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.