David Livermore on EUCAST and Breakpoints

David Livermore University of East Anglia

As the EU’s grand confection – a single currency for diverging economies– draws towards its denouement, it comes as some relief to point to the success of a less ambitious but more successful harmonisation: EUCAST. This has brought useful agreement, provided a little employment and may even spread a healthy contagion beyond Europe’s borders… 

Specifically, EUCAST – the European Committee on Antimicrobial Susceptibility Testing has two major achievements to its credit:

First, it has brought a harmonisation of breakpoints across Europe so that single definitions of susceptible, intermediate and resistance are now accepted throughout the continent, whereas previously there were separate national committees with different breakpoints in Norway, Sweden, the UK, France and Germany, whilst most of the southern Europe followed CLSI.   Despite slow incorporation onto certain automated testing systems, EUCAST values are increasingly adopted for day-to-day laboratory testing

Second, and in contrast to the protracted territorial squabble between CLSI and the FDA, EUCAST has reached a Memorandum of Understanding with the European Medicines Agency – the drug regulator – and serves as their advisor on breakpoints.  Decisions on indications and pathogen spectrum remain firmly with the Agency.  This agreement has functioned for 5 years, through the licensing of tigecycline, daptomycin and telavancin, with ceftaroline pending.   It precludes the unfortunate situation, not unknown across the Atlantic, where pharmaceutical company X, with a generous breakpoint from the FDA, omits to talk with the CLSI, for fear of a lower value. It also prevents the problem where device manufacturer Y is obliged to comply with FDA breakpoints to have its product licensed, whilst its customers demand a panel that tests to CLSI’s criteria, which are becoming more conservative than the FDA’s.

This article isn’t to detail the organisational structure of EUCAST, which can be found on http://www.eucast.org/organization.   Briefly, it operates with funding from the European Centres for Disease Control (ECDC) and the European Society for Clinical Microbiology and Infectious Diseases (ESCMID). Its Steering Committee, which makes the primary decisions on breakpoints, comprises representatives from European national breakpoint committees whilst its General Committee, which reviews proposals, has wider representation from across EU and non-EU Europe, also Russia, Turkey and Australia. Representatives of pharmaceutical and device manufacturers are invited to present data for review by the Steering Committee when they seek to license new agents or indications, but they do not sit on EUCAST’s decision-making committees.

Breakpoint decisions are largely predicated on pharmacodynamics, as increasingly are those of the CLSI whilst the FDA puts more weight on clinical outcomes in relation to MIC.  These pharmacodynamic breakpoints may be adjusted by a dilution up or down, to ensure that they do not slice through the MIC distribution for wild-type isolates of major species groups. They may also be adjusted on the basis of clinical evidence and experience. A category of ‘Insufficient evidence’ is noted for drugs that might be of interest against a pathogen but where clinical data are scant (e.g. daptomycin vs. enterococci), whilst low non-species-specific breakpoints are included for obscure species. Last, an epidemiological cut off (‘ECOFF’) is specified, defining the upper edge of the normal distribution of MICs for isolates without any diminution of susceptibility.  This corresponds to what others call a biological breakpoint, though EUCAST is at pains to avoid the term. ‘Intermediate’ is taken as ‘may respond at high dose’ and, for some marginal agents (e.g. macrolides against haemophili or ciprofloxacin against pneumococci) nearly all isolates count as intermediate.  This differs somewhat from CLSI, where intermediate is viewed more as a buffer to minimise errors between MIC and disc categorisations.   Once assigned – and ratified by EMA for agents  – EUCAST publishes breakpoints on its website, along with a brief rationale, a summary of which also appears in Clinical Microbiology and Infection as ESCMID’s journal of record.   Values are not set in stone (as with the FDA) and can be reviewed at the request of the manufacturer, professional societies or the regulator. There is a low bar to initiating a review, but strong justification is needed for a change.

Is the system perfect? Personally – and this comment applies as much to CLSI – I believe that the pendulum in defining resistance has swung too far from mechanisms towards pharmacodynamics, with excessive optimism in the precision of MICs.  Second, I find it incongruous that EUCAST breakpoints are allowed to split populations with common modes of resistance despite a determination not to split wild type distributions. Third, there is the unfortunate ‘loss’ (perhaps to be rectified in the future!) of the higher breakpoints used previously in the UK and elsewhere for urinary infections; as a result laboratories are suddenly finding 40% resistance to amoxicillin-clavulanate in urinary E. coli whereas they previously found 5-10%---- with no evidence that the extra ‘resistant’ isolates are associated with poor outcomes.  

