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. 

Antibiotic Uppers

I was inspired this week by a few news articles and blogs that appeared recently.  One in particular was a piece by Maryn McKenna, author of Superbug.  She writes about the frustration of activists dealing with political and social inertia. I have spent the last several years discussing the perfect storm of factors working against the discovery and development of new antibiotics needed in our fight against antibiotic-resistant pathogens. It is fair to say that the last 10 years have been mostly downers in this regard.  So I can certainly empathize with the difficulties of trying to move boulders uphill. 

But I also have my own moments of optimism (perhaps misguided) – like now.  Over the last year we have seen the European regulatory agency, EMA, leading the way to the feasible and rational design of clinical trials to support the approval of new antibiotics.  The FDA has said they will reboot their entire process (which probably cannot get worse) (famous last words).  Since regulatory reform was one of the key potentially reversible roadblocks to the development of new antibiotics, I believe these developments are very positive and I am becoming optimistic about the future of antibiotics.

We have recently seen very significant government investments in antibiotic R&D including funding through BARDA to cover at least a portion of the expensive phase III trials to get antibiotics to market approval. GSK was awarded  nearly $100 million in support of its ‘052 antibiotic active against many resistant pathogens  (unfortunately, those trials have now been halted).  Tetraphase was awarded up to $67 million in support of TP-434 (see below).  The Innovative Medicines Initiative in Europe has also just announced similar important investments in antibiotic R&D (see the last blog). These very important investments provide additional, clear incentives for the continued discovery and development of new antibiotics.

Another source of optimism to me is the continued rapid growth in antibiotic sales in the emerging markets. Antibiotic sales in these markets have already outpaced the US market by over 30% and are rapidly approaching the point where they will be equal to Europe and the US combined.   These markets will become more and more attractive to companies who are poised to exploit them.  This indicates that more companies will re-enter the antibiotic R&D arena as Sanofi-
Aventis has recently done.  To me, this makes the patent extension included in the GAIN act (recently signed into law by President Obama) totally irrelevant except for those small companies who are developing products with otherwise short patent lives.

We now have a number of antibiotics that will be effective against at least some of the most fearsome resistant Gram-negative pathogens in the late stage pipeline.  These include ceftazidime-avibactam from Astra-Zeneca which will be active against KPC-producing organisms resistant to carbapenems and virtually all other antibiotics and ceftolozane from Cubist – a drug active against many highly resistant Pseudomonas strains. Tetraphase should soon be completing their phase II study of TP-434, a tetracycline active against many multiply-resistant Gram negative pathogens including Acinetobacter and which is available orally as well as IV. There are other antibiotics about to enter late stage development with complementary activity against other multiply-resistant pathogens as well. 

So, I am now in one of my more optimistic moods regarding the future of antibiotic R&D.  But of course this all depends on; a successful FDA reboot; a large PhRMA industry that sees an advantage in rising antibiotic sales in emerging economies in spite of their continued need to slash and burn to make up for patent losses; and perhaps, even on welcoming public markets for small biotechs desiring to go it alone.  So, I guess I am a somewhat cynical optimist after all.

Innovative Medicines Initiative Explained

GUEST BLOGGERS - DAVID PAYNE AND KIM BROWN of GSK. 

When David sent us an email with ‘does anybody understand IMI ?’ we felt we needed to put this opportunity into better perspective. The New Drugs 4 Bad Bugs (ND4BB) project (6th Call for proposals) came about from high level discussions with the European Commission on how they wanted to do something concrete to address antibiotic resistance  (Press release).  The conclusions of these discussions led us to the Innovative Medicines Initiative (IMI homepage ) as the most immediately available source of funding.  IMI was set up in 2008 to support collaborative research projects between networks of industrial (EFPIA goal and membership) and academic experts to reduce drug discovery bottlenecks, and boost pharmaceutical innovation within Europe.  The effort applied to the project by the EFPIA companies is then matched with funding from IMI; this funding from IMI goes directly to European academics, institutions or small medium enterprises (SME) that have organized themselves into a consortium to address the goals of a research project.  All the EFPIA companies had the opportunity to participate in ND4BB.  The current topic text was the result of discussions amongst those EFPIA companies interested in participating (listed below), and developed in consultation with (and with input from) other stakeholders, such as the European Commission, IMI’s Scientific Committee, and IMI’s States Representatives Group.   

The first project (Topic 1) is focused on creating and enabling an antibiotic clinical trial network for evaluating the clinical efficacy and safety of novel antibacterials, initially from AZ and GSK.  In addition,  Topic 1 has opportunities for  institutions that have not previously run clinical trials to receive training to become compliant clinical trial sites for the future. Sites of particular interest are those in regions of high levels of resistance, or where a specific resistance mechanism predominates. This will create a footprint of compliant clinical trial sites that can be adapted to optimally evaluate new antibacterials against infections resistant to current standard of care antibacterials.

The second project (Topic 2) is focused on improving our understanding of how to design agents that will optimally penetrate Gram negative pathogens – we see the lack of rational approaches to this problem as a major barrier to creating a pipeline of Gram negative antibacterials . Overall, there is €16M available for a consortium of European academics to tackle this problem and EFPIA members will be providing tool compounds and additional support for the various projects. We encourage broad and innovative thinking to address the goals of this project.

