary example, she could easily have chosen the antibiotic telithromycin (Ketek) removed from the market for certain indications back in 2006.  Of interest, the FDA has apparently contracted with Harvard Pilgrim Health Care to develop and test a data mining system to survey electron medical records to answer safety questions.

Back in 2005, I worked with the Manhattan Institute to frame an approach to Janet Woodcock’s Critical Path proposal.  In this proposal, Dr. Woodcock exhorts sponsors to develop new tools using new genomic, proteomic and other novel scientific methods to push rapidly forward towards a new paradigm of drug development.  In this new paradigm, drug safety and efficacy studies would be informed by biomarkers developed and validated using the new scientific tools.  The task force at the Manhattan Institute examined the proposal and developed a white paper, Prescription for Progress; a Critical Path to Drug Development.  The context of the white paper was within the realm of biomarkers and, mostly, the development of drugs for oncology and inflammation.  But one general approach that we did present to the FDA still resonates for me and, I think, for some at the FDA.  We suggested that a drug could be conditionally approved based on favorable Ph. II data in a life threatening indication or where there was no other therapy available.  One example we used in our presentation to the FDA in 2005 was Vioxx.  If Vioxx were developed for use in patients with rheumatoid arthritis whose pain was unresponsive to other non-narcotic pain relievers in a phase II trial, the drug would then be approved for use only in that patient population.  A registry would then be required for all patients for whom the drug was prescribed to assure that the drug was not being used off label and to assess safety risk.  Thus, the drug would fill an important medical need only within the specific needy population.  The sponsor would sell the drug and recoup some costs while continuing into phase III trials that might study the drug in a wider population.  Before the drug would be approved, though, there would be considerably more use occurring outside the clinical trials than we usually have at the end of phase III.  Therefore, our understanding of the safety of the new drug in a larger population would be enhanced and this would reduce the safety risk going forward.  In the case of Vioxx, perhaps the cardiac risk would have become evident during its restricted use in the rheumatoid arthritis population.  The sponsor might have then been able to argue that the benefit risk ratio is still favorable within that population, and ultimately have had Vioxx approved in a narrow indication as opposed to the very broad indication for pain relief where hundreds of millions of prescriptions were written.

If we could study antibiotics in a very needy population, such as patients with serious infections caused by highly resistant pathogens, perhaps a new antibiotic could follow a similar route.  The questions as posed in a recent blog remain the same.  What would the details of such a study look like?  Will it be feasible or not? 

The article by Dr. Okie in the New England Journal did not even touch on antibiotics.  Hmmmm . . . .

She Speaks!

Hey everyone – I just received my copies of my book as promised by Springer. I think I’ll put them in a safe deposit box. 

But to business.  I have seen a flurry of activity by Dr. Hamburg, Commissioner of the FDA that is relevant to Antibiotics – the Perfect Storm.   And my spies tell me that Dr. Temple has been active as well. Since I am not a journalist, and do not cover Dr. Hamburg’s speaking engagements, and since I am not involved in the FNIH process or other direct interactions with Dr. Temple (outside of the usually advisory committee meetings and public workshops), I have to rely on spies and news reports.  Nevertheless, a story is emerging.

Two recent new reports have reported on Dr. Hamburg’s statements on antibiotic resistance and the antibiotic pipeline.  According to Alicia Mundy of the Wall Street Journal, at a recent appearance at the National Press Club, Dr. Hamburg noted the increasing resistance to available antibiotics.  She laid this at the feet of antibiotic use both for human health and for crops and in chickens and livestock. She called for more judicious antibiotic use.  This comes at a time when the FDA is (finally) poised to act on the use of antibiotics in agriculture. But, according to Mundy, Dr. Hamburg also said that the state of the antibiotic pipeline is “distressingly low” and that “the range of antibiotics is disturbingly limited.” 

It is comforting to know that Dr. Hamburg is at least devoting some of her time and energy to antibiotics.  I know from my days on the Institute of Medicine’s Forum on Emerging Infections, where she was a frequent participant and co-chairman, and from Dr. Hamburg’s history in New York during the outbreak of resistant TB in the 1990s, that she is acutely aware of the issues of antibiotic resistance. I admit that I have been worried (and am still not reassured) that Dr. Hamburg would be so overwhelmed with crisis management within a large and unwieldy bureaucracy that she would have no time to think about the antibiotic mess at the FDA. 

