Markey and Grassley as Brutus.

First, there was Ketek (telithromycin).  Then there was the spectacular FDA nosedive into gagaland as far as antibiotics are concerned. Now, the prestigious Government Accounting Office has issued a report on non-inferiority trials used in the approval of drugs by the FDA (http://www.gao.gov/new.items/d10798.pdf, http://www.reuters.com/article/idUSN276362720100827).  The report adds nothing new to the FDA’s guidance on non-inferiority trial design.  It does, however, clarify the mysterious influential group the FDA is seeking to pacify in their new guidance documents. The GAO, in turn, and I presume the congressmen who requested the report (Markey and Grassley), seem to have been speaking to those same statisticians who want us to run trials in community acquired pneumonia with 7500 to 200,000 patients so we can use mortality as an endpoint.  Such trials are impossible to run and even if they could be run, would take so long that the designs would be obsolete by the time they were completed. These are the same folks who want superiority trials or even placebo controlled trials when the designs are simply not feasible on planet earth.

If the congressmen wanted an objective, scientific opinion that would take all factors into account, including the future availability of antibiotics, they could have (read should have) asked the Institute of Medicine of the National Academy of Sciences.

In the wake of the Ketek scandal of 2006, congress piled-on on the FDA demanding answers as to how such a drug could have possibly been approved. For one view of this scandal, see David M Shlaes, Robert C Moellering. Telithromycin and the FDA: implications for the future. Feb 2008 The Lancet Infectious Diseases, Vol. 8 No. 2 pp 83-85. The results of this unnecessary scandal have been a loss of critical FDA personnel and a subsequent lack of leadership at the FDA, consistent interference in FDA’s efforts, especially in the critical area of clinical trials for new antibiotics, by congress, and constant and unpredictable waffling along with an antibiotic approval record that will leave our critical antibiotic pipeline in imminent danger for at least the next decade. While the congressmen try and make points with their constituencies, more and more companies abandon antibiotics research while more superbugs emerge to threaten our health.  What can we possibly be thinking?

Here are comments from various congressmen on the GAO report.

Senator Grassley said: “This study gives the FDA another reason to carefully consider its use of these sorts of trials when approving new drugs for the market. Every step should be taken to strengthen drug reviews done by the FDA for the consumers who rely on and benefit from life-saving and life-enhancing pharmaceutical drugs.”

“Non-inferiority trials are an essential tool for evaluating the safety and effectiveness of certain kinds of critically important drugs such as antibiotics—but they pose difficult scientific issues,” said Chairman Waxman. “I’m pleased to see that FDA’s March guidance clarified the standards for these trials. I hope FDA will work with industry and academics to address remaining issues on how and when to best conduct these trials. Although the pipeline for antibiotics is critically bare, no one benefits from ineffective drugs—and so I encourage FDA and industry to continue to collaborate to do everything possible to ensure that safe and effective antibiotics are developed.”

Rep. Dingell said: “This GAO report provides a very good assessment of the concerns related to the use of non-inferiority trials and the recent strides FDA has taken to address those concerns. Non-inferiority trials have a role in the drug review process. However, they must always be designed and interpreted in a way that clearly demonstrates a high level of safety and efficacy. I look forward to FDA’s continued progress in this regard. American consumers should have no doubts about the effectiveness of the drugs they consume.”

Rep. Markey said: “The GAO report shows that these so-called ‘non-inferiority’ trials have often proved to be an inferior means of reviewing the safety and efficacy of new drugs. While the FDA has made strides to improve evaluations relying on non-inferiority trial data, the GAO report highlights important limitations of non-inferiority trials. I will continue working to investigate and implement empirically sound changes to ensure that the FDA can protect the public’s health and that the drugs in our medicine cabinets have gone through a thorough test of their safety and effectiveness.”

These congressmen (especially Markey and Grassley) speak as if the trials that we have been carrying out for the last 5 decades did not assure either safety or efficacy.  Of course, this is not the case at all for antibiotics and I challenge the congressmen to demonstrate that we have approved inefficacious antibiotics with no more effect than placebo at least for serious infections over the last 50 years. I think that this will be hard to prove even for a number of so-called mild infections as well. But this argument is not about safety and efficacy really.  The argument is about how far we can or should go to prove to what level of certainty that drugs are safe and efficacious.  No drugs are 100% safe and no drugs, even antibiotics, work for all patients all the time. We have to find a way forward for antibiotics that provides us sufficient reassurance of safety and efficacy while at the same time providing for the realities of clinical trial conduct on the ground. There is a way forward, and many have pointed these options out to the FDA and congress, but their pleas seem to have met with a deaf ear. The GAO report gets us no further along these lines than we were as long as 10 years ago. 