But, these are lesser cavils; overall, the EUCAST system is a major improvement over the country-specific breakpoints that went before.   These never had much logic when bacteria and pharmacokinetics didn’t respect political boundaries (different currencies for countries with different economic cultures and traditions is quite another matter, though…).   Which begs the question as to whether EUCAST and CLSI breakpoints too will coalesce, especially as both organisations base their values primarily on pharmacodynamics. In the short term the answer seems to be ‘no’. Although both have recently reviewed cephalosporin and carbapenem breakpoints they’ve achieved answers a dilution or two apart.  What’s more, if both committees ever do agree completely, there will be an embarrassing little problem, for CLSI’s income derives from selling its Standards, whilst EUCAST’s guidance is available free gratis, over the internet.

Generic Antibiotics - Which Way is Up?

In a number of previous blogs, I have noted the apparently hypocritical and inconsistent approach taken by the FDA regarding old approvals of generic antibiotics.  Recently, the FDA was awakened from its long sleep by an article in the New England Journal of Medicine on an old macrolide antibiotic, azithromycin.  In the study, the authors show that there is an elevated, but very small risk of cardiac arrhythmias from taking azithromycin – a potential already recognized by the FDA and already noted in all labeling for macrolide antibiotics.  The FDA responded to the article by noting its intention to relabel azithromycin and other macrolide antibiotics.  But at the same time, the FDA reasserts its approval of use of azithromycin and other macrolide antibiotics for

·      Acute bacterial exacerbations of chronic bronchitis

·      Acute bacterial sinusitis

·      Uncomplicated skin infections.

But – STOP THE PRESSES!  Uncomplicated skin infection no longer exists as an indication for the FDA.  The so called mild respiratory infections now require placebo-controlled trials to prove benefit over risk – while here the FDA is noting increased risk but they already state that for these mild respiratory infections – no placebo-controlled trial = no proof of benefit.  Therefore, these indications should logically now be withdrawn for all macrolide antibiotics.  And here is the perfect opportunity – an example of potentially increased risk.   What is the FDA doing?

Of course the FDA is completely and totally aware of the apparent paradox in their approach to generics – but they refuse to do anything.  There is nothing new about this.  The only thing new here is the reminder that, in fact, the reality is that they will not touch generics in any meaningful way while, at the same time, they restrict entry of new antibiotics to indications that physicians and patients still find useful even if the FDA does not (acute otitis media – great entry into pediatrics; acute bacterial sinusitis and acute bacterial exacerbations of COPD).  Without some drugs approved to treat these infections – all use – and there is a ton of it – would be off label.  We wouldn’t want that (or would we?).

By the way – in this case, the FDA in the US and the EMA in Europe are on the same page – I just think it’s the wrong page.

If you are confused by the approach of the regulatory agencies to generic antibiotics – welcome to my world. 

Antibiotic Investment - Alice in Wonderland!

I spend a good deal of time talking with investors and even more time with pharmaceutical companies large and small and with the regulatory agencies.  I am beginning to notice a trend among the three groups of clients that I would like to share.

In the antibiotics world, there seem to be two general classes of investor.  There are those who want to invest in “early” stage companies – usually preclinical through phase I – and those interested in “late” stage opportunities – those that are phase III ready or even later.  Everything in between is up for grabs between the two groups and depends on the size of the fund, experience of investors and, in fact, the financial situation of the opportunity.

But I am always confused by all this.  Take Novexel for example.  Novexel was acquired by Astra-Zeneca for up to $500MM prior to completion of its phase II trials – so the acquisition was based mainly on preclinical  and phase I data.  There is still the possibility for such acquisitions to occur given the reliability of these early data.  In fact, Novexel raised a late round of funding during the phase II trials to position itself to be ready to go to phase III but also to strengthen its negotiating position during potential M&A discussions. Two new investors came in at this point and did very well since the AZ buyout occurred within about a year to their investment.  Is Novexel an example of something between early and late?

