David's New Book

Monday, March 13, 2017

Antibiotics - Europe Struggles, Too.

Last week, the European parliament released a resolution on access to medicines in Europe. There is a good deal in the resolution noting the important threat of antibiotic resistance and emphasizing that the problem must be addressed. But while Europe through the European Commission, controls drug regulation through CHMP and the EMA, it has no control over drug pricing and reimbursement.  That is left to individual national authorities. As a result, one might view the resolution through the eyes of European nationalists.  In their view, Europe as an institution is unalterably divided, weak, conflicted and unable to come together to influence policy. While in many areas this is clearly not true, in the case of antibiotics, Europe is reduced to dithering because of this lack of control over the key issue of pricing and reimbursement.  And this comes at a time when we need a unified approach.  To see what I mean, I highly recommend that you try wading through the report yourself. But I’ll try and highlight a few of the key issues for you.

Parliament welcomes the IMI initiatives – a public-private effort.  That’s good because European taxpayers are providing much of the funding for IMI. At this point, IMI is cooperating with BARDA and the Wellcome Trust on projects that fund antibiotic research and development.  IMI seems to have a very diverse funding portfolio where antibiotic research plays a relatively minor role – but every little bit helps.  

The European regulators have been leading lights in our efforts to get feasible pathways to develop needed new antibiotics targeting resistant pathogens (see my blog – towards the end of the page). The parliament recognizes this, but at the same time cautions the regulators to put in place measures to ensure patient safety.  But, of course, the regulators have already done this by providing for post-market reviews and other measures to continually monitor the safety of drugs approved with less or even minimal data. So, what does the parliament’s caution to regulators mean? 

The major issue facing us is one of money.  The purse strings in Europe are still held by the various national authorities. So, in this most important of domains, the parliament attempts to offer advice.  But the advice is, at best, contradictory. On the one hand, parliament notes the threat of antibiotic resistance and the market failure that led us to where we are.  On the other hand, it decries the fact that new drugs are becoming so expensive as to threaten national budgets. Parliament rightly states that cost-benefit and pharmacoeconomics should be used to set prices – tying price to value.  At the same time, they suggest that health technology assessment agencies (like NICE in the UK) be used to guide national negotiating and pricing positions. I’m worried that this will lead to the necessity for clinical superiority studies of all new antibiotics active against resistant pathogens in order for them to achieve the kind of reimbursement that will be necessary to provide companies with a return on investment.  I don’t agree with John Rex’s position that such studies are almost never appropriate.  I do believe that if we are considering them (as for pathogen-specific antibiotics) they are unlikely to be sufficiently powered in clinical trials leading to approval. The studies leading to approval are going to be highly dependent on non-clinical data including both in vitro findings and especially PK/PD in animal models as John discussed in his blog last week. Will HTAs be willing to use the same data as regulators to establish that an antibiotic clearly active against resistant pathogens is superior to the antibiotics to which the organism is resistant or will they demand a non-feasible clinical demonstration of such?

In sum, Europe struggles as does the US, to find a way to provide a meaningful return on investment for companies who invest in the discovery and development of antibiotics that will be sorely needed to stem the tide of resistant infections. In general, the effort to fund the research side of things (led by the US and UK in my view) has been a successful one. Where we all fail is at the end game – paying for a desperately needed new product without which lives would be lost unnecessarily. On both sides of the Atlantic, the issue is swallowing the fact that such products will, inevitably, require an investment that was hitherto unforeseen.

Thursday, March 2, 2017

FDA Workshop on Animal Models for Pathogen-Specific Antibiotics


On 1 Mar 2017, FDA hosted an eagerly awaited workshop on animal models in support of narrow-spectrum agents for A. baumannii (Abau) and P. aeruginosa (Pae). It was a full & interesting day at the end of which my confidence that we can plausibly complete acceptable registration programs for narrow-spectrum agents for these two pathogens (and others that are even less frequent) is really improved. (For links to workshops and references – see my notes below).

