Thursday, July 28, 2011

Bayer-Trius - Has the World Gone Mad?

Bayer and Trius recently announced their collaboration on the development and commercialization of Trius’ antibiotic, torezolid, currently in Phase III trials. Under the agreement, Bayer will commercialize torezolid in China, Japan and all other countries in Asia, Africa, Latin America and the Middle East, excluding North and South Korea. For these rights, Bayer is paying $25 million up front plus 25% of the total development costs. Milestones could add another $69 million to Bayer’s bill – but the specifics of this were not disclosed.

There are several fascinating aspects of this deal.  (1) Bayer is focused on Asia and other emerging markets.  They are leaving the stagnating US and European markets to Trius or other partners. (2) Bayer itself, with this deal, is putting its foot back into the antibiotics field after having spun off their entire research and development group and several products in 2006.  Like Sanofi, they have clearly lost substantial internal expertise and their ability to fully evaluate external opportunities in this area is probably much more limited than in the past. Nevertheless – they have put their toe back in the water. (3) Bayer may recognize that pneumonia will be an important indication in their market segment, but that it will be unavailable in the US unless the FDA changes quickly.

Overall, in my non-business person view, this is a good deal for Bayer.  Their investment is rather small for a phase III product and is even rather small for the market segment they are targeting.  It may also be a win for Trius helping to get the remainder of their phase III program financed and off the ground. From the scientific point of view, I think there may be room to question Bayer’s judgment here – but their risk is relatively small for a potentially large gain.

This deal emphasizes as much as anything else the fact that the US is approaching irrelevance in the minds of many in the pharmaceutical business who are interested in developing and commercializing new and needed products. This irrelevance, as noted in previous blogs, comes from the inability to develop antibiotics for approval in the US in a number of key indications like pneumonia, plus the stagnation of the US antibiotic market overall.

The Bayer-Trius collaboration also emphasizes another driver for antibiotic development – that of hope.  There is hope that, given the medical need globally, and given the rapidly emerging economies, that commercially viable products can be delivered in spite of, and if necessary without, the US.  There is also the hope (slim though it might be) that the FDA will see the light someday soon.  From my mouth to God’s ears!

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Thursday, July 21, 2011

Novartis and Antibiotics - On the Edge

NOVARTIS HAS RETURNED THE RIGHTS TO AMADACYCLINE BACK TO PARATEK PHARMACEUTICALS!! This was correctly predicted by a Pharmawire article back in June (the link requires a subscription – sorry).   At the time, this news was news to Paratek. But in Novartis 2nd Q Report they note in a single sentence that clinical development on the compound had been discontinued (go to link – search for PTK).   As I noted during my discussions with Pharmawire back in June, I have strong reason to believe that this was in large part motivated by Novartis’ inability to secure agreement from the FDA on a feasible trial design for community-acquired pneumonia in the US.  Amadacycline is a perfectly good drug for skin infections and pneumonia.  Their phase II study of skin infections was well done and the drug performed well compared to linezolid – always a good sign.  I think that the inability of Novartis to capture this important US market segment was dissuasive to their commercial group. 

At the same time, they have reorganized their clinical development group and one of their most senior infectious diseases clinicians was “retired.” I remember back 10 years ago when I would give talks about the abandonment of antibiotics by large pharma, two companies used to rise to talk about their commitment to the area – Glaxo and Novartis.  The physician from Novartis who was their most vocal spokesperson is the one who was “retired.” 

They still have an antibiotics discovery group that is in the process of moving from Boston to Emeryville, California and rebuilding.  But if their commercial people were dissuaded by amadacycline, what do they currently think about their internal program?  Will they continue to invest internally in antibiotic research?  Will they continue to seek new antibiotic opportunities externally?  Although these questions remain unanswered, I have suspected for some time that they would be bowing out of the field altogether.

If Novartis should take this last and final step to back out of antibiotics altogether, I think we can lay much of the blame at the feet of FDA and their continuing inability to provide feasible ways forward for the development of antibiotics in commercially important indications such as community-acquired pneumonia and others.

Comments are welcome.

Wednesday, July 20, 2011

Parachutes: Early vs. Late Endpoints

George Drusano, Paul Ambrose and Brad Spellberg - Special Guest Bloggers.

