Mortality Déjà Vu All Over Again

As I approach my retirement and I note with sadness the seemingly large number of friends who have contracted terminal illnesses, it is true that my thoughts turn to my own mortality from time to time.  But that is not the subject of today’s blog. Recent discussions with various thought leaders lead me back down the road of a consideration of endpoints in clinical trials of new antibiotics.  Specifically, in this case, how we will carry out trials looking at the efficacy of antibiotics in hospital-acquired and ventilator associated pneumonia.   You may remember FDA’s draft guidance on this topic (see my blog on this) where they propose all cause mortality at day 28 as the endpoint for such non-inferiority trials.  You may also remember the prolonged and agonizing discussion that took place during a later advisory committee meeting on this topic (I also blogged on this).

The FDA position is that they are unable to identify prior data on the clinical response to inadequate therapy or no therapy of HAP or VAP in the literature or in previous antibiotic trials.  Therefore, they cannot assign a treatment effect to antibiotics and therefore they have no justification of a non-inferiority margin using clinical response endpoints. Many thought leaders actually agree with this position and further claim that clinical response is vague and ill defined. So the FDA examined the literature using both observational studies and previous trials comparing inadequate to adequate therapy of these infections.  They identified a treatment effect of 42% on all cause mortality. Then, of course, they did their discounting thing to get to an effect of 20% and a proposed margin of 10%.  During the advisory committee meeting, the committee actually agreed that this margin should be calculated based on an odds ratio type approach.  This forces sponsors to carry out trials such that the patients studied have a 20% mortality (the sickest patients) and forces significant increases in trial size as you go below 20% mortality (the expected norm).  For these reasons and others, I have stated and continue to believe that this design is infeasible and that no one will carry out such a trial.

As we went ahead with the reboot process, I thought (obviously mistakenly) that the mortality endpoint for pneumonia would be dead (pun intended). Apparently it is still be actively discussed. And, in fact, as the FDA pointed out during their advisory committee meeting, if you use a different method to calculate the 10% NI margin – the relative risk method - trial numbers actually go down as mortality decreases.  In their calculation, at a 15% mortality, which is more typical of modern trials in HAP/VAP, only 287 patients would be required in each arm given other reasonable assumptions. This is feasible.  But, if the FDA, statisticians and thought leaders agree on this -  should we care?

My belief, in addition to the problem of feasibility using mortality as an endpoint, is that it is confounded.  That is, many of the deaths seen in such trials are due to comorbidities and not infection.  How many of the deaths that we see in such trials are we talking about?  One good study would suggest that there is about 13% overall mortality attributable to underlying disease and not infection.  I have discussed this with Brad Spellberg – he thinks this is high and he assumes that the real number is closer to 10% or about 50-67% of the total mortality (15-20% overall) seen in current trials of HAP/VAP. Statisticians argue that for non-inferiority this is not “confounding” in their world.  In my world, it means that those deaths – at least half of them - are unrelated to infection, are irrelevant, and drive the non-inferiority trial conclusion to the null hypothesis – non-inferiority.  I have never heard a statistician say that this is a good thing (at least until recently).  Brad notes that the trial is feasible assuming you use the ITT population and not just those with a bacterial pathogen identified at baseline.  I agree.  I also think (and Brad may agree)– “who cares?”

On clinical response, there are now strong data from pharmacometrics deriving from trials of tigecycline and from levofloxacin that demonstrate that clinical response is clearly related to drug exposure and that firmly establish a treatment effect. Further, the treatment effect is large – from 40-60% depending on how it is calculated.  Just based on the set point, without doing a lot of discounting, very large NI margins could be justified.  In fact, based on this reasoning, I have proposed a 17.5% NI margin on clinical response as an endpoint in the per protocol population.  The trial uses feasible numbers of subjects and the endpoint and NI margin are well justified.

Further, clinical response is more sensitive and thus more likely to reveal a difference between treatments than is mortality. In this regard, Brad notes that four recent non-inferiority trials in VAP demonstrated that one of the treatments was inferior yet none demonstrated statistically significant differences in mortality (although two did show such a “trend”).

