FDA Antibiotics Task Force!

The FDA recently announced the formation of a new task force to support innovation in antibacterial drug development.  I have received a number of calls about this and have recently been misquoted.  So I thought I would try and let you know my perspective on all this myself.

The one good thing about the GAIN act is that it requires the FDA to review and revise as necessary its guidance on the development of antibacterial drugs such that drugs active against important resistant pathogens (the ESKAPE bacteria) can be brought forward to patients and physicians in an expeditious manner. The FDA says that this task force was formed based on this clause in the GAIN act.  But, in fact, the FDA came to realize that the strategy that they have been trying to implement for the last 12 years – that of increased stringency of non-inferiority trial designs for antibacterials – is not only not working, but is actually driving the industry out of the business.  This is something I have been preaching all this time and something Bob Moellering and I predicted would happen way back in 2002! And since 2002, things have only gotten worse.

An advantage of this clause of the GAIN act is that it provides congressional cover for innovative approaches that might be viewed by some as increasing risk.  It is clear that trial designs where we only study small numbers of patients will increase the risk of seeing unpredicted adverse events once the drug achieves wider use.  But my own calculations suggest that large trials have been unable to detect rare events in any case.  These events have been rare enough that they are no different than many marketed antibiotics and other drugs in any case.  Therefore, to me, and I think to patients who are infected with these resistant pathogens, the slightly increased risk is clearly worth it since the alternative is no therapy.  But for the FDA – the cover from congress, especially after the Ketek debacle of 2006, is clearly important.  Its important since it is very likely that a new antibiotic, at some point, will result in some adverse event that is rare and was not predicted by prior data.  When that happens, rest assured, congress will once again rise to the occasion to try and make votes out of the fact that no drug is 100% safe and FDA scientists, clinicians and staffers will pay the price.  I just hope the GAIN act is enough cover for the FDA folks. 

Back in May, when the FDA asked the Brookings Institution to help them review their stance on antibacterial drug development, Janet Woodcock stated that the FDA was going to reboot.  Janet, Rachel Sherman and others at the FDA finally got it.  They finally understood that we were going backwards and that it might be true that new antibiotics active against resistant pathogens could be available everywhere BUT the US if they continued down their current path.

Another fascinating aspect of all this is that the FDA obviously recognizes another problem they face.  Their normal advisory committee process is fatally flawed because of overly restrictive conflict of interest rules.  This puts them in a position of relying on people who have insufficient experience and expertise regarding the FDA’s key questions to provide reasonable advice.  For this reason they turn to think tanks like Brookings.  And it’s a good thing, too!

I firmly believe that this process will work!  I believe that we will end up with feasible designs and innovative approaches to getting urgently need antibiotics to Americans who need them.   I am singularly impressed by the determination of Janet Woodcock, Rachel Sherman and the anti-infectives division to finally tackle this problem head-on.  The big question for me is when will we get something on the table.  At the last Brookings meeting, I suggested that we use the European Draft Guidance as a starting point and go from there.  I think there was much support for this idea since Europe is way ahead of the US in its thinking in this area.  Their non-inferiority trial designs are feasible and use clinically relevant endpoints.  They have listed a number of innovative new approaches to the rapid development of antibacterial products meeting areas of high medical need – like resistant infections. 

So – FDA – lets get going!  I am ready, willing and able to do anything needed to get this moving quickly!

Antibiotics, ICAAC and Bronchitis

I am writing this blog on the last day of the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in San Francisco.  As someone whose living depends on the pipeline of new antibiotics coming through, I am depressed.  I always attend the poster review session the first day of the meeting where the 10 best data sets on new products are briefly reviewed.  This year, as in the past few years, there have been precious few gems among the 10 best.  The two most interesting to me were the presentations by Rempex where they are developing a combination (Carbavance) between an old Japanese carbapenem, biapenem, and a new B-lactamase inhibitor, RPX7009 – a boronate.  Although this class of inhibitors has a bad reputation from the past, the data on this molecule and on the combination look encouraging.  Merck – you may get a run for your money! 