“It’s not the fall that kills you, it’s the sudden stop.”--Chuck Yeager

A recent news story described a skydiver who jumped out of an airplane at 15,000 feet  He had 2 parachutes (primary and backup).  Both failed to deploy.  Nevertheless, after landing in some bushes he walked away with 2 broken bones and some bruises.
Smith and Pell previously called into question the efficacy of parachutes in a thoughtful analysis of the existing literature at the time.1  Their conclusions were shocking.  It turned out, no one had ever conducted randomized, placebo controlled trials of parachutes.  Furthermore, the current news story is only the latest of many describing people who have jumped from “lethal” heights without parachute support but survived with only minor injuries.1  Such scientific descriptions have called into doubt one hundred years of “anecdotal” successful experience with parachutes.
Because of the absence of historical evidence of sensitivity to device effect (HESDE) for parachutes versus placebo/background therapy, the conduct of non-inferiority trials of parachutes must be reconsidered.  While parachutes do not seem to improve end-of-therapy survival based on available published literature, they do appear to provide early benefit to the jumper.  Analyses from the late bronze age2-3 showed that, compared to cliff jumpers using background therapy (e.g., flapping arms real fast), early after the jump those with functioning parachutes had superior mood scores and improved physiology (including lower heart rate, lower blood pressure, and cleaner underwear).
Thus, the primary endpoint for parachute non-inferiority trials should not occur at end of therapy (i.e., at impact) since there is no HESDE for that endpoint.  Rather, based on these relevant and timely bronze-aged studies, the primary endpoint should occur at 48 to 72 seconds after jumping, since that’s when screaming and bodily functions of parachuted vs. control cliff-jumpers differed the most.2,3  Specifically, the primary endpoint should include a composite of: 1) loudness of scream; 2) proportion of words screamed with 4 letters in them; and 3) change in weight of underwear in flight.  As for all endpoints and irrespective of data, the non-inferiority margin for such a scientifically rigorous endpoint should be 10%, because we said so.
Other, less scientifically rigorous critics have felt that it was important in some vague, abstract way for the jumper to be physiologically normal when the jump was completed, not just happier and cleaner early during the jump.  Thus, we are willing to concede that less important, secondary endpoints that are not used to define success of therapy could be analyzed at end of therapy.  Such exploratory endpoints could include the volume of the “thud” or bone snapping that occur at the time of ground-contact, or the magnitude of post ground-contact shrieks.  Unresolved are what type of performance characteristics such endpoints would have.  For example, can physician observers accurately describe the intensity of such thudding, snapping, or shrieks simply by listening, or does a specific device need to be employed?  Should such measurements be made in decibels, killidecibels, or another measure?  How many inches of extrusion from the surface of the skin must a compound fracture extend for it to be considered meaningful to jumpers post ground-contact?
Furthermore, since the distance splintered bone rises above the skin and the volume of thudding, crackling, and shrieks are just biomarkers and not symptoms, they may have no relevance to the jumpers.  Rather, it may be necessary to use a validated Patient Reported Outcome (PRO) instrument so jumpers can directly document the symptoms they are feeling post ground-contact.  Presumably voice recognition software could be used to capture the PRO results, since jumpers with less effective parachutes may fracture key bones in their limbs post ground-contact, and thus be unable to write on PRO forms.  Alternatively, various sorts of rudimentary scratch marks and other primitive symbols that are feasible to generate with fractured hand bones may convey the patient’s symptoms accurately on a well designed PRO.
A final, critically important point.  The jumper in the current news story had 2 parachutes, a primary and a backup.  Such a jumper should be ineligible to enroll in future non-inferiority studies because the effect of the second parachute could potentially mask the lack of efficacy of the first parachute.  Not even a single additional parachute should be allowed for jumpers in future trials.  Sadly, this means that the authors will not be eligible to enroll (BS has indicated he will jump only with a minimum of 5 parachutes in place, for example).  However, we are confident that those truly dedicate to regulatory science will lead by example by enrolling in such studies and volunteering to wear only 1 parachute.
We believe that the science of designing and analyzing parachute non-inferiority clinical trials has been greatly advanced in recent years.  While initially skeptical that non-inferiority trials could be justified based on available science, we now believe that early endpoints focusing on patient reported symptoms provide a “scientifically rigorous,” “compromise” pathway forward.

1.     Gordon Smith and Jill Pell.  2003.  Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials.  Br Med J.  327:1459-61.

2.     Hippocrates,* George Drusano,* Paul Ambrose, and Brad Spellberg.  947 B.C.  The impact of parachutes versus traditional therapy on how cliff jumpers “feel, function, and survive”: a Bayesian analysis of early versus late endpoints.  Journal of Ha, We Made You Look!
*these authors contributed equally to this work

3.     Asklepios, Paul Ambrose, George Drusano, and Brad Spellberg.  1106 B.C.  Really, after reading reference 2 you still went on to 3?  The Punked Journal.