So – which would you prefer, an endpoint that is clinically relevant and meaningful (patient is returned to their baseline clinical status), days on the ventilator may be less, ICU days may be less and the patient is discharged alive from the hospital. Or, would you prefer an endpoint where at least half of the measured effect is completely unrelated to infection?  I know where my vote is.

And by the way – lets get some more robust pharmacometric data on treatment effect in this indication by examining pharmacometrics in the doripenem and ceftobiprole trials (that means you, FDA).

Defending and Dogging the FDA

I know.  You're asking, "Who is writing this blog?"  Its still me.  I'm not schizophrenic yet! But I ran across several news articles regarding the fact that the FDA is insisting that Basilea run two trials to get approval of ceftobiprole, an anti-MRSA cephalsoporin that retains some activity vs. Pseudomonas, for the treatment of hospital-acquired pneumonia instead of the single trial they have submitted.  But that result was entirely predictable as far as I can tell.  The original two trials conducted by J&J and Basilea for complicated skin infection were rejected by the FDA as having been of inadequate quality - essentially - too many mistakes in enrollment and even possible fraud among investigators.  J&J argued that even removing all the questionable enrolling sites, the trial still demonstrated the efficacy and safety of the drug for skin infections, but the FDA stood its ground.  Now - I'm not defending the FDA on this aspect of things. I don't know which argument should prevail here - but a number of really smart people think that J&J proved that ceftobiprole works for skin infections.

But the FDA has said that they will accept a single trial in pneumonia - but it needs to be large - or a single standard (smaller) sized trial when backed by data in another indication.  With the rejection of the data on treatment of skin infections, there are no data to support the single trial in pneumonia presented by Basilea. Also - how big is the safety database?  Can the rejected trials be used to show safety? So where is the surprise here? What were they thinking?  Maybe I'm missing some key information that Basilea can supply. . . .

Now - back to dogging the FDA.  We're still waiting for the FDA to rescind previous infeasible guidance documents,  especially those in both community acquired and hospital acquired pneumonia. I have covered this multiple times in this blog, most recently here.  They are struggling with how to deal with early endpoints that were concocted to conform to their guidance on justifying non-inferiority margins where they had to turn to 80 year old literature that is completely inadequate to determine the treatment effect of sulfonamide antibiotics or penicillin such that our new antibiotics might have a standard for comparison.  But these endpoints are probably not valid, the scientific basis for using the endpoints is questionable at best, and there is no reason to go to these lengths. The FDA has a treasure trove of data on the development of previous antibiotics that can be mined.  They have pharmacokinetic data, the susceptibilities of the pathogens involved and the ultimate clinical outcome of interest - cure at test of cure.  These data can be put together using pharmacometrics to provide a no-treatment level of response and therefore a treatment effect level that can be used to establish a robust justification for non-inferioirty margins using cure as the endpoint. So - where are we?  So far - nowhere.  But I am assured by the FDA that they "are on the case!"  We are all waiting . . . .

Cubist Rocks!

I got a call from a reporter the other day asking me what I thought about the Cubist acquisitions of Optimer and Trius (See the link for the Cubist website).  My response was – Cubist Rocks!  These acquisitions are probably going to be good for Cubist in many ways – but they are a sorely needed shot in the arm for the future of antibiotic research and development around the world.  These acquisitions validate the investments in academia and biotech aimed at identifying new antibiotics against resistant pathogens and even antibiotics that are not particularly members of new classes of antibiotic – an extremely rare bird.  They will provide impetus for future investors and investments. They should inspire large pharma to think twice about their current lack of vision in the antibiotic space and to rectify this obvious financially attractive blind spot.