The other interesting presentation was from Trius on a topoisomerase inhibitor with a very broad antibacterial spectrum.  It targets Gyrase B and ParE and is a completely novel class.  Its actual binding site is the ATP site.  Unfortunately, many compounds targeting this site have died a toxic death – so the jury is still out – but the data are encouraging so far. The remaining presentations were quinlones or quinolone relatives offering no particular advantage to existing products either marketed or in late stage development.  It seems unlikely that any of these will get off the ground even though at least one has serious investor money behind it.  So – two out of the 10 best . . .I’m depressed.

On a totally separate note, an interesting study of antibiotics in the treatment of exacerbations of bronchitis was recently published. (A caveat – I was unable to get access to the actual article since I would have to pay $$$ – so I am relying on the abstract and news reports for my information).  The investigators in Spain, Dr. Lior and colleagues, studied over 300 patients with diagnosed chronic obstructive lung disease who had acute worsening of their symptoms (exacerbations).  These patients were only moderately ill.  The point of the study is that while it is clear that such patients with severe exacerbations benefit immensely from antibiotics with reduced mortality rates, it is not at all clear that those with milder disease benefit. This study attempted to answer that question.

Half of the patients were treated with an antibiotic, amoxicillin-clavulanate, and the other half received placebo in a blinded fashion.  Those that received antibiotics were 14% more likely to achieve cure of their symptoms within 8 days and showed a longer time to their next episode – 233 days vs. 160 days.  The study provides strong evidence for a treatment effect of antibiotics in moderate exacerbations.  I believe that by altering the design of the study focusing on those most likely to have new bacterial pathogens as the cause of their exacerbation would have led to an even more impressive treatment effect.  This is important because both in Europe and the US, to study a new antibiotic in the treatment of this disease, we would have to run such a placebo controlled trial.  But, as was the case for otitis media in children, equipoise may be lost.  It may no longer be ethical to run such a trial and, it is going to become harder to convince physicians and patients to participate (rightly so!).

I know that I am running up against the pundits who only want us to develop antibiotics for “serious” infections who believe that misuse and abuse in the community breeds resistance.  And I agree with their view in this regard.  But at the same time, new antibiotics for community acquired pneumonia should be developed – most of us agree on that.  So the only thing that will happen is that they will be used “off-label” for "milder" infections like bronchitis.  (By the way - if you are the patient with lung disease experiencing such an exacerbation - I wonder if you would consider the disease to be mild). Further, if antibiotics work, which I think they do for some patients, and I think we can identify those patients, we should be able to develop new antibiotics and get them approved for use in this condition. 

New Antibiotics? Go Public!

I am now contemplating a talk I have to give at ICAAC this year (Intersciences Conference on Antimicrobial Agents and Chemotherapy for the uninitiated – the biggest infectious disease meeting of the year in general).  My topic is New Antibiotics – what should PhRMA be doing?  In my view – they should either spin off what assets they have, or form independent business units with their antibiotics franchises or just get out of the way. As I have been saying for years – for antibiotics in PhRMA companies – smaller is better.  A product with peak year sales of $300 million is not even a rounding error for a company like Pfizer that brings in $67 billion a year in sales.  As they and many others have demonstrated since 1999 – they couldn’t care less.  In the battle of public health vs. shareholders – guess who wins?  Of course – I don’t argue that this view is somehow perverted – its not – its just the way business is run.  These companies exist to provide a return on investment for their shareholders and not to run a public health non-profit. 

Amazingly – some companies like Astra-Zeneca and perhaps GSK and now, maybe even Sanofi-Aventis, are apparently convinced that antibiotics can still provide enough of a return that they can justify an effort to advance the cause of the public health.  Bravo! I am still not exactly sure what is going on at Merck – the other company that is (at least sort of) in the antibiotics R&D business.