So how does the funding work ?  Under IMI individuals can not apply for funding, applications have to be made as a consortium. For example, a consortium of clinical investigators and SMEs with a Principal Investigator need to apply to run the clinical trials in the proposal. Researchers across Europe are encouraged to connect with other interested parties to initiate a consortium and/or communicate their interests and expertise through the IMI Partnering Tool (Link to Partner Search) which can also be the genesis of a consortium. The optimal consortium is then selected by an expert panel consisting of independent academics appointed by IMI.  To ensure a fair application process, EFPIA representatives cannot directly communicate with prospective applicants, so any specific enquires should be emailed to the IMI offices (INFODESK@imi.europa.eu).

Essentially the way this will work for clinical trials is that IMI will provide funding for the European clinical trial sites and the sponsoring EFPIA company will fund an equal share of the cost.  As antibacterial clinical trials have never been run by such a consortium, the risks of added complexity could extend timelines. However, by initiating this project with their compounds, GSK and AZ hope to build confidence around the approach, create an established network of compliant clinical trials sites for future use, and establish Europe as a center of excellence for antibacterial clinical trials.  Those following David’s blog will appreciate that this type of funding support is key to maintaining and encouraging companies to commit to antibacterial R&D.

Finally, a major theme of the proposal will be that the EFPIA members and academic groups participating in ND4BB will share information on antibacterial R&D in a way that we have never done before. This will encompass everything from learnings from clinical trials to past experiences of why particular projects or compounds failed. The hope here is that we will increase the overall efficiency of antibacterial R&D and companies will have broader access to potential liabilities associated with different approaches, targets and novel chemical series to better inform their strategies.

The eagerness of the EC and IMI to play a role here is exemplary and this current proposal is an ambitious first step. Additional funding is available (the total amount could be up to €600M) and we are working on additional projects which will be the subject of future ‘Calls’. We hope ND4BB establishes a framework that will attract additional projects/clinical programs and other EFPIA companies to collaboratively participate in a new way of working collaboratively in antibacterial R&D.

GlaxoSmithKine

AstraZeneca

J&J

Basilea

Sanofi  

Europe Leads the Way!

The European Medicines Agency (EMA) has just released their long-awaited addendum to the antibacterial guidance they released late last year.  It is an amazing document compared to the guidance documents released in the last few years by the FDA in the US.  Clearly, this was the work of a very thoughtful group of smart individuals who kept trial feasibility high on the priority list of considerations.  They also worked hard to avoid the FDA trap of justifying non-inferiority margins at the expense of real-world considerations like trial numbers and endpoints.

In general, the EMA addendum uses clinical response at test of cure as their endpoint.  No fuss, no bother.  Their suggested non-inferiority margins for various indications are as follows:

Complicated UTI – 10%

Community-acquired Pneumonia – 10%

Complicated Skin and Skin Structure Infection – 5-10%

Complicated Intra-abdominal Infection – 12.5%

Hospital-Acquired Pneumonia and/or Ventilator Associated Pneumonia – 12.5%

In my view – these trial designs are all quite feasible in terms of patient numbers with two possible exceptions – anything less than a 10% margin (the 5-10% for skin infection) is probably not realistic and 12.5% for HAP/VAP is, in today’s world, is also probably not feasible.  There is even a feasible pathway forward for an oral only antibiotic for community-acquired pneumonia - an option that does not exist at the FDA (at least for now).

The EMA allows for up to 24 hours of prior antibiotic therapy within the 72 hours prior to enrollment.  They recommend that only a single dose be allowed for UTI and CAP patients – but that is still quite a feasible approach and stands in stark contrast to the FDA.   The EMA also suggest that sponsors perform an “exploratory” analysis of patients who received and did not receive antibiotics.  This suggests to me that this will not be a review issue at least for now – but it behooves sponsors to confirm this during their discussions with the EMA.

In another amazing coup – the EMA recognizes the efficacy of antibiotics for Acute Otitis Media in children similar to those studied in two placebo controlled trials as published in the New England Journal last year (see my blog on this).   This means trials (non-inferiority design) for antibiotics can once again be carried out in children with AOM – a situation that was going to be impossible under the requirement for a superiority design.  This is a critical move on the part of EMA because it opens an entry indication for treatment of pediatric infections that has been unavailable since 2003 or so.

Finally, in another startling development presaged by their general antibacterial guidance, the EMA opens the door for various superiority or open enrollment designs for the approval of drugs that target pathogens rarely causing infection where the medical need is high.  This will include antibiotics active against specific pathogens where resistance is a major problem and antibiotics tackling key resistance mechanisms that may still be rare today.  In their addendum, the EMA clearly recognizes the difficulties in carrying out such trials and the inherent risks in approving such therapies, even with a limited label, based on small numbers of treated patients.  But they also recognize the public health risk of the lack of antibiotics to address these highly resistant pathogens and are paving a pathway forward for sponsors to develop these needed products. The EMA notes (as does the FDA actually) that it is up to sponsors to come forward with specific proposals – but this addendum clearly shows that the EMA is open for business and, more importantly, for protecting the health and safety of patients around the world.  The FDA has to reboot their entire approach to achieve what the EMA has already done – and we’re not there yet!

So – the antibiotic waters in Europe are warm!  Come on in!!

Next week – the Innovative Medicines Initiative explained.