So – the basics.  Cubist is a small pharmaceutical company with revenues of about $1B almost entirely from sales of Cubicin (daptomycin), an IV antibiotic only active against Gram positive pathogens.  95% of sales are in the US.  Cubist’s ability to leverage markets outside for the US still leaves something to be desired (obviously). The original patent on daptomycin will expire in 2016, but patents on methods of administration and on the more pure form of daptomycin expire around 2020. Sooner or later, Cubist must find a way to replace Cubicin.  They have a promising antibiotic for Pseudomonas infections, ceftolozane (+ tazobactam) in phase III development, but nothing to addresss the Gram positive market represented by Cubicin.  The addition of Trius’ tedizolid will provide a strong alternative to linezolid as an oral (and IV) therapy for Gram positive infections. This compound has clear advantages over linezolid (which will become generic in 2015) and should do well in the marketplace – especially in the US and especially with Cubist’s experienced marketers behind it.

Cubist will pay up to $818MM including milestones for Trius (with $700MM being the purchase of Trius from its shareholders).  This also includes the interesting early stage clinical and preclinical programs at Trius.  It will be interesting to see how all that is merged into Cubist over the next year or two.

Trius had to go through FDA hell and partnering oblivion to emerge victorious in the end. They had to deal with changing FDA endpoints, a generally confused and inconsistent FDA overall and with an extremely skeptical group of potential large pharma partners. They were forced to raise money privately, with an important licensing deal with Bayer for Asian rights and through an IPO to get through two phase III trials for tedizolid, one trial at a time, cautiously raising money at each step of the way. This tortoise has finally won the race.  The fit with Cubist is a good one.  Tedizolid is a solid inheritor of the Cubicin franchise, and can complement Cubicin during Cubicin’s phase out (if that ever happens) as an oral follow-on to Cubicin therapy.  I think the Trius pipeline is also a good fit for Cubist.

So Cubist-Trius is a win-win for the world!  The world gets a badly needed additional choice for oral therapy of Gram positive pathogens, and IV choice beyond linezolid. The pharmaceutical industry gets a shot in the arm (and a kick in the head) for antibiotic R&D. And I get to feed the optimistic side of my view on the future of antibiotics and resistance.

On the Optimer purchase – I have little to say. Cubist was forced to choose to extend its contract with Optimer or not last month – obviously they chose an interesting path forward. Of course, lets not forget that Cubist has its own candidate for the treatment of C. difficile diarrhea (Surotomycin) already in phase III trials.  Optimer’s Difficid is already approved for that indication, although sales are not great ($23MM in 2012).  To my view, that molecule has definite advantages over oral vancomycin but may have been priced too high for the advantages it does offer.  Nevertheless, Cubist is paying up to $800MM for Optimer as well.  But how Difficid fits with Surotomycin and how Cubist will handle this I couldn’t say.  All in all –this seems like not a bad problem to have.  Hey – I have two good products for the same disease – what do I do?

So – Cudos to Cubist.  Congratulations to both Trius and Optimer. And good health to all those of us who are going to need new antibiotics as we yield to the inevitable passage of time. 

Interview American Council on Science and Health - FDA and Antibiotics

I was interviewed by the ACSH on the commentary we published in AAC.  To see the interview - click here.

FDA Reboot of Antibiotic Development

Today you can see our commentary (Shlaes, Sahm, Opiela and Spellberg) (you need a subscription – sorry), published in Antimicrobial Agents and Chemotherapy, entitled, The FDA Reboot of Antibiotic Development. In our commentary, we explore the disaster of the last decade of FDA regulation of antibiotic development, the recent record of FDA antibiotic approvals and the state of antibiotic resistance in the US. In short, the FDA now realizes that their oversight of antibiotic development over the last 10-15 years has, in part, led to a dangerously thin pipeline of new antibiotics.  And they are (thank goodness) rebooting as Janet Woodcock had promised over a year ago.

As part of our analysis of the situation in the US, we looked at key bacterial pathogens in a representative sample of US hospitals both within and outside of intensive care units for the years 2009-2012. We focused on resistance to third generation cephalosporins (exemplified by ceftazidime-resistance) and on resistance to carbapenems (exemplified by imipenem). We realize that there are drawbacks to these choices, but our data was the most robust for these antibiotics. What we found was astounding and is shown in the Table below (from the article) (click on the table to enlarge).