We don’t have all the answers, but the basic shape of the answer is apparent and FDA is firmly committed to making it happen. An extended version of what I heard today is found below my signature, but here are the core elements:

First, there is an urgent need for new agents for Pae & Abau. That said, finding agents that cover ONLY Pae or Abau seems often easier than finding broad agents that also cover them.

Once a candidate is identified, the clinical development program is very difficult. This was discussed at length last summer and the problem is that the relative rarity of these infections makes Abau- or Pae-only agents hard to study at standard statistical strength. There’s been discussion about using the Animal Rule (aka, Tier D) as an approach, but this doesn’t seem plausible as Abau and Pae lack the explosive virulence that makes primate models of plague et al. so compelling in that context. Also, most of the Animal Rule agents were already approved for other uses.

So, and for new agents, we’re now into the land of Tier C where we use strong animal models + at least some clinical data to achieve approval. This is not a path to be pursued unless there is no other choice, but it is a path we should make available.

And that, then was the point of the 1 Mar discussion. The essential elements that emerged were that the animal model program would be some combination of exhaustive PK-PD exploration in smaller animals (mostly mice) followed by a small number of confirmatory studies in larger animals (up to and including pigs). The larger animals are intriguing for the ability to do all the things you see in man ­– extended infection courses with substantial life support. Importantly, all models would incorporate internal controls using humanized exposures of control agents that both should & should not work.

The clinical program would, simply put, be as much data as you can generate. Having at least some clinical data is critical on my levels to making a compelling case both to the ID community and the payers. As just one motivation for working hard on this, experience in Europe with Exceptional Circumstances approvals shows that products do not do well unless such are provided.

As stated above, I see this as a strong step. The next iteration in this debate appears likely to be the 14-15 June 2017 NIAID-sponsored workshop on PK-PD (no link yet for this – but do mark your calendar). Exciting times!

All best wishes, --jr

Follow me on Twitter: @JohnRex_NewAbx

Extended notes from the 1 Mar 2017 FDA workshop on animal models to support narrow spectrum agents
1.     There is an urgent need for new agents for P. aeruginosa (Pae) and A. baumannii (Abau)
a.    Infections due these pathogens have high mortality and resistance is real and common
2.     But, It’s really hard to find drug candidates that include Pae and Abau
a.    Some companies have made progress by narrowing their focus to JUST Pae & Abau
b.    Compelling narrow-spectrum candidates vs. both bacteria have now emerged
3.     Frustratingly, developing an agent limited to one of these pathogens is really hard
a.    An FDA workshop last year (Drug X-1, 18-19 Jul 2016) showed how tough it was
b.    Today’s workshop picked up where last summer’s left off and began with presentations on Unmet Need followed by brief reviews of two drug candidates (Polyphor and Entasis)
c.     These companies both proposed programs that might (just barely) be feasible
                                     i.     But, just barely … and not proven
d.    And, what about Stenotrophomonas or something else even more rare and difficult?
a)    So, the workshop today asked what be required of the animal models if want to seriously entertain a Tier C-type data package (Rex JH et al. Lancet ID 13:269-75, 2013) for approval of a new agent:
e.    Tier A: Multiple standard P3 trials
f.      Tier B: One standard P3 trial
g.     Tier C: Zero standard P3 trials but some clinical data
h.    Tier D: No clinical data except for safety
4.     Tier D (aka, the animal rule) is not a consistently plausible path. Prior uses of this rule have depended on
a.    The incredible virulence of the bacteria (plague, tularemia, anthrax)
b.    The fact that a very aggressive infection is produced easily with a low inoculum in healthy animals
c.     The fact that infection pathogenesis looks a LOT like the infection man
5.     But, Pae and Abau do not lend themselves to such simple and clear animal models as
a.    Healthy hosts are often very resistant to infection
                                     i.     Hence, we often have to manipulate the host

                                   ii.     Degree of mimicry of infection in man is not as high
b.    Not all strains are equally virulent

