Monday, October 28, 2013

Superbugs - Europe Wins Again!

Recent press reports note that Basilea, a troubled Swiss biotech, has finally won European regulatory approval for their antibiotic, ceftobiprole.  Why might this be important?  Well, as most physicians, certainly infectious diseases physicians know, it is much better to treat patients with severe staph infections with a B-lactam antibiotic like a penicillin or a cephalosporin that with almost anything else – especially vancomycin.  But with the emergence and rapid spread of the superbug MRSA starting in the early 1980s, since they were resistant to all the B-lactams, vancomycin was all there was really. Just in the last few years, two B-lactams, ceftaroline (from Forest) and ceftobiprole (from Basilea) were discovered and developed for their activity against MRSA.  Finally, we would have B-lactam antibiotics to treat these superbug infections.  Ceftaroline has now been approved in the US and in Europe for the treatment of community-acquired pneumonia and skin infections.  Ceftobiprole, which actually started out ahead of ceftaroline, was almost killed by poor quality control during their pivotal clinical trials.  This resulted in no approvals for the drug either in the US or in Europe in spite of over 100 million dollars spent in clinical trials.  Basilea ended up suing its partner, J&J, over this and winning over $100 million in settlements.

But Basilea has persisted and filed for approval for hospital acquired pneumonia and community-acquired pneumonia with EMA.  Apparently, EMA has accepted their dossier and approved the drug for these indications (even though I can’t find this on the EMA website).  I am jumping for joy!  Why?  Ceftaroline, the only other B-lