Antibiotics - The Perfect Storm - The BOOK - NOW AVAILABLE

Wednesday, April 23, 2014

Superiority Trials for Antibiotics

I want to try and clarify some issues around what people talk about when they discuss superiority trials for antibiotics. I was recently told that my statements have led to some confusion here. 

Well, I don't think I am confused.

When one thinks of generating superiority data for a new agent, there are several possible meanings of the idea of a “superiority trial”:

1. Head-to-head: A head-to-head prospective comparison of the new drug vs. an existing drug.

2. Sub-analysis: A superiority sub-analysis (or analyses) embedded in a non-inferiority trial.

3. External (Historical) control: An indirect comparison of a new drug with data from patients treated (inadvertently) with ineffective therapy for resistant pathogens

The first meaning (head-to-head) is the one that seems most commonly assumed but is actually unrealistic except under rare circumstances. In such a design, one group of patients would be randomized to some sort of standard of care whereas the second group would receive the new drug (perhaps alone or in a combination). In the case of antibiotics, though, this is exceedingly tricky. The standard of care patients are assumed to be getting therapy that might actually work. Indeed, the trial can’t be designed to deliberately seek superiority in a way that puts patients at risk: it is a requirement of the trial that a patient can NOT be enrolled if thought infected with a resistant organism!

Thus, the design of head-to-head superiority trials makes a demonstration of superiority unlikely, a point noted clearly by the regulators in their publications. The only possible loophole is that if the only available regimen is highly toxic (e.g., colistin-based), then a demonstration of superiority might be possible. However, the success of even one drug here would then create a new tool for future trials that would make it impossible to study the next new drug via a head-to-head superiority trial.

So - what are the alternative superiority designs for antibiotics? There are three possibilities in my view.

1. Embed a superiority trial within the context of a standard non-inferiority trial.  In this design - you have to show that, at the very least, your new drug is not inferior to some gold standard treatment. If you achieve superiority in a non-inferiority trial - that is your new drug is not only not inferior - but is actually superior to the gold standard - you can make that claim and get approved on that basis. But if you are non-inferior in the large population, you can carry out a pre-designed analysis on a subpopulation (patients where the activity of the gold standard drug might be equivocal for example) and try and show superiority there. If you can't - you can still be approved based on your non-inferiority to a gold standard antibiotic. Here you have hedged your bets and you are unlikely to lose your drug.  If you cannot show non-inferiority - then maybe you deserve to lose it.

2. Historically or externally controlled superiority trials. These are my favorite designs for superiority trials for antibiotics.  But they are not without controversy and clear disadvantages. The big gorilla here is the word "historical."
(a) The first such design would use a historical control based on pharmacometric analysis of previous but contemporary trial data. The best example of this is Paul Ambrose's analysis of the tigecycline trial in ventilator associated pneumonia.  In that analysis, his group clearly shows that patients who do not achieve therapeutic drug levels are more likely to fail.  The results in inadequately treated patients show what happens when you treat resistant infections with antibiotics that are unlikely to work because you cannot achieve high enough levels of drug to kill the infecting bacteria. Obviously, this is the case if the organisms are resistant - that is if the amount of antibiotic required to kill them is beyond what can be achieved in the body.  If you can show that your drug is superior in effect to this inadequate therapy - you should be able to achieve approval.  The big problem is that the controls are still historical and therefore the patient populations under study might be different.
(b) A second approach would be to carry out a prospective observational study of patients with highly resistant infections being treated with so-called standard of care (like colistin or tigecycline or others). This treatment would have some result in these patients. You then carry out a trial where patients receive your new drug, either in combination with "standard of care" or with some gold standard antibiotic. Only those with infections resistant to the accompanying therapy would be evaluable to see if your new drug was better than standard of care. You compare to the patients in whom you carried out your prospective observational study.  In this case, if the inclusion and exclusion criteria in the observational study and your later trial are very similar or the same, you can look for a superior result in your treatment group.

In this discussion, I have ignored the issue of endpoints. What constitutes a response to therapy in these trials?  That is too much for this blog - but I have one word for you - pharmacometrics!