But take heart.  There are other ways to bring antibiotics to market.  Look at Cubist and Cubicin (daptomycin), their anti-MRSA and -VRE (superbugs) drug.  After being unable to find a partner to finance their late stage trials, Cubist went to the public markets and raised enough money to get them to an approval for a single indication, serious skin infections for their antibiotic. They then went on to obtain approvals for other indications like blood stream and heart valve infections all of which increased sales.  Cubicin is on its way to be a billion dollar seller – the gold ring for an antibiotic. Cubist has even in-licensed a new antibiotic, ceftolozane, for the treatment of severe infections caused by resistant Gram negative bacteria like Pseudomonas aeruginosa (another superbug). Ceftolozane is now in phase III trials in preparation for registration for market.

When Cubist went public in 1996 it raised $15 million.  Of course, at this price, Cubist’s investors and the after-market must have had to put in more money to allow Cubist to move forward.  Not much has changed. Nevertheless, this remains a viable strategy for biotech – especially in the US market.  I say this because the IPOs recently have still been meager in terms of ultimate share price but the after-market has remained robust.

Trius, with their new oxazolidinone, tadezolid, was, like Cubist, unable to find a partner to take the compound into phase III development in preparation for an application for market approval.  Tadezolid is a compound similar to linezolid from Pfizer that has garnered a $1.4 billion market.  Linezolid goes generic in 2015. There are many reasons for the fact that Trius was unable to partner their product. The FDA was lost (and still is to a certain extent), thus raising the regulatory risk for antibiotics.   In addition, in my view, their early proof of concept trial was flawed and may not have provided the kind of risk reduction that potential partners wanted. So Trius bravely went forward to the public markets since they obviously had confidence in their product. Trius was forced to cut their offering price by over 40% and raised only $50 million. This forced them (I think) to take a stepwise approach to phase III by running one phase III trial at a time (two are required for registration).  They have now completed both trials. Tadezolid now has a partner in Bayer. Trius was, with all this, able to maintain a discovery effort and now has drugs in the preclinical phase of development.

Cempra is a biotech with two products in clinical development.  Solithromycin is a compound for the treatment of community-acquired pneumonia so far only available in oral form.  It is active against resistant pathogens and so far looks quite safe. Taksta is fusidic acid – an antibiotic that is marketed in every country in the world except the US and is used primarily for skin and bone infections. Like Trius, Cempra has been unable to partner either product.  And, like Trius, Cempra was forced to shave their IPO asking price – this time from $11-13 down to $6 per share.  They ultimately raised $48 million.  But they will have to go to the after-market, their investors and may have to prioritize which trials they do when in order to make it to market with their first product.  Nevertheless – they are on their way and at least one, if not both, of these antibiotics may ultimately find their way to patients and physicians around the world.

Finally, there is Durata.  I love telling this story.  George Horner was the CEO of Vicuron, a biotech that was acquired by Pfizer for $1.9 billion!  Pfizer acquired two products from vicuron one of which was dalbavancin for the treatment of skin infections.  Dalbavancin’s differentiating feature was that it could be given once a week instead of daily. But the trial package submitted to the FDA was not satisfactory to the agency and Pfizer halted development.  George Horner offered to take the asset off the hands of Pfizer and complete development.  Thus Durata was formed and is back in George’s hands (or at least sort of).  Again – Durata was apparently unable to partner dalbavancin and decided to go to the public markets. Like everyone else, they had to take a bit of a haircut but still raised $68 million.  Dalbavancin is now in phase III trials and headed to market.  Durata, with a revenue stream, may then be able to in-license other products to expand their hospital presence. 

So – PhRMA – get out of the way!  These small companies can afford to market niche products and accept lower returns than the giant conglomerates that are PhRMA today. They can bring needed antibiotics to market and, in my view, they can frequently do it faster and smarter than the large, bureaucratic behemoths of PhRMA.