6.     So, and if a clinical trial with standard statistical dimensions is NOT possible, can we (how can we) lean more on PK-PD?
7.     Q: Can we? A: Yes, provided
a.    We are completely transparent about why we’re doing this
b.    We make it clear that stronger clinical data simply are not feasible
c.     We describe the limits on the overall dataset in the product label
d.    And the community is suitably cautious about their use
8.     Q: How can we? A: The basis of approval might thus be (and this is subject to further discussion)
a.    Clear demonstration of target PK-PD parameters in multiple small animal (mouse) models – various sites, various strains
b.    (perhaps) some confirmation of this in a medium-sized animal (rabbit)
c.     And finally (perhaps) very limited confirmation in a well-standardized large animal model (e.g., pig)
d.    Across all models, make use of benchmark control molecules
                                     i.     Give humanized exposures with drugs that should / should not work
                                   ii.     Use standard benchmarks to prove the model is sensitive
e.    And finally, collect whatever clinical data you can.
                                     i.     Statistical interpretation then makes allowance for the clinical trial limitations
                                   ii.     You could think of this as using the animal data to support a larger alpha or a Bayesian prior

Monday, February 27, 2017

The FDA, Ketolides and the Cempra Decision

OK.  So this is a few months late. Mea culpa.  But since the FDA advisory committee meeting on Cempra’s solithromycin, I have had a number of questions from readers and colleagues on the FDA decision to request additional safety information before approving Cempra’s antibiotic for the treatment of pneumonia. I would point out that Harald Reinhart has already posted a timely analysis of the situation.   

To put things in perspective, we must go back to the Ketek (telithromycin) scandal of 2006. Ketek was approved in 2004 for the treatment of pneumonia, exacerbations of chronic bronchitis and sinusitis – by a circuitous route (see my book Antibiotics the Perfect Storm for details).  After several reports of serious liver toxicity appeared, the FDA re-reviewed their prior approval. It has been calculated that the rate of liver injury caused by Ketek is 5.5 per 100,00 courses of therapy and the rate for serious liver toxicity is between 0.5 and 1 case per 100,000 courses of therapy. These numbers are similar for what you would see with other macrolide antibiotics and are better than rates for serious reactions to other antibiotics like the penicillins as Bob Moellering and I pointed out.  The FDA withdrew their approval for bronchitis and sinusitis, but left the approval for treatment of pneumonia in place judging that the risk benefit for pneumonia was still favorable.

When solithromycin was being studied by Cempra, the company touted the lack of binding to the nicotinamide acetylcholine receptor as being the key to its lower levels of toxicity for both the eyes, in cases of myasthenia gravis and even for liver toxicity. But as it finally became clear in their toxicology studies of solithromycin in animals, the liver was the main target organ for toxicity from this drug.  In their phase 3 clinical trials there was certainly a trend for more liver injury in the solithromycin treated patients compared to those receiving moxifloxacin (see FDA briefing document). Then – the company embarked on longer-term solithromycin treatment trials for chronic bronchitis and for non-alcoholic steatohepatitis (fatty liver disease) hoping that the anti-inflammatory effects of the drug would be beneficial here.  They did this knowing that long-term treatment in monkeys increased the risk for liver injury.  Sure enough – the few patients treated in these long-term trials did show evidence of liver injury.  This was enough to make the FDA advisors hesitate to agree that the company had demonstrated that the drug was safe – although the majority did agree that the drug worked for the treatment of pneumonia. The FDA responded with a requirement that the company carry out additional safety studies to reassure us that there is not a greater risk of serious liver toxicity than we see with other antibiotics.