My reading of guidance from both the FDA and EMA is that they are willing to consider such designs and, in my view, they would be accepted under the right circumstances.  One problem (among many) for the embedded superiority design is that the authorities might consider this a subpopulation analysis.  They generally don’t like that even if it is specified up front. But if that’s true, they should remove the possibility from their guidance.

I write this in the hope that this will clear up some of the confusion about what I have been saying for several years now. Externally controlled superiority trials might be feasible for new antibiotics targeting resistant pathogens. Embedded superiority trials within a non-inferiority trial (Brad Spellberg finally convinced me on this one) might also be feasible and in this way, at least you end up with a valid non-inferiority trial at the end of the day even if your superiority goals are not achieved – you have not put your new drug at risk.  


Friday, April 11, 2014

The John Quinn Memorial Fund

Hey everyone – remember John Quinn who passed away last October?  Since then, I have been working diligently with his widow, Maria Virginia Villegas and Jorge Cano to establish the John Quinn Memorial Fund. John spent the last months of his life working closely with his wife, Maria Virginia, an established investigator and infectious diseases physician, at the CIDEIM (Centro Internacional de Entrenamiento e Investigaciones Medicas) in Cali, Colombia. John enjoyed his work which involved guiding graduate students and post-doctoral fellows in their research on nosocomial infection and antimicrobial resistance. The John Quinn Memorial Fund has been established to carry on John’s work under the supervision of his coworker and widow, Maria Virginia.  MaVe (her nickname) is an extraordinarily energetic and capable infectious diseases physician and microbiologist.  She has established a network of hospitals in Colombia who collaborate to limit the spread of resistant pathogens and to investigate basic mechanisms of antimicrobial resistance in these pathogens. Her research is based on this large network of hospitals. 

After many months of work, Jorge has been able to establish a mechanism to provide for tax-deductible contributions for those of us in the US to give to this very deserving effort. It will take anywhere from $25 to $30,000 US dollars per year to fund one graduate student or post-doctoral fellow. These young investigators will be supervised directly by Maria Virginia. I have started the process with my own donation and I hope you will all follow my lead.

To give, go directly to The Give Colombia web site and click on Donate. Alternatively, go directly to the donation site. You will fill in your credit card info (or use pay pal) and then click on “continue and review” at the bottom of the screen. On the next screen, you will note the opportunity to “Add Special Instructions.”  Just note that your donation is exclusively for CIDEIM/John Quinn Memorial Fund and your donation will get to the right place.

I can’t think of a better way to honor John’s memory than to support the kind of research Maria Virginia and her team are doing.  It is especially important to provide an opportunity for this kind of training to young aspiring investigators from Colombia. I hope you will all join me in supporting this effort.

Friday, April 4, 2014

The Wall Street Journal, the FDA and Antibiotics

I don’t know what happened.  Suddenly, the Wall Street Journal has been struck by the superiority trial disease in antibiotic development. Luckily, in most (but clearly not all) cases, this is a curable condition.  In two (1, 2) recent editorials, the WSJ has reiterated the complaints of Senator Grassley and Congressman (at that time) Markey that non-inferiority trials for new antibiotics are insufficient to show that they actually provide any advantage over older drugs, many of which are cheap and generic. But this is an utter falsehood and is misleading to consumers and practitioners.

Don’t get me wrong – I think, unlike some of my colleagues, that it will be possible to succeed in superiority trials for antibiotics.  But these will be very small, externally controlled trials for patients with unmet needs or they will be in embedded in a very targeted way in non-inferiority trials where resistance to the comparator drug is common. Superiority trials will never replace the non-inferiority approach to antibiotic development as some would prefer.

In one of the WSJ editorials, they highlighted two drugs recently reviewed by the FDA Advisory Committee on Anti-infective Drugs (AIDAC), tedizolid and dalbavancin.  Both drugs were studied in non-inferiority trials against comparator antibiotics in the treatment of serious infections of skin and soft tissues. Both these new drugs and their comparators were about 80-90% efficacious in treating these infections according to the FDA’s interpretation of the data. The AIDAC voted unanimously in favor of approval.