All this political maneuvering puts our very lives at risk as we head into older age. As we age, we will be in greater danger of contact with hospitals with their antibiotic resistant bacterial pathogens like MRSA, multiply resistant Klebsiella that essentially cannot be treated, and now the NDM-1 superbug arriving on our shores from India. Everyone who does not want a new antibiotic active against these organisms raise their hands and vote for the congressmen listed above.

More on superbugs, the FDA and government later . . .

Guidance?

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The long-promised Draft Guidance on Acute Bacterial Skin and Skin structure Infections (ABSSSI): Developing Drugs for Treatment has arrived (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071185.pdf).  As discussed on several previous blogs, the basic trial design, with its requirement for cellulitis (75 sq. cm) for all infections studied (abscess, wounds and cellulitis) and its 48-72 hour endpoint of halting progression of the lesion and lack of fever seem feasible. One issue is that infections such as diabetic foot infections, commonly encountered by clinicians, are not encompassed within this guidance.  Any drug to be approved for ABSSSI that offers any sort of advantage over existing compounds, or even that is promoted when generics are not, will be used off label for many of the indications not covered in the guidance.  Is that what we want?  When I posed that question to the FDA back in march they responded with an emphatic “No”. 

Another issue, consistently raised by Brad Spellberg, is that the endpoint is clinically irrelevant.  Who cares if spread of the lesion is halted by 48-72 hours or not?  We all want to see a cured patient at the end of therapy or in the days or weeks that follow.    It is true that the FDA endpoint probably correlates with a relevant clinical endpoint, but why not use the relevant endpoint?  The answer is because the FDA is stuck in some political battle with statisticians who vociferously require we use endpoint established 75 years ago when sulfonamides were compared to UV light therapy for erysipelas.

The FDA also has sponsors conducting a number of other “studies” for them so they can gather data around skin infections – nothing wrong with that.  They suggest that sponsors develop an instrument for Patient Reported Outcomes for ABSSSI during Phase II.  Right!

But to me, the most upsetting part of the guidance is in their explanation of their approach to setting the non-inferiority margin.  This is the crucial statistical argument that will make the difference, based on the numbers of patients required for study, between feasibility or not.  In a previous blog, Discounting Antibiotics (http://antibiotics-theperfectstorm.blogspot.com/2010/08/discounting-antibiotics.html), I reiterated points made by the FDA at the August workshop where trial design for ABSSSI was discussed all of which are included in the new guidance.  Briefly –

·      They look at the difference between UV light and antibiotic treatment where UV treatment has an effect.  Therefore, the treatment difference (M1) they calculate is not with placebo but with another effective therapy thus underestimating M1.

·      They then calculate a 95% confidence interval and then take the worst number (lowest difference or poorest treatment effect) that would occur one time in 40 trials and use this (under)estimate of M1.

·      Then, wanting to be extra-conservative and desiring to cover possible differences in patient population and trial design from the 75 year old trials until now, they discount the treatment effect still further by some arbitrary percentage.  They assume arbitrarily that antibiotics today would perform worse than they did 75 years ago. But, in fact, both published data (Corwin, P, L Toop, G McGoech, et al., 2005, Randomized Controlled Trial of Intravenous 1356 Antibiotic Treatment for Cellulitis at Home Compared With Hospital, BMJ, 330(7483):129), data  from Pfizer and from Trius, presented at the FNIH meeting , all show that modern trials duplicate the 75 year old results of Snodgrass quite faithfully.

·      The above gets us from a 30-40% treatment effect down to the FDA’s estimate of a whopping 12%.

·      The non-inferiority margin cannot be greater than the treatment effect. Of course, the FDA has already reduced the treatment effect by using improbable numbers as shown above. So, the FDA then says, arbitrarily, that the margin cannot be more than 50% of the treatment effect.  This gets us to a non-feasible NI margin of 6%! But there is no particular scientific basis for 50%.  It could be 90% or 10%. 