The world is now about to completely change.  It is clear, at least conceptually, that there will be a regulatory pathway for the development of antibiotics for “unmet” medical needs. For me, this means the treatment of patients with serious infections caused by pathogens resistant to reliable efficacious therapy – so called extensively-resistant or pan-resistant strains of Gram-negative bacilli. The development pathways being discussed would allow for rapid testing of a small number of such patients leading to some sort of approval with a restricted label.  At the same time, companies would have to demand a high price for such products since the target population will be small and therefore the margin for each course of therapy would have to be high.  Have we seen this approach before?  Of course – think oncology. But in the case of antibiotics – we can actually save lives whereas for oncology products we mainly prolong life by some rather small amount of time.

Every company and both the EMA and FDA are actively engaged in planning for the development of new antibiotics along these lines. Thus, this year, we will see successful negotiations on such trial designs in Europe certainly – but I am optimistic that we will see this at the FDA as well.

When I speak to investors, they seem completely unaware of this paradigm shift in the antibiotic world.  They are still thinking about traditional “early” and “late” stage development.  And, for some opportunities, it is clear that has not changed.  But for others, the world is topsy-turvy.  Early is late!  So – investors – the antibiotic waters are warming quickly.  Time to get wet!  And not only investors – all you pharma companies that got out of antibiotics to jump into oncology – take another look!  Antibiotics are oncology only better!  BMS, Roche-Genentech, Lilly, Abbott, J&J, Novartis, Merck, - I’m talking to you!  Pfizer – I think its not a good time to speak to you . . .

Upcoming Guest Blogs – David Livermore on Breakpoints at EUCAST and David Payne on Explaining the Innovative Medicines Initiative.  Stay tuned. 

Antibiotic News

First, I have to apologize for being so long in contributing a blog since my last one.  I have a couple of excuses.  I’ve been busy.  The antibiotic news lately has been scant and much of it I don’t even understand as noted below.

The GAIN act passed both the senate and the house in the US over the past couple of weeks. It was attached to the PDUFA reauthorization legislation that allows the FDA to continue to charge companies more and more money to carry out efficient reviews of New Drug Applications among other tasks. PDUFA was highly sought by both FDA and the pharmaceutical industry – so – win-win.  GAIN, however, to my eyes, is more controversial.  The main piece of GAIN that has attracted attention is the “incentive” for industry to continue or restart antibiotic R&D by extending the patent exclusivity of antibiotics active against resistant pathogens.  But this incentive, for the most part, isn’t. The extension seems designed only to help those companies, mainly biotech and perhaps some academic groups, who are developing drugs with very short patent lives.  Otherwise, the benefit of the exclusivity extension is completely gone when discounted for inflation over the years of exclusivity of most newly marketed antibiotics.  So – as an incentive for large pharmaceutical companies – I just don’t get it. And we need the large pharmaceutical companies to get into the game so that they can help fund biotech and academia so that phase III trials can be accomplished.  Luckily, the markets may do that for us – thus GAIN becomes, as far as incentives go, a very limited step forward.

GAIN might accomplish two things.  It allows congress folks like Dick Blumenthal to crow about how they are helping provide needed new antibiotics for Americans without spending government money.  GAIN also has a vague clause that states that the FDA has to provide new guidance for antibiotic development.  This might actually provide the FDA cover from congress itself as it seeks new, more rapid but also more risky development pathways for antibiotics that target unmet medical needs like activity against superbugs.

Logo (Photo credit: Wikipedia)

In another bit of news last week, the Innovative Medicines Initiative announced a new public private partnership to foster R&D for new antibiotics.  They are targeting the development of new clinical trial designs for antibiotics for unmet medical needs and new discovery pathways for antibiotics active against Gram-negative pathogens.  This is all well and good and we all welcome this effort.  But, as always, the devil is in the details.   And in spite of trying to carefully study and understand the details as presented in all the documents on the IMI website, I find I am completely confused.  It looks like all the large funding blocks have already been committed to the two largest European PhARMA (EFPIA) contributors, GSK and AZ. So, if another company wanted sufficient funding to support phase III trials, I am not sure it would be there in any case.  It also looks like the partnership is designed to partner companies or academics with EFPIA members and that opportunities for R&D outside the EFPIA group is limited. It looks like I am not the only one with questions on this front. Finally, it looks like the research awards will be similar to those done within the context of the European Framework grants – NO!  NOT THAT!!!  Anything but that!!!

So – consider this a plea for clarity.  Can someone from IMI explain all this?