  

Antibiotics in the News

The NIH recently reported  an outbreak at the NIH hospitals where 11 patients died with infection caused by a KPC carbapenemase producing Klebsiella resistant to virtually all antibiotics.  The outbreak was finally uncovered by DNA sequencing of all Klebsiella strains isolated either as part of the infection or from patients who were just carriers.  This was an enormous effort but it did allow physicians and epidemiologists at the hospital to track the infection to help stem its spread. The story was picked up by several news outlets after its publication last week. This in turn led to the inevitable question – where are the new antibiotics we need to treat these infections? 

This last question led to several subsequent reports including one from the Washington Post and a segment of the Diane Rehm show on NPR public radio. While most of the time on the Diane Rehm show was dedicated to understanding the outbreak, there was a brief segment on exploring where the new antibiotics are or are not. I was interviewed along with Ed Cox.  I tried to make points around the difficulties with discovering new antibiotics, with the marketplace, with industry consolidation and with companies just dropping out of antibiotic R&D altogether.  But I only got to 2-3 of these.  Ed pointed out how the FDA is looking at accelerated and higher risk pathways for new products for these very resistant infections.  I know that Ed also understands that we have to have feasible pathways for traditional development as well – but he didn’t get a chance to go there either.

At the same time, a Financial Times article highlighted how many pharmaceutical companies are negotiating their trial designs for registration of antibiotics for the market in Europe putting the FDA in second place. This emphasizes the risk that the US is running. If trial designs are negotiated in Europe where the development pathway for antibiotics remains reasonable and feasible (see my last blog on this), the US will be left in a take it or leave it position when these trials are completed.  None of us want to be in that position.  This is such a turnaround from the 1990s when EU was the conservative and more difficult regulatory agency and the FDA was more approachable and tried to make sure trials were feasible. But EU never got to the point where the FDA is now – requiring infeasible trials with endpoints that many physicians believe are clinically irrelevant and that I think are unnecessary. 

Hopefully the FDA will act quickly to provide feasible and reasonable trial design paradigms for antibiotic approval here in the US.  The fastest way for the FDA to accomplish this would be to rescind all previous guidance (again) and to harmonize with EU.  Then they can slowly evolve away from that position if needed.  But this strategy would give the industry, patients and physicians an immediate pathway forward that would be global.  What is wrong with that idea?  Why can’t we just do that?  I hope to ask that question at the Brookings Institution in a couple of days. 

Fluoroquinolones - More Toxic than Ketek?

An article just published in the Canadian Medical Association Journal suggests that, at least among patients older than 65 years of age, serious liver toxicity occurs at a rate of 7.98-8.62 per 100,000 patients treated with levofloxacin and moxifloxacin respectively compared with 6.44 per 100,000 for cefuroxime, a B-lactam usually considered to be safe.  But clarithromycin, a macrolide,  a class known to be associated with rare toxic liver reactions, had a rate of 3.95 per 100,000 patients treated in this large Canadian study.  Of course these rates are low overall – about 10 fold lower than the rates of fatal aplastic anemia we used to see with chloramphenicol (for those of you who remember back that far). 