Tedizold was studied in comparison to linezolid or Zyvox.  Linezolid is given twice per day while tedizolid is taken once per day. Tedizolid was given for a six day course of therapy while linezolid was used for its FDA approved 10 day course of therapy. Although the phase III trial could not show a difference, it is very likely that with prolonged therapy, tedizolid will cause less bone marrow toxicity than linezolid and that it will be associated with fewer problems with drug-drug interactions – especially those with anti-depressant drugs. So both the phase III trial data and other data provided by the sponsor on tedizolid suggest that is will be superior to linezolid in a number of important parameters – less toxicity, shorter length of therapy, less worry about drug interactions.

Dalbavancin is in the same class of antibiotics as vancomycin and the latter was the comparator for its non-inferiority phase III trials. Both vancomycin and dalbavancin are administered intravenously.  But dalbavancin can be administered as a single dose of a one-week treatment period.  This opens up the possibility for single dose therapy in the emergency department and prevention of hospitalization for some patients. For patients with kidney failure, a single dose of dalbavancin could last for up to a month. Even though, from a treatment efficacy point of view, vancomycin and dalbavancin were comparable, dalbavvancin may still offer advantages over vancomyin. There were some safety concerns for dalbavancin and I have my own concerns about using a drug that you cannot get out of a patient if there is a problem.  But none of these were important enough for the AIDAC to ignore the potential advantage of single dose therapy of serious skin and soft tissue infections.

It is theoretically possible to show superiority even in the context of a non-inferiority trial.  But when your treatment success rates are 85% as was the case in these trials, it is hard to show that your drug would be superior at the 10% level (95% success). Nevertheless, other advantages may be more important than efficacy.  Simpler dosing regimes, potential for prevention of hospitalization, for earlier discharge from hospital, lower toxicity, fewer drug interactions to name a few.

The other issue that the entire process raises for me is, once again, that of the competence of the FDA’s advisory committees.  I looked at the roster for the meetings that occurred on March 31. I’m not sure that there is anyone there with clinical trial design experience in the area of antibiotics.  Certainly there is no one from industry with such expertise. This again shows that the FDA is hog-tied by its inability to get good advice from true experts because of overbearing and, in my view, unnecessary conflict of interest regulations.

So – I am thankful that the AIDAC did the right thing.  I am surprised and disappointed that the Wall Street Journal is trying to take us back to the bad old days of 2006 and the Ketek scandal. And I remain frustrated by the FDA’s inability to get good advice from experienced antibiotic developers.

Saturday, March 29, 2014

The FDA and Me

Some of you may remember that last Fall, in the midst of the government shut down, I wrote a blog publicly expressing my desire to work (once again) for the federal government – specifically for FDA.  I offered my services free of charge starting this year since I planned on retiring from my consulting business December 31st of last year. I also felt that my retirement would free me of any conflicts of interest that the FDA might be concerned about.  I thought that I would provide you faithful readers with an update of my interactions with the FDA on this topic.

I was rejected.  Of course, I feel I have been rejected by more attractive places to work in the past.  In fact, in my consulting business, I found that sometimes, when I gave a negative opinion about a company’s sole asset, I was rapidly fired.  Some companies with more than one asset would listen to negative opinions and stop pursuing whatever avenue I criticized – but that also put me out of a job with them. And, as an academic, trying to publish papers and get grants funded, I can tell you that I’ve had a lot of experience with rejection.  I can take it. But I was particularly disappointed with FDA’s rejection.

My primary motivation for working with FDA was to help the commissioner’s office understand the real world impacts of the policies that the Division of Antimicrobial Products was putting in place through their constantly changing (recently mostly for the better) guidance documents on the development of antibiotics. I felt that the commissioner’s office – primarily Janet Woodcock – had their hearts in the right place.  It just seemed that they did not have the technical expertise to properly evaluate what the Division was doing.  Their main expert, Rachel Sherman, was about to leave the FDA (and has since left I understand). Around this time, Bob Guidos of the Infectious Diseases Society, left his job there and started to work at FDA.  I still don’t know what he does there – but there he is.

I started my contacts with the FDA in late November.  I wrote Dr. Woodcock and we arranged to speak in December – Bob Guidos joined our conversation. Dr. Woodcock pointed out that I would be unable to work for them for free – they would have to pay me.  Well, OK then. I then provided, at their request, a written summary of areas where I thought I could help.  Specifically, I mentioned considerations in the design of small superiority trials in areas of unmet needs and the design and definition of endpoints in more traditional non-inferiority trials.  I emphasized various ways we could use pharmacometrics to help in these considerations. I spent some time on the mortality endpoint for hospital-acquired pneumonia that I still think is the wrong way to go. Over the next month, Bob got back to me asking for more details whereupon I sent him several of Paul Ambrose’s papers with an explanation of the approaches I was considering.  I pointed out that the FDA had much of the data that we would need to carry out the appropriate analyses and that we could always get Paul or George Drusano to help.