But take heart everyone out there in antibiotics land.  The FDA has already indicated that they will be flexible in their discounting of M1 depending on arguments presented by sponsors.  And, in fact, Trius has already negotiated at 10% non-inferiority margin for their upcoming Phase III trials in ABSSSI. 

So that leaves with the question as to why the FDA constructed their whole non-inferiority section the way they did. The only explanation I can see is that it was done to satisfy some pressure from statisticians within and outside the agency who are all stuck on Snodgrass and the pre-antibiotic era trials.  But the only thing this approach, formalized within FDA guidance, will do is alienate and frighten sponsors and investors away from research and development in antibiotics. 

So, FDA, in our era of emerging superbugs, which is more important, your political standing with statisticians or the pursuit of public health?

Watershed or Waterloo for Antibiotics?

On September 7, the FDA Anti-infectives Advisory Committee will review the New Drug Application for ceftaroline submitted by Cerexa/Forest. Although I do have a consulting contract with Cerexa, I haven’t spoken with them in over a year and have absolutely no confidential knowledge of their data or anything else around ceftaroline’s phase III program.  What I will discuss here is what is available publicly based on meeting presentations and a recent publication describing the data in their skin infection trials.  In this regard, see my previous blogs about the FDA and clinical trial designs in pneumonia (http://antibiotics-theperfectstorm.blogspot.com/2009/12/fda-pneumonia-and-new-antibiotics.html)  and in skin infections (http://antibiotics-theperfectstorm.blogspot.com/2010/04/skin-infections-follow-up.html; http://antibiotics-theperfectstorm.blogspot.com/2010/06/skin-no-4-word-turns.html).

Cerexa carried out two phase III trials in CAP comparing ceftaroline to ceftriaxone in over 1300 patients.  Only PORT score III and IV patients were eligible making this the most comprehensive study of antibiotic efficacy in seriously ill, hospitalized patients with community-acquired pneumonia to be performed (to my knowledge).  In these seriously ill patients, they showed that ceftaroline cured 84.3% compared to ceftriaxone with 77.7% in the clinically evaluable population.  It looks like a fair percentage of patients received at least some prior antimicrobial therapy but that the numbers were similar in the two groups.  It also looks like about 20% of patients had documented infection caused by S. pneumoniae.  Cure rates for these patients were 85% and 69%, respectively.  Adverse events appeared similar between the two groups and only led to rare discontinuations of therapy.  The issue for the FDA will be the relatively small number of documented bacterial infections and the number of patients who received prior therapy.  I am sure that Cerexa has analyzed the latter group separately, but I am unaware of those results. The FDA is now targeting earlier endpoints, specifically lack of fever and “clinical improvement” at 72 hours rather than the 8-15 days post therapy test of cure used by Cerexa. They also target documented bacterial infections. Nevertheless, the Cerexa data are robust and were derived from seriously ill patients. 

Cerexa also carried out two phase III trials in patients with complicated skin infections.  The data are published by Corey et. al. in Clinical Infectious Diseases available online as of August 9.  The trail was again carried out in over 1300 patients comparing ceftaroline to vancomycin plus aztreonam. The test of cure visit was 8-15 days after completion of therapy.  About one third had major abscess – this will be problematic for the FDA unless Cerexa can show they also had accompanying cellulitis.  Cerexa did require at least 2 cm of surrounding erythema to include patients with abscess.  Another third did have cellulitis.  About 12-15% had infected wounds.   The next most common infection was infected ulcer. Overall, lesions measured 150 sq. cm in both arms of the study.  Almost 40% had at least some prior antimicrobial therapy. I could not find data stratifying cure rates by prior antimicrobial therapy. About one third had an elevated white blood cell count and one third had fever at baseline.  Almost two thirds of patients had a microbiologically documented infection and almost 500 patients total had MRSA infections with cure rates around 94%.  Cure rates were similar for the two arms of the study across all different infection types.  Adverse events were also similar between the two study arms. Again, these were large trials with robust data.

For cSSSI (now ABSSSI according to the FDA), the FDA would like to see studies focusing on cellulitis.  So, if there is an abscess, a wound infection, etc., surrounding cellulitis would be required and the endpoint for therapy would be related to the response of the cellulitis.  The FDA would like to see an endpoint at 72 hours with halting lesion progression and with patients afebrile. They would like to eliminate prior antimicrobial therapy. So the new FDA view of skin infection trials, like pneumonia trials, is different from the large trials carried out by Cerexa (after agreeing the design with the FDA at the time).