Evidence that FDA management is beginning to get more involved comes from spies.  Apparently Dr. Robert Temple has harkened back to Mark Goldberger’s (ex-Director of the antibiotics division at FDA) suggestion from 2002 that we approve antibiotics based on a small number of high quality cases.  That is, we recruit patients with serious disease caused by resistant pathogens that would be untreated or poorly treated with approved antibiotics, treat them with a new drug showing that it works (is superior).  The devil here, as it was back in 2002, is in the details.  Which infections are OK?  Is bacteremia from any source OK?  The FDA has rejected that approach many times over the years.  Is hospital-acquired pneumonia OK?  If so – what kind of difference would the new drug have to show?  How many patients would that require? How many patients would have to be studied? 10?  20? Hundreds?  Are historical controls OK?  If so in theory, how would you justify the treatment effect for the historical controls?  If historical controls are not OK, is it ethical to not treat patients with a drug that will, with a greater than 50% or even 80% probability, work?  At least, maybe, we are back to considering these approaches at top levels within the FDA.  The basic question remains – can we make anything happen that will speed approval of needed new antibiotics?

The other piece of news, Angie Drakulich reports in PharmTech.com that The FDA and generic drug manufacturers are discussing user fees to speed approval of new generics.  This would allow the FDA to carry out a timely review of generic drug safety and manufacturing standards according to the FDA.  As those of you who have been following my blog know, generic antibiotics has become one of my key issues since the Ketek scandal.  During the Ketek scandal, it was clear that many generic drugs were approved for use in otitis, sinusitis and acute bacterial exacerbations of chronic obstructive pulmonary disease.  But they were approved based on clinical trials that the agency now considers to be obsolete and invalid. At the same time, several of these generic drugs have safety problems.  At the time, I asked the FDA to review these generics and either remove their approvals for these indications or at least change their labels.  Nothing has happened in the last four years.  Maybe user fees will allow the FDA to actually work on this problem.

When it comes to the FDA, I am no longer ever optimistic.  But I am heartened to see that the eye of top management has, at least, been drawn to the very serious problem of rising antibiotic resistance coupled with our shrinking antibiotic pipeline. 

Superbugs, Antibiotics and Drug Safety

I’m back.  Vacation was great.  Now I’m being punished for having taken one. Oh well . . .

Well, NDM-1 has arrived in the US.  These Gram-negative bacteria cause everything from urinary tract infections to brain infections and pneumonia.  The can be treated, usually, by only one or maybe two antibiotics, and sometimes, by none. Of course, as noted in previous blogs, KPC-2 bearing Gram negative bacteria have been here for a long time and have already invaded 35 states that we know about.  Since we do not carry out active surveillance, what we know about these resistant bacteria probably only represents the tip of some undetermined iceberg. A recent report on CBS News shows the devastation these infections can wreak on patients and families to say nothing of their physicians struggling to treat what used to be a fairly simple infection in days gone by.

Of the 90,000 deaths occurring due to infections acquired in US hospitals every year about 70,000 involve antibiotic-resistant bacteria.  These numbers do not reflect resistant infections acquired outside the hospitals which may be much more frequent if sometimes less serious.

With serious infections caused by bacteria that are more and more resistant to the antibiotics we have in our armamentarium, we still face enormous roadblocks to the discovery and development of the new, effective antibiotics we need now.  Our need for new therapies is likely to become desperate in the near future if we don’t act now.

The FDA is entrusted with ensuring that the drugs that are marketed in the US are safe and effective.  But these terms are relative.  The question is, to what extent must we go to prove sufficient safety and efficacy for the treatment of which infections?  The more serious and life threatening, the more we can tolerate adverse events as long as we can pull the patient through. But what about efficacy?  How can we prove efficacy is these patient populations?  They are the hardest to actually enroll in trials because they are so ill.  The results of therapy are frequently hard to interpret because they are so ill.  Is the fact that they survive enough?  Can we compare such patients to historical controls?  How good would the database of historical controls be for KPC-2 infections since this superbug has just emerged on the scene recently, and since there are sometimes at least one or two presumably effective antibiotics left to treat it. For example, lets look at NXL-104 – ceftazidime, a combination of a resistance inhibitor (NXL-104) and an antibiotic that is already marketed that is being developed by Astra-Zeneca. NXL-104-ceftazidime is very active against KPC-2 bearing Gram-negative bacteria. For patients with such infections where there are few if any other choices, is it ethical to withhold what will very likely be effective therapy?  We can predict efficacy for antibiotics so well using preclinical models that many would argue that it would be unethical to withhold such potentially life-saving therapy under these circumstances.  But would the FDA approve, at least conditionally, an antibiotic developed in this way?  Since, presumably, only a small number of patients might be studied – perhaps in the low hundreds, what do we do about a database to establish safety?  These are all questions being debated and discussed by the FDA, industry, the Infectious Diseases Society of America and others. 

A decade ago, Mark Goldberger, when he was Director of the anti-infectives division at FDA, called for high quality studies using a small quantity of seriously ill patients in trials of antibiotics. In the decade that has passed since then, we have rolled backwards in our ability to streamline and improve the relevancy of antibiotic development.  Companies are dropping out of the field right and left.