The Centers for Disease Control (using methods different from ours) conducted a study published in 2008. In the CDC data, taken from ICU isolates, the resistance among E. coli to third generation cephalosporins was 5% while in our analysis it stands at 8-11%. K. pneumoniae resistance to third generation cephalosporins was 15% in the CDC study.  In our updated analysis it ranges from 20-27%.  Resistance to carbapenems among these isolates is now between 7 and 11%. For A. baumannii the resistance is even more drastic.  In the CDC report 11% were carbapenem resistant while our data show that number to be over 50%.

These data indicate that for Acinetobacter baumannii infections, the carbapenems are already obsolete.   This holds true for both intensive care and non-intensive care patients and for urinary and non-urinary infections. The same can be said for our third-generation cephalosporins (here indicated by ceftazidime) in the treatment of K. pneumoniae infections.  For these organisms, the carbapenems are also rapidly losing efficacy. Even among E. coli isolates, our third generation cephalosporins are no longer completely reliable although the carbapenems remain a solid backup.

Clearly, if this does not yet constitute a public health crisis, we are rapidly moving towards one. We will continue to face more and more infections for which are treatment options are worse and worse, even with the late stage pipeline of new antibiotics we now have in place. The FDA is responding to this desparate need.  They have issued new guidance (as covered in a previous blog) on the development of antibiotics targeting patients with highly resistant infections. They still need to revamp more traditional approaches to antibiotic development before their reboot can be considered to be near completion. The next steps on the FDA reboot cannot come too soon.

In our commentary, we also point out that regulatory reform will still probably not be enough.  We will still need value-based pricing (see last blog) in order to make the final leap to enticing large pharmaceutical companies back into antibiotic R&D. We hope that both complete regulatory reform and value based pricing come to pass since the alternative is too terrible to contemplate. 

Antibiotics and Politics

I was intrigued by a recent piece in Genetic and Engineering News on the political scene around antibiotics and antibiotic resistance.  One focus of the article was on the STAAR (Strategies to Address Antibiotic Resistance) act currently wending its way through congress. There is much to like about this effort.  It provides for a sort of advisory (not really oversight) board of experts (specifics to be determined) to coordinate efforts across all of HHS including NIH, CDC and FDA. Of course, its not like this has not been tried before – e.g. the Antimicrobial Resistance Task Force involving the same three agencies.  That task force was limited by funding and turf battles.  How the same sort of boondoggle will be avoid in the pending legislation I don’t know. Another bit would be to add IDSA’s LPAD (proposal for the FDA on Limited Population Antibiotic Development from the Infectious Diseases Society of America) to STAAR. As I say, as a concept there is much to like here.  But as soon as you get into the details, it’s a morass.

First, the statutory requirement  for LPAD legislation is not at all clear to me.  Second, since the FDA has issued guidance on what is essentially and LPAD pathway, one might question the relevance of the legislation. Also – without clear leadership and a hard line manager at HHS, I don’t see the coordinating aspect of STAAR coming together to say nothing of the need for actual dollars to back the new efforts. So I’m skeptical.  I hope that someone from, say IDSA, can set me straight.

Beyond the politics, this entire effort misses the point.  I hate to point this out – but where have the dollars for surveillance for resistance been coming from for the last two decades?  In large part this is being funded by industry.  Of course, as industry drops out of antibiotic R&D and as their products become generic – these dollars will dry faster than mud in a drought. For surveillance and for the new products that we need to deal with resistant organisms we need MONEY!!!!  Unfortunately, these dollars will have to come from pricing for the new products we so desperately need.  This price increase will also probably have to be global to one extent or another.  Europe – I’m speaking to you!!  Yes, UK France, Germany – regulatory reform won’t be enough – new antibiotics to replace colistin might actually cost you silver. And who knows about pricing in China?  Are there any experts out there willing to share their knowledge.  How about India?

Clearly the time for value-based pricing has arrived.  We are already providing funding (mainly through BARDA) for antibiotic R&D in addition to making trials smaller, faster and less costly through regulatory reform. The last step in the pathway is pricing. Rather than spending effort on STAAR – maybe we should focus on the one thing that will make the most difference – MONEY and VALUE-BASED PRICING!