So, what will the FDA do with these data?  The data are robust.  The patients were clearly seriously ill in both the cSSSI and CAP trials. And Cerexa designed these trials in concert with FDA review before embarking on the trials.  The FDA has just changed its mind in the last year or so.  Perhaps a post-hoc analysis of the data in light of the new FDA thinking will provide reassurance to the agency. In my view, if the FDA analysis of the data agrees substantially with the analysis by Cerexa, they must approve ceftaroline.  A failure to approve this drug will be Waterloo for antibiotics.  We can kiss investors and probably several other companies goodbye.  In the worst of all possible cases, they might ask for additional phase II type data linking the Cerexa trial endpoints with some new endpoint (still not even defined for CAP).  This might not be good, but at least it would not be the disaster that requiring new phase III trials would be.  

September 7, therefore, is a watershed moment for the FDA.  Lets hope that it’s not Waterloo for antibiotics. 

FDA and IPO

This week Trius, a biotech in California, went to the public markets in an attempt to raise money to support its proposed Phase III trials for its antibiotic, torezolid.  First – a few disclaimers.  I do not consult for Trius (I’m one of the few consultants who don't).  I did not buy stock.  I have no inside knowledge whatsoever.  I have not discussed their IPO with analysts.  So, I probably don’t know what I’m talking about – but at least I have no conflict of interest! 

The FDA prides itself, and rightly so, in being business neutral.  The FDA does not take business considerations into its deliberations on proposal by sponsors or in evaluation of data or anything else.  But there is a connection, fortunately or not, between the business world and the public health need for new antibiotics to fight resistant bacteria since new antibiotics must come from the pharmaceutical industry.  So, what does this have to do with the FDA?  That gets us to Trius and their IPO.

Trius was first established as Rx³ in 2004.  In late 2006 or early 2007, they became Trius Therapeutics and licensed an oxazolidinone (like Zyvox) antibiotic from Dong-A Pharmaceuticals in Korea.  In 2008 they embarked on Phase II trials in complicated skin infections for their drug (now called torezolid).  After their Phase II trials, Trius was faced with two problems. First, I’m sure their investors were thinking about some sort of exit – as in cash.  Second, Trius and their investors wanted to embark on Ph. III trials by establishing a partnership, by being bought by a larger company, or, by going to the public markets for financing. 

In my personal opinion, their Phase II trials were not designed to convince potential partners. A very large majority of patients enrolled had abscesses. The FDA and others are not sure antibiotics play a major role in curing this disease since the abscesses can be and are treated surgically.  Trius also failed to include a comparator antibiotic such as Zyvox, which would be their major competitor, in the trial.  So one cannot judge how torezolid stacks up against the competition.

So, Trius ends up having to go to the public markets for financing for their proposed Phase III trials.  This occurs at a bad time.  The markets, as everyone can see, are not at their most welcoming to new entrants these days.  And, just as Trius was about to pull the trigger on their IPO, the FDA decided that they did not know how sponsors should even conduct phase III trials in skin infections, the indication being sought by Trius for torezolid.   While the FDA sorted out the issues they (but no one else) had with skin infection trials, Trius was forced to pull its IPO since without a regulatory path forward, no one was going to invest.  Well, the FDA seems to now have sorted out its problems and will issue guidance on skin infection trials in the near future.  Trius has negotiated a phase III trial design that is currently acceptable to the FDA.  So Trius restarted its IPO process. But, the FDA has been giving mixed signals lately.  As recently as the August 2-3 workshop on clinical trial design and conduct, the FDA indicated that very tight non-inferiority margins might be required – but this is not what Trius had negotiated with the FDA.  These kinds of confusing statements had everyone in an uproar.  The investors voted with their feet.  The proposed stock price for Trius’ IPO went from $14 to $5.  They raised $50 million.  I’m sure this is much less than they originally anticipated in 2009.

Trius may be OK financially since they will now have access to after market monies to help finance their trials.  Their investors may not have achieved the cash exit they desired, so they may not be too happy.