One major point that must be considered in all of these debates is – a lack of new antibiotics active against key resistant strains is, itself, a safety issue.  The FDA must recognize that acts of omission might also be important contributors to a safety risk for the population.  This key ingredient must be added to the stew of strategic thinking on antibiotic development if we are ever going to get anywhere. 

Absence

Just to let you know - there will be no new blogs for the next two weeks.

Superbug - NDM-1

While at the ICAAC meeting (ending today), I learned a great deal about the emerging threat of the NDM-1 (New Delhi Metallo) beta-lactamase and its rapid spread throughout the world. Beta-lactamases are enzymes found in resistant bacteria that hydrolyze penicillin, cephalosporin and carbapenem antibiotics.  While they do not hydrolyze the monobactam antibiotics of which oly aztreonam is sold on the market, most organisms that have NDM-1 also have other enzymes that hydrolyze aztreonam.  So this means that our most powerful and least toxic antibiotics are off the table to treat these infections.  In fact, most strains are only susceptible to two or three antibiotics.  Tigecycline, a drug I helped develop, remains active against most strains.  Colistin is active in vitro, but since we don’t exactly know how to use it or how toxic it is, physicians are hesitant to use it unless absolutely necessary.  Many strains are also susceptible to an antibiotic called fosfomycin that is mainly used for urinary tract infections.

One good approach to NDM-1 bearing pathogens is to combine aztreonam with an inhibitor of the aztreonam hydrolyzing beta-lactamase enzymes.  There are currently two such inhibitors in clinical development – NXL-104 from Novexel and now at Astra-Xeneca and Forest, and MK-7655, a very similar molecule from Merck. These inhibitors are currently being developed in combination with ceftazidime (Astra Zeneca), ceftaroline (Forest) and imipenem-cilastatin (Merck).  None are pairing them with aztreonam.  When the clinical development of these inhibitors was first contemplated, metallo-beta-lactamases were not the threat that they are today.  The options for the companies are to add yet another combination for treatment of metallo-beta-lactamase bearing pathogens using the inhibitor plus aztreonam or to replace their current partner with aztreonam or do nothing and hope the NDM-1 problem will fizzle.  At ICAAC, David Livermore made an impassioned plea for the development of the combination with aztreonam.

Governments could, in fact, provide additional funding for the companies to develop such a combination and could commit to purchasing some minimum volume of drug. I would hate to bring the government in to such considerations because they move even slower than big pharma.  But this is something that governments should now be contemplating – especially the one in the UK where the numbers of NDM-1 infected patients are rising rapidly.

Bronchitis - a Foot in the Door?

In discussing the FDA Guidance for mild infections with a highly placed FDA official recently, I discovered something new – an appreciation of reality.  The FDA realizes that no one has stepped forward to try and conduct trials in acute bacterial exacerbations of chronic obstructive pulmonary disease (COPD) since the superiority trials required are simply infeasible.  Of course, we do not need (mostly) a new antibiotic for these infections today – but who knows what we will need in 10-15 years.  During our discussion, the FDA official underlined the fact that the current guidance does not apply to severe exacerbation where patients are intubated, since they recognize that antibiotics play a lifesaving role in therapy and that withholding antibiotics from such patients is clearly unethical. But the Cochrane database suggests that even patients with moderate disease exacerbations will benefit from antibiotic therapy (http://www.ncbi.nlm.nih.gov/pubmed/16625602). Furthermore, the treatment effect of antibiotics overall was on the order of 50% for clinical endpoints and 23% for mortality.  A careful analysis of the database and additional attempts at examining antibiotic benefit in patients more moderately as opposed to very severely ill would be very helpful in this regard. 

Based on my discussions, I am looking for a volunteer sponsor.   They would need to do the appropriate literature research, propose an NI margin, provide a protocol synopsis and discuss a clinical trial plan with the FDA. Another option is for the FNIH group to do this work. 

But I believe the door to non-inferiority trials in acute bacterial exacerbations of COPD could be opening just slightly if we can make the right arguments. Are there any volunteers out there?

FDA, Goalposts and Antibiotic Trial Design - YAY!!!

It was a remarkable day yesterday.  In spite of new guidance (still flawed in my view) on clinical trial design in pneumonia and in skin infections, the FDA review of the data developed under the old guidelines by Cerexa/Forest for ceftaroline was balanced and informative.  The incredibly tight data and very well designed studies saved the day.  Not only did the ceftaroline data, with studies powered for a 10% NI margin, come in at 4 or 5% overall, but almost all of the subgroup analyses carried out by both the sponsor and the FDA (and some of these subgroups were small!!) came in with NI margins under 10% compared to either ceftriaxone in the pneumonia studies or vancomycin plus aztreonam in the skin infection studies. But in addition, the spectacular data allowed the FDA to accept studies carried out under an old paradigm and to use a post-hoc approach to examine putative new endpoints in an exploratory way.  I discussed the idea to use this approach with the FDA back in April.  