Of course, like telithromycin, solithromycin is active against pathogens, especially those that cause pneumonia, that are resistant to other macrolide antibiotics.  This is an important advantage because it could decrease use of the quinolone antibiotics that are associated with an increased risk of C. difficile diarrhea – a potentially fatal complication. These ketolides also offer a potentially more efficacious alternative to the penicillins for penicillin-allergic patients. Did the FDA over-react here? In the case of Ketek – they left the approval for pneumonia intact – partly based on evidence obtained post-market over millions of treatment courses. For solithromycin, we have no such assurance.  How do we know that solithromycin is not, in fact, more toxic than telithromycin or a number of other antibiotics?  The animal data certainly gives one pause and the number of treated patients is too small to judge the extent of clinical toxicity here. Another bothersome fact is that the arguments of Cempra that this drug would be much less toxic based on data surrounding a single receptor and its interaction with various macrolides turned out to be so much hot air.

So, unusually, I must come down on the side of FDA and its advisors in the case of solithromycin.

Monday, February 13, 2017

Antibiotics - Recent Developments

Thanks to John Rex for notifying me about the two developments I will discuss here.

The first is an upcoming (March 1) FDA Workshop entitled, “Current State and Further Development of Animal Models of Serious Infections Caused by Acinetobacter baumannii and Pseudomonas aeruginosa.”  The FDA recognizes that clinical trials for pathogen-specific antibiotics will be difficult when the number of infections targeted by the product is expected to be small. They also recognize the value of animal models in predicting both antibiotic dosing and efficacy in humans. As summarized by the FDA, the purpose of this workshop is to discuss “the additional scientific work needed to evaluate current animal models of infection and evaluate potential animal models that may predict response in humans could advance the development of antibacterial drugs targeting a single species.” No briefing materials are posted for the workshop, so I can’t provide specifics as to FDA thinking here.  During the last FDA workshop on pathogen-specific antibiotics, we discussed the potential to use the animal efficacy rule that the FDA has established for special pathogens like antrax and plague where clinical trials for efficacy are not feasible at all.  This is Rex et. al.’s (requires subscription – sorry) Tier D pathway for antibiotic approval. I thought that the consensus at the workshop was that such an approach was not necessary since some clinical data relevant to efficacy could be obtained even if the data were limited.

On the other hand, as I noted, Paul Ambrose kept pointing out that if inferential trials for these products were not possible, animal models and PK/PD could provide a strong rationale for approval. It looks like the FDA may be trying to put investors’ money in Paul’s mouth (or something like that).  It looks to me, trying to read between these lines, like the FDA wants to try and put a more standard definition around the kind of animal models, perhaps even specifying strains of bacteria to be studied and methods to be used, such that uniform datasets can be evaluated when looking at different products. I would anticipate that some clinical data will also be required for approval.

It seems clear that this will be an important workshop for those interested in pathogen-specific antibiotics and especially for those with expertise in animal models and PK/PD. Will we see further guidance on this from FDA this year?

A separate development that might be of interest to antibiotic developers comes from Europe and EMA.  I mentioned in my previous discussion of pathogen-specific antibiotics that Europe had more tools available with which to approve products where robust clinical trial data are not readily available. One of these is conditional market approval (CMA).  The FDA has a similar pathway for approval – but it relies specifically on the availability of biomarkers – something we do not have for antibiotics (with the exception of TB). The EMA just completed an analysis of products approved under their conditional approval pathway since 2006. According to EMA, “medicines that were granted a CMA target seriously debilitating or life-threatening conditions such as HIV infection, breast cancer, severe epilepsy in infants or multi-drug resistant tuberculosis. 14 were orphan medicines.”  But a CMA is valid only for one year at which time the conditional approval must be renewed or new data must be presented to allow for full approval.  In 90% of cases, sponsors complied with the requirements of EMA in seeking full market approval and in 70% of cases, sponsors were able to comply with pre-discussed timelines for achieving full approval. Obtaining the data required for full approval took an average of four years.  But this means that for those four years, important new medicines were available for the patients that needed them during which time companies were able to successfully gather data to further support marketing approval (See Figure below). Although the FDA is still faster than EMA for full approvals in general, one must envy the Europeans for their more broadly applicable conditional approval pathway.