And that was that. I have had radio silence since January and have concluded that I have been rejected. Maybe they have hired Paul or George – but I don’t think so. Of course, I really shouldn’t be surprised.  I have been extremely critical of them for years – probably since around 1999-2000.  I thought of it as tough love – and I thought they did too – but maybe not.

Don’t worry. I am now going to pursue other outlets for my desire to continue to be active in the area of policy on the discovery and development of new antibiotics where I think we still have lots of work to do. (Hint – pricing and economic considerations).

Sunday, March 23, 2014


Gilead and Hepatitis C Drug Pricing.  Speaking about pricing, I was infuriated to read Andy Pollack’s report of congressional self-righteousness on the topic of Gilead’s pricing for a new, less toxic, more effective and shorter therapy for chronic Hepatitis C infection. Also see Josh Bloom’s article on the same topic a few months ago. Let’s think about this for a few minutes.  Hepatitis C is the most common infectious cause for liver transplantation in the world today. Before Gilead’s Solvadi, the standard treatment was 24 – 52 weeks of interferon plus ribavirin.  Interferon causes fever, chills, depression, low blood counts and a number of other problems.  It has to be administered by intravenous injection monthly. Other drugs have to be used to counteract its side effects. Ribavirin is given as a pill (many pills) and causes anemia among other things.  Sometimes transfusions are required to maintain blood counts throughout a course of therapy. And after you have finished the entire course, the failure rate of this therapy can be as high as 50%. Even though Solvadi has to be given either with interferon And ribavirin or just combined with ribavirin (depending on your type of HCV virus infection), the treatment course is just 12 weeks. There are fewer side effects and the therapy works much better curing about 80% of patients. And when I say cure – I mean cure.  No more need for therapy.

Solvadi, perhaps in the future, could be used with other new, less toxic drugs such that ribavirin and interferon could be avoided altogether.  That is now the holy grail of HCV therapy.
Not every patient infected with HCV has to be treated.  Some will just carry the virus (and presumably could pass it on to others) but will not suffer harm from their infection. About 80% of patients who become infected with HCV will develop a chronic infection.  But only about 15% of them will go on to develop complications from their infection that would require therapy. Some of this 15% will go on to get liver cancer or will require liver transplantation. Because there is a limited population that would require therapy, Gilead needs to charge a high price to recoup their investment in Solvadi (and all the other drugs that failed before Solvadi). Not only that, but it is easy to show that even at the price Gilead is charging, $84,000 per 12 week course of therapy, the reduction in side effects and the greater benefit of therapy is easily worth every penny.

Yet Representative Henry Waxman and other Democrats on the House Energy and Commerce Committee are demanding that Gilead justify their pricing.  While I think this will be easy for Gilead to accomplish, it is frustrating that Congressman Waxman is getting on his self-righteous high horse without adequate knowledge of the situation (I’m being charitable here since I can think of no other rational explanation for his behavior). I am getting on my own soapbox here because this could have implications for antibiotic pricing and the last thing we need is someone putting a damper on this at this critical time in the evolution of antibiotic research.  

Compared to oncology drugs (most of them), treatment with Solvadi or antibiotics against bacterial infection result in CURE!  Not ongoing therapy forever, not in a few months of additional life in the hospital or hospice, but CURE!

Antibiotic Pricing.  In the better news department, an article in Barrons notes that the Disarm act, currently in front of congress, would remove punitive fiscal measures from DRG reimbursements when hospitals use expensive drugs under certain circumstances.  In this particular case, congress is targeting patients with high unmet needs where the drug is limited to restrictive populations.  In other words, the bill apparently is specifically designed to allow the kind of pricing for highly specific antibiotics that would be required for companies to earn a return on their investment.  This means the $15-30,000 per course of therapy that was discussed at the Pew meeting last year would be reimbursed by Medicare, Medicaid and other payers.