In another piece of news closer to my heart, Nabriva announced a deal with Forest. Hopefully, their novel IV/oral Gram-positive and RTI compound active against resistant pathogens will ultimately see the light of day.

Related articles

• The Investor's Guide to the New PDUFA (dailyfinance.com)

Here They Come!

It looks like the European and (with any luck) the US regulators will just about make it in time . . .maybe.  

An interesting news article just popped up from Edmonton, Canada where officials are investigating an outbreak of  Gram negative bacterial infections resistant to all of our most effective antibiotics.  These bacteria were introduced by a patient who had received medical care abroad, but who was not placed in isolation upon admission to the hospital in Edmonton.  The patient apparently died of her infection. Several other patients subsequently became infected. An investigation is ongoing and it made the local press and television.

Another  article  also caught my eye.  Dr. Huttner and colleagues examined the use of certain so-called last resort antibiotics between 2005 and 2010 within the 152 hospital VA system in the US.  They clearly showed an increasing use of polymyxin (up about 30%) and tigecycline (up over 5 fold) during the years of study.  Polymyxin is an antibiotic of questionable efficacy and is associated with frequent kidney and nerve toxicities.  Tigecycline (dear to my heart) is limited in the dose that can be used because of gastrointestinal intolerance and it has been shown to work poorly at recommended doses in very seriously ill intensive care unit patients. Nevertheless, both these antibiotics are on the upswing.  Why – because more and more patients are being infected by highly resistant Gram-negative pathogens – similar to those causing the outbreak that caught the news in Edmonton Canada.  For these infections, there are no other choices. 

There is hope.  There are antibiotics in the late stage pipeline that will address at least some of these pathogens – but unfortunately not all.  The question is – how quickly can they be brought forward?  That is the question that the regulators must decide and decide now.  And what about those pathogens for which there is little in the current late stage antibiotic pipeline?  There are some at earlier stages of development that might be useful.  How quickly can these be tested in infected patients?  Here again – regulators and sponsors will have to get together and move things along quickly. But the time for infeasible trial designs and a long FDA reboot process is over.  The time to act is NOW!

FDA REBOOT!!

In nothing less than a remarkable presentation to the Brookings Institution yesterday, Janet Woodcock, Director of CDER at FDA, stated that the FDA will reboot its approach to antibacterial development. Rachel Sherman, the Associate Director for Medical Policy at FDA remarked that Dr. Woodcock had said to her FDA colleagues that she would not preside over the demise of antibiotics – not on her watch! With these words, the non-FDA audience in the room – and I suspect some of the FDA audience both in the room and on the phones – were flabbergasted. During the last 15 years of interacting with the agency, this was the most positive, even exhilarating set of statements I have ever heard regarding antibacterial development from the FDA.  We have come a long way from the day when Bob Temple announced to a group from PhRMA back around 2000 that infectious diseases developers had been “getting away with murder for years.” 

Dr. Woodcock, in her presentation, reviewed how we had arrived at this point.  She emphasized the role of telethromycin (Ketek).  Safety concerns on a drug with a controversial and complicated history that was finally approved led to demands for “more rigor” in the clinical investigation of antibiotics – specifically around the non-inferiority trials that are always used as pivotal studies to support marketing approval for these drugs.  In their re-examination of non-inferiority trial designs, their search for justification for the margins used for these studies combined with concerns over the objectivity of the usual outcome measure – “cure” – led to tighter margins requiring higher patient numbers and new outcome measures. The new trial designs proposed in draft guidance were, mostly, simply infeasible.

In another surprising statement, Dr. Woodcock acknowledged in a way the loss of trust in the agency.  She stated that this reboot would not affect the FDA’s current agreements with sponsors on the design of ongoing trials.

What does this proposed reboot look like?  It is hard to say from the conversation during the daylong meeting.  But it is clear that the agency wants to focus on areas of unmet need – those patients where current therapy is inadequate in terms of efficacy or where efficacy is at least questionable and where toxicity may be an important consideration (e.g. colistin).  Dr. Woodcock mentioned the possibility of pathogen-specific studies instead of indication-specific ones.  She agreed that for these patients a tradeoff in certainty around the data vs. potentially efficacious and less toxic therapy would be worthwhile. The words “historical controls,” “natural history studies,” “Bayesian designs” and “orphan drug status” were all used.  Clearly, for these patients, everything is on the table for discussion.