But we all should be panicking.  The Trius IPO experience tells us that investors no longer trust the FDA.  They don’t trust the agency to keep its word, they don’t believe that there is a stable path forward for antibiotics at the FDA, and they are generally skeptical about antibiotics as a therapeutic area – all for good reason given recent FDA behavior.  But this means that investments in antibiotic research will be all but frozen.

The FDA has a chance to redeem itself.  On September 7^th during the advisory committee meeting to consider ceftaroline.  (Full disclosure – I do have a consulting contract with Cerexa – but they haven’t spoken to me in over a year). The world will be watching.  The FDA, regardless of the ultimate outcome for ceftaroline, has to be reasoned and reasonable. 

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• Trius slashes its IPO price to the bone (fiercebiotech.com)

Discounting Antibiotics

No, this is not about cheap Z-packs (azithromycin) on the Internet.  From an online dictionary – discount - to leave out of account; disregard. This is what the FDA is doing to antibiotics when they “discount” the antibiotic treatment effect in calculating their recommended non-inferiority margins.  What is he talking about you ask!

In studying new antibiotics in clinical trials, we usually use a comparative design to show that the new antibiotic is at least not inferior to some already approved and active control antibiotic.  The extent of non-inferiority that might be possible in the worst of all possible statistical cases is what we term the non-inferiority margin.  So, for example, if we run two trials of a new antibiotic with the NI margin set at 15%, the chances of falsely concluding that the new antibiotic is not inferior to the control is less than 3%.  Lately, the FDA has been conservative and has been asking for trials with an even more conservative margin of 10%. Well – you remember from antibiotics 101 that non-inferiority trials assume that the control antibiotic used is actually better than no antibiotic at all (placebo). 

So, how does the FDA decide on the margin and why do we care? In the case of skin infections they are using the trials of sulfonamides carried out in the 1930s where the antibiotic was compared, not to placebo, but to UV light therapy that actually was shown to be somewhat effective in therapy of erysipelas, a serious skin infection. So the first level of discounting is that the FDA is not using a true placebo (no robust trials like that exist).  In looking at those 75 year old data, they look at the difference between UV light and antibiotic treatment.  But – in looking at this difference, they calculate a 95% confidence interval and then take the worst number (lowest difference or poorest treatment effect) that would occur one time in 40 trials.  This unlikely number, which may grossly underestimate the treatment effect, is what they use.   This is the second level of so-called discounting. Then, wanting to be extra-conservative and desiring to cover possible differences in patient population and trial design from the 75 year old trials until now, they discount the treatment effect still further by some arbitrary percentage.  They assume arbitrarily that antibiotics today would perform worse than they did 75 years ago. This is a third level of discounting.

The non-inferiority margin cannot be greater than the treatment effect. Of course, the FDA has already reduced the treatment effect by using improbable numbers as shown above. So, knowing the treatment effect, the FDA then says, arbitrarily, that the margin cannot be more than 50% of the treatment effect.  There is no particular scientific basis for 50%.  It could be 90% or 10%.  This is then the fourth level of discounting. This discounting gets us to the latest FDA-generated conundrum. Based on these sorts of statistical shenanigans, during the recent FDA/IDSA workshop on clinical trial design for anti-infectives, the FDA implied that a 5-6% margin would be feasible for skin infections and a 7% margin would be good for nosocomial pneumonia. Such trials are simply infeasible.  The patient numbers required are too great. And they know it. And, as I also noted above, given that the chances of actually approving an antibiotic that is 10% inferior to the control antibiotic are less than 3% given two successful trials at the 15% margin, what are we thinking?

I just discussed this with George Talbot.  He told me that he had spoken with Dr. Joe Toerner of FDA, who gave the August 2 presentation that summarized the FDA’s current thinking on determination of the non-inferiority margin for skin infection studies.  (George and Joe are co-Chairs of the Foundation for the NIH Working Group on endpoints for skin and community-acquired pneumonia trials.)  Joe noted that the new FDA guidance on non-inferiority trial design allows for some flexibility around the usual 50% discount of the treatment effect.  I personally corresponded with Ed Cox on this and he also implied that the FDA would be flexible on the discounting in calculating the non-inferiority margins required for skin infection studies. Bottom line – the FDA may well continue to accept a 10% non-inferiority margin for skin infection trials.

So – all of us who want to have new antibiotics for our resistant infections – take heart!  There is hope!  But man!  Talk about Sisyphus!