But more fascinating to me is that the rates of serious liver toxicity associated with these fluoroquinolones are all higher by several fold than the rate estimated for  telithromycin (Ketek) liver toxicity.  There the rates were calculated (this link requires a subscription or payment) to be about .5-1 in 100,00 patients treated.   You remember Ketek – the scandal that resulted in the FDA virtually halting antibiotic development in the US (at least in most indications).  I should note that the methods used in the fluoroquinolone study and that used for the FDA studies are not the same.  Nevertheless, these data support the contention that Ketek was no more toxic than many other antibiotics already approved for indications like sinusitis, bronchitis and otitis.  But approval for use in these indications was withdrawn for Ketek – but not for any of the generic antibiotics or even any of the other branded antibiotics like levofloxacin even though some were as toxic as Ketek.  What will now happen to levofloxacin and moxifloxacin?  My guess – nothing – not even relabeling.  Ketek was just in the wrong place at the wrong time and served as a focal point for congressional anger and frustration with what they apparently saw as a flawed antibiotic development process in the US.  Of course, what this led us to is a paralyzed development process for antibiotics in the US that the FDA now says has to be entirely rebooted.  I think Ketek was good in a way for making us examine some of the principles upon which our process is based.  But Ketek also engendered action on the part of regulators without consideration for the consequences.  We are all now paying for these decisions in antibiotic R&D that has shrunk and continues to shrink based on PhRMA’s correct view of the increased regulatory risk (in the US) in spite of rising levels of resistance and increasing numbers of untreatable infections in the US and abroad.  This is a price that we will continue to pay with interest for several years.

Should we withdraw our withdrawal of Ketek? 

Rebooting Hospital Acquired Pneumonia at FDA.

As I mentioned in my last blog, I was recently invited to participate in another meeting with the FDA at the Brookings Institution.  At the last meeting (summarized in a previous blog) Janet Woodcock made the extraordinary admission that the FDA would have to reboot in order to get antibiotic development out of the cellar in the US. 

In this installment, I would like to explore a feasible way forward for hospital acquired and ventilator associated pneumonia.  The FDA guidance for these indications currently suggests designs where the endpoint is mortality and where patients are precluded from receiving prior antibiotics.  These designs have been discussed several times in this blog and are completely infeasible and in many ways not at all real world (over 80% of ICU patients receive antibiotics for e.g.).

Ventilator-associated pneumonia is a particularly problematic indication because of great controversy around diagnostic accuracy and the fact that the disease incidence is shrinking making these patients difficult to find for enrollment in clinical trials.  Adding to the difficulty are US rules suggesting that nosocomial infections might not be reimbursed by Medicare that, in turn, provide a disincentive to actually make an official diagnosis in the chart of hospital-acquired pneumonia.

Many studies suggest that antibiotics for this indication have a treatment effect of 40-60%. When looking at mortality, but more importantly for our purposes, even when looking at clinical outcome via pharmcometrics these numbers hold up. In spite of this, the FDA has proposed a 10% non-inferiority margin within the microbiologically documented population and the EMA proposes a 12.5% margin. The patient numbers required by these margins, even when looking at clinical outcome as an endpoint, may be difficult to achieve today. But the treatment effect numbers suggest that in a clinical trial setting, we can think about non-inferiority margins of 15-20% that still retain at least 50% of the treatment effect. This range of margin would almost certainly bring these trials within the range of feasible patient numbers.

So here is a proposed design with trial numbers that might be required (note that for a combined HAP/VAP trial at least 30% of patients would be required to have VAP).

Patient population.

Patients would be allowed up to 24 hours of prior antibiotic within 72 hours of enrollment in the trail (as per EMA). Patients who had failed prior therapy (predefined in protocol) would be allowed to enroll regardless of the time course of the prior failing antibiotic.

Endpoint - clinical response at test of cure. 

Analysis population – ITT and modified ITT (per protocol).

Non-inferiority margin – 17%.  For a trial with a 60% treatment success rate, 90% power  and 70% evaluability rate, 500 patients would be required per trial or 1000 for two trials.

Option for a single trial – using support from a previous trial in severely ill (PORT III-IV) trial in community acquired pneumonia, a single trial in HAP/VAP would suffice for approval. For a 17% NI margin as noted above but at 80% power, the trial population would be 750 patients total.

This proposal harmonizes, to a large extent, the FDA and EMA proposed addendum.  I have increased the non-inferiority margin above that suggested by EMA to account for both the very large treatment effect of antibiotics for this indication including that seen for an endpoint of clinical outcome, and to allow for increased feasibility at a time when the disease incidence and therefore patient availability are decreasing. 