The advisory committee voted unanimously to approve ceftaroline for both community acquired bacterial pneumonia and acute bacterial skin and skin structure infections (http://www.reuters.com/article/idUSN0723105820100907).  Breakpoints remain a key issue. 

Aside from the good news on ceftaroline, a number of important issues for antibiotic development were discussed at this meeting.

FDA and Pneumonia –

In the FDA analysis of the ceftaroline data – here is how they defined their modified intent to treat group:

 - The inclusion criteria for enrollment in the (ceftaroline) trial required signs and symptoms consistent with pneumonia, chest radiograph confirmation of an infiltrate, and pneumonia of specified severity based on PORT Risk Class. Therefore the FDA-mITT population included randomized patients who received any amount of study therapy and had demonstration of a baseline pathogen as stated below:

Patients with sputum specimens as the respiratory specimen for culture were required to have at least 10 WBC/LPF and < 10 squamous epithelial cells (Applicant required only presence of WBCs and < 10 squamous cells).

Patients with adequate sputum specimens as defined above or blood culture positive for the following organisms or positive urinary antigen for S. pneumoniae were included:

-Streptococcus pneumoniae

 -Haemophilus influenzae

-Moraxella catarrhalis

 -Streptococus pyogenes

 -Staphylococcus aureus

 -Klebsiella pneumoniae

Note: Haemophilus parainfluenzae was not considered to be a pathogen in the FDA population

Patients with certain Gram-negative enteric organisms were included if the patient was classified as PORT III or greater, the sputum specimen was adequate as described above, or isolate was from another appropriate sample, such as bronchiolar lavage or pleural fluid.

FDA also included patients from whom Legionella spp. was identified.

The Agency reviewers’ endpoint (at day 4) required subjects to fulfill two criteria:

1. Clinical stability as defined by the Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS) Consensus Guidelines for the Management of Community-Acquired Pneumonia in Adults. The IDSA/ATS criteria for clinical stability, primarily determined by vital signs, were as follows:

Temperature ≤ 37.8°C, measured orally, rectally, or tympanically

Heart rate ≤ 100 beats/min

Respiratory rate ≤ 24 breaths/min

Systolic blood pressure ≥ 90 mm Hg

Oxygen saturation ≥ 90%

Normal mental status

2. Symptom improvement criteria involving four components:

Cough

Dyspnea

Pleuritic chest pain

Sputum production

The FDA-MITT population from the ceftaroline data analyzed by prior vs. no prior antibiotics was too small to yield meaningful data.

Skin infections –

Analysis population - Randomized patients who received any amount of treatment with lesion size ≥ 75 cm² having one of the following infection types: ‘major abscess’ with ≥ 5 cm of surrounding erythema, ‘wound infection’, deep/extensive cellulitis’ or ‘lower extremity SSSI in patients with diabetes mellitus or PVD’. The Applicant (Cerexa) also presented information on 19 patients with infection type defined as “bite” that met size criteria and were not of human or animal origin and were consistent with literature reports of MRSA infection; these patients were also included in the FDA-MITT population.

Endpoint – day 3 – cessation of spread of lesion and afebrile.

In patients with no prior use of antibiotics within 24 hours, treatment differences were inconsistent across trials, favoring ceftaroline in one study but favoring vancomycin + aztreonam in the other.

Discussion points for the committee (Tom Fleming in this case) were around vital signs vs. clinical symptoms and signs. Dr. Fleming believes (apparently so does the Institute of Medicine) that vital signs are biomarkers that require rigorous validation whereas clinical signs are actually linked directly to how a patient feels and therefore are OK as endpoints. Most infectious disease physicians would take issue with the fact that slowing pulse, slowing respiratory rate and decreasing temperature in pneumonia patients need validation – but apparently Dr. Fleming doesn’t care.  Where does the FDA stand?

Another area for discussion revolved around the measurement of lesion size in trials of skin infections.  For the ceftaroline trial, lesions were measured in two dimensions – length and width, to get a rectangular area.  Several committee members rightly pointed out that cellulitis is not rectangular.  I think that now that halting of lesion spread is a clear endpoint for the FDA (we can all argue about whether this is appropriate or not), more sophisticated measure will be required – but are easily feasible these days.  

In another really good sign, Dr. Follman, a statistician at NIH, noted how conservative the FDA determinations were for both the treatment effect and for the NI margin required – see my previous blog on this as well.