At the same time, the FDA clearly would like to link these approvals with a label including a limitation of use.  It is here that things get dicey since it is not clear that they would have the authority to actually enforce such a label. This, I think, is the basis of their desire for the LPAD legislation now being considered in Congress. On the other hand, if such a drug were approved for such a narrow indication that only a few patients would be treated with the drug, the high price and perhaps even the spectrum of the drug would automatically enforce restricted use. This could easily be confirmed through a use registry. 

It also seemed to me that the agency was committing to reboot its entire approach to guidance for the more usual indications such as hospital acquired and community acquired pneumonia and others. The importance of this was emphasized by a number of other speakers during the meeting – notably Helen Boucher of the Infectious Diseases Society of America. To reboot industry, we need to have a way for all new antibiotics to get to the market – not just those that can treat very small populations of patients with specific types of resistant infections.  We need an armamentarium of antibiotics for the future since resistance is hard to predict and many of our antibiotics have been around for a long time and resistance to most is already increasing.

As in all things in regulated industry – the devil is in the details. And the details need to be worked out BEFORE guidance is released this time.  Towards that end, the FDA understands the need for competent external advice outside the usual advisory committee mechanism.  Their approach to getting this advice should be to use small FDA teams equipped with specific questions meeting with small groups of advisors (the Brookings meeting was too large to really get anything concrete done) in a non-formal setting.  The Brookings meeting was a good start to identifying the specific areas of inquiry.

For industry - For those companies planning to negotiate designs in Europe first – I think the FDA will be more open now.  Consider a simultaneous advice session.  In general, for those companies reconsidering antibiotic R&D – I believe that the US will be open for business – when I am not exactly sure.  The water is at least warming – but its not summer yet.

Culture Wars and Antibiotics

Two weeks ago, a well conceived article was published in Forbes. It discusses the problem of the lack of productivity of large pharma. The problem is very real.  Just look at the number of patent expirations threatening this industry and the state of their pipelines.  A great example is Pfizer – a company that is shrinking as fast as it can to offset their loss of revenue from Lipitor sales. Another good example is Astra-zeneca – a company that is also fighting loss of market exclusivity with layoffs. Obviously, a better way to deal with the problem is more productivity either from in-house research and development or from external sources. So why is this not happening? 

There are multiple causes for the poor productivity of the pharmaceutical industry overall.  These include scientific issues – its just plain getting harder to find new, safe and effective drugs.  Another contributor is the increasingly stringent and risky regulatory environment affecting products from obesity and diabetes therapies to antibiotics (don’t get me started!). But I think Bruce Booth, in his Forbes piece, has really hit on another underappreciated factor – the increasingly bureaucratic and metrics-driven approach to R&D within the pharmaceutical industry.

At Wyeth at one point, the Discovery group was asked to produce 15 clinical candidates per year (IND ready).  Did this increase their late stage pipeline? What do you think?  What it did, probably, was decrease the quality and increase the risk of the compounds entering phase I development. As described by Bruce Booth, Wyeth R&D was run by committee(s).  But each committee member had their own particular agenda.  Each functional area had their own constraints and concerns – work load, not wanting to be blamed for project failure, etc. So they would try and either block a project or at least make their reticence known to the committee so they could at least say, “I told you so” later.  In the industry, it is always easier to say NO at the beginning than it is to take a risk and support a potentially costly project that, 80% of the time, will fail anyway.

When you layer committees one on top of the other – business development, safety, R&D, the problems compound more often than they are solved. 

Bruce Booth’s solution is similar to one I have been pushing.  He would create geographically localized therapeutic area units with all the critical support required (I presume this is what he means) like toxicology, manufacturing, clinical development, regulatory, etc. He suggests giving them five years of budget and then leaving them alone.  The therapeutic areas would then report directly to the “top” (whatever that is) rather than to a committee. My suggestion has always been to shrink the companies altogether by giving each therapeutic area its own P&L.  That might be achieved by providing a budget (instead of profits) from the mother company or it might be (better) by allowing them to live within their P&L based on profits from revenues derived from marketed products. Essentially, what I am suggesting is taking the Centers of Excellence in Drug Discovery of Glaxo one giant step further towards independence from the leaky, unstable giant mother ship.  

I have said in multiple previous blogs that this would be a great strategy for improving the situation of antibiotics within the pharmaceutical industry.