Rebooting Pneumonia at the FDA

I was recently invited to participate in another meeting with the FDA at the Brookings Institution.  At the last meeting (summarized in a previous blog) Janet Woodcock made the extraordinary admission that the FDA would have to reboot in order to get antibiotic development out of the cellar in the US.  Helen Boucher pointed out that this reboot would have to encompass all aspects of anti-infective development – both the traditional development pathways where FDA guidance has made development infeasible as well as identifying new pathways forward to address areas of key unmet needs for new antibiotics. Both Janet and Helen are right!  I am hoping that this reboot will be a major topic of discussion at the upcoming meeting. 

With that in mind, I have recently been considering what a reboot of the guidance for community acquired pneumonia trials could look like.  Here are my thoughts.

First, rather than jumping into endpoints like symptomatic response at day 4 as the FNIH and FDA have suggested, lets step back.  The justification for this entire step is to align modern trials with 80-year-old placebo-controlled trials to justify the NI margin.  Of course, even with a staggering 40% treatment effect, we end up with a margin of just 10% - how did that happen?  FDA magical discounting – that’s how.  But the clinically relevant endpoint is cure at test of cure – when the patient is sent home needing no further therapy for their pneumonia.  That’s the endpoint that patients and physicians care about – not whether they are feeling better on day 4 or not.  What are the data that these two endpoints, for any given patient, are well aligned?  Lets look at a pharmacometric analysis of the treatment of pneumonia in patients stratified by PORT score and determine the treatment effect in a modern context. 

Then there is the issue of prior antibiotics.  The FDA says none. This is based on the famous daptomycin trial.  Daptomycin failed in pneumonia because it is inactivated by surfactant.  Prior antibiotics masked, but did not completely hide, the inferiority of daptomycin to ceftriaxone in these trials.  The FDA is putting all their eggs in the daptomycin basket with no confirmatory data.  In fact, the data from the ceftaroline trials might argue that patients with getting prior antibiotics are sicker and do less well overall than those not receiving them. 

But prohibiting all prior antibiotics makes trials potentially unethical – how can you delay antibiotics for very sick patients when you know this might increase their risk of mortality? It also makes it impossible to enroll American patients in trials – but these are the very patients the FDA wants us to study.  

Europe (EMA) says prior antibiotics are OK – but wants sponsors to try and limit this to a single dose and they want to explore the effect of the prior antibiotic on the clinical response at the endpoint.  Great – FDA – harmonize with Europe! Then lets explore (that is - it is not a review issue!) the effect of prior antibiotics in several trials and see where the data lead us.

So here is a potential design for the FDA (and EMA too) –

CABP patients as defined (EMA addendum)

The primary endpoint is clinical outcome at test of cure.  The NI margin is 10% for the ITT population. One could add the identical endpoint for the microbiologically documented population with an NI margin of 15% with the population pooled over two trials as has been recently suggested by the FDA.

A secondary endpoint could be the clinical outcome in those patients not receiving prior antibiotics with an NI margin of 15%.

Exploratory endpoints could include –

Examine the difference in clinical outcome both at TOC and at the early 4 day endpoint between no prior and prior abx – both in control and test arms. 

Compare the TOC endpoint vs. FNIH early endpoint for within patient and overall consistency. 

These outcomes can be explored within the ITT and the microbiological documented populations.

This proposal recognizes the lack of clinical relevance for the early endpoints in community acquired pneumonia.  It also deals with the infeasibility of prohibiting all prior antibiotics while exploring the effects of prior antibiotics on non-inferiority studies in this indication.  The proposal allows for the development of oral-only antibiotics by allowing the study of less severely ill patients for those drugs. Currently, the development of antibiotics available only by the oral route is not possible at the FDA.   And the proposal harmonizes the EMA and FDA guidances overall.

I hope we will be able to discuss this proposal and others with the agency at the Brookings meeting in August.