Wednesday, July 13, 2011

Brief Update

Sanofi-Aventis -As predicted in a previous blog, it appears to be true that they are back in the antibiotics business for real.  Sanofi just signed a Glaxo-like deal with Rib-X for Rib-X's discovery program and they are speaking with a number of other small companies and with academic groups.  Sanofi is the first company to come back to the area after leaving it since Roche first departed antibiotic research in 1999!  We all need to change our charts!

The GAO - has found that the CDC is not doing an adequate job of surveying for resistance nor are they adequately tracking antibiotic use.  Wow!  The surprise of the century!  If you don't provide money, you can't study things or at least not as carefully as you would like.

Gonorrhea - are getting resistant to everything.  This has been coming for a long time.  Now its here.  But the market is not large enough to support the studies that would be required to register new drugs to treat the infection.  Government - your turn!

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Europe Strikes Again!

EU member statesImage via Wikipedia

The recent report of fully resistant strains of gonorrhea just adds fuel to the need for incentives to develop new antibiotics.  Once again, Europe takes the lead.  In another report apparently complementary to the previous work commissioned from the London School of Economics (LSE) on antibiotic resistance, the Office of Health Economics (OHE) specifies the kind and size of incentives necessary to stimulate antibiotic discovery and development for Europe.  This analysis was apparently commissioned by GSK and is meant to provide additional considerations for the Council of the European Union which is taksed with making a decision based on the previous conference,  “Innovative Incentives for Effective Antibacterials”.  The conclusions of that conference were adopted by the Council and that body must come up with proposals for stimulating antibiotic research and discovery by the end of this year.  The major proposal from the LSE was to use a combination of push and pull type incentives to stimulate antibiotic research and development.  The push would involve support for R&D – in my view phase III is the most important target here. The pull would involve some sort of guaranteed market or payment system upon approval of an antibiotic that meets specific criteria for being active against key resistant pathogens.

The OHE report attempts to specify the type and to quantify the amount of incentives that might be required.  They target the NPV calculation by noting that, as part of a worldwide market, if Europe could provide an NPV of around 147 million (~$200 million), this would be sufficient.  In their analysis, the look carefully at exclusivity extensions for the antibiotic per se and conclude that this would add little additional value to the product (hence no improvement in NPV).  I presume this is because of the effect of accumulating inflation on the later years of sales. I like this since I have been saying it for years.  They also note that providing a “transferable” patent exclusivity extension or the so-called wild-card extension where in exchange for marketing a needed antibiotic a company like Pfizer could get an additional period of exclusivity for Lipitor, a >$10 billion product. The OHE notes that there is much opposition to such a proposal (to put it mildly!) partly because it inappropriately shifts the cost burden to sick patients needing medication. They seem to favor a guaranteed market paid out over several years.  The problem is that if one were to rely only on such a pull mechanism, the guarantee would have to be on the order of €1-1.5 billion. The other pull mechanism that would work would be to triple the price of such new antibiotics compared to today’s antibiotics.  This would, I guess, be difficult for a number of the EU member states to swallow.

This is where the push comes in.  Here is where this report gets fuzzy.  The OHE discusses a public development project or public private partnership for drug development.  But they state that it would not be appropriate to fund phase III.  This I don’t understand since funding earlier phases removes too little risk and still leaves small companies and academics without a way forward other than the pubic markets and large company partnerships – both of which are rapidly going the way of the Dodo bird. As I have frequently noted, the push must involve funding partially or fully phase III trials.  But – if one does this, the size of the guaranteed market can be reduced substantially since much of the upfront expense will have been removed from the NPV calculation. 

Once again, Europe is very far ahead of us in its thinking on incentives for antibiotics. They realize that such funding is a win-win for everyone including for member states in terms of future savings realized through the ability to adequately treat infections caused by resistant pathogens. What Europe must keep clearly in mind, however, is that there must be a clear regulatory pathway available for the development of antibiotics for indications where they are needed.  Right now, in the US, for pneumonia, that does not exist. We are still awaiting the result of European regulatory deliberations on new guidance for the development of antibiotics.  But without a regulatory path forward, the road is blocked regardless of the incentives offered.

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Friday, July 8, 2011

Current Regulations Distort the Competitive Environment for Clinical Trials

I have recently been thinking about the number of small companies trying to develop antibiotics.  They are all pursuing indications like skin infection, urinary tract infection (UTI) and intraabdominal infection (IAI) since trials in pneumonia are not feasible in the current FDA environment and trials in mild bacterial infections such as otitis media, acute bacterial sinusitis and acute bacterial exacerbations of COPD are not feasible under the aegis of either EMA or FDA.  But this means that in order for companies to just get their product on the US market, they must be approved in skin, UTI or IAI even if their product might be very well suited for use in respiratory tract infections.  It seems to me that the most egregious distortion of the competitive environment for trials will occur for skin infections, but UTI and IAI will not be spared.

What this means is that everyone about to pursue phase III trials in the US will be ignoring respiratory infections and studying their antibiotic in one of these indications. The trial sizes will be large since most of these indications will require non-inferiority trials with a 10% non-inferiority margin leading to trial sizes (for two trials) of 12-1600 patients. I am beginning to question whether there is enough capacity globally to carry out the number of such trials that I see coming forward in the near future – especially for skin infections. I think that the availability of indications like pneumonia and other respiratory infections would take at least some of the pressure off these other indications in terms of patient numbers.  In addition, of course, the area of greatest medical need today is for agents to treat patients with hospital acquired pneumonia, which is the very area where no one will be going at least with the FDA.

This distortion of the antibiotic clinical trial environment will have several consequences.  It may take longer to enroll these large trials since there will be more competition for the same patients.  Companies will be forced to go to countries where there may be less experience in trials simply to compensate for the loss of centers to competition in more experienced countries. Trials may become more expensive since they will have to enlist additional centers to improve enrollment rates.  Some centers may take advantage of the competitive environment to increase their rates further adding to the additional expense.

I think that this is an area of concern that has not received much attention anywhere. But for those considering such phase III trials, especially those smaller companies trying to embark on phase III, I believe that this distortion in the competitive environment for trials will be an important problem in the next several years.  

Superiority Trials in Antibiotic development

Thomas Bayes's signatureImage via Wikipedia

In previous blogs, I promised that I would come back to the subject of superiority trials of antibiotics and the use of Bayesian statistical methods as the basis for designing such trials.  I have been discussing this approach with a number of infectious diseases clinical trialists for the last year or two.  But I am not a sophisticated enough statistician to actually put such a plan into practice.  On the other hand, I think I now have enough of a basic understanding of the Bayesian method (first described in a posthumous publication by Thomas Bayes in 1763) to conceptualize the approach.  The one article that was the most helpful to me was written by Roger Lewis and Robert Wears and published in 1993. 

First, it is useful to understand the distinction between classical statistical approaches and the Bayesian approach.  Basically, in the classical approach, we compare pre-existing hypotheses and attempt to rule out one of them – usually the so-called null hypothesis which is the negative of the hypothesis to be tested. Such an approach will require a specific population of patients to reach the appropriate statistical conclusion – accepting or rejecting the null hypothesis.  Mostly, a positive study provides a low probability that the null hypothesis is true (P=<0.05). It does not provide information on the likelihood that the hypothesis that we are actually trying to test is true or not. We just reject the idea that it is not true.  In taking care of patients, who thinks like that?  We would all be going crazy dealing with double negatives.

Another problem with the classical approach is that the conclusion depends on exactly why you take certain steps within a trial.  The example used by Lewis and Wears is the following.  Suppose you expect a mortality of 30% for a given disease.  After treating 10 patients you stop the trial because only one has died giving a mortality of 10%.  But the P value is only 1.49.  But – if the trial were run differently, a totally different conclusion might be drawn.  Suppose the investigators decided that they would continue enrolling patients in the treatment arm until they had a death?  In that case, the P value reflects the probability of having to have enrolled 10 patients before seeing the first death – P=0.04!

In complete contrast to the classical method, Bayesian approach actually allows one to calculate the probability of a defined outcome. This probability is expressed as a distribution over a population. In the Bayesian approach, prior knowledge is utilized to provide an a priori probability distribution for the effect under consideration.  Usually, there is little prior knowledge, but in the case of many bacterial infections, we may have some advantage based on prior animal testing, human PK and approaches involving PK/PD. 

Data is then acquired in a study or trial. Using the Bayesian approach, interim analyses are permitted and in fact may ultimately reduce the population required for study by increasing the probability that the effect being studied is real. These “posterior” estimates are therefore extremely useful and informative during the conduct of the trial.

In fact, Bayesian statistics closely resembles clinical reasoning.  When a patient comes in with a set of co-morbidities and an acute infection, we try and assimilate this information to provide a probability of some outcome.  The PORT score for determining risk of mortality in community acquired pneumonia that is commonly used to determine whether patients can be appropriately treated as outpatients or whether they require admission is just one example of this sort of approach.  There are many others – when should one obtain which diagnostic tests to rule out a pulmonary embolism is another good example.

So how can we apply such an approach to superiority trials for antibiotics?  That will have to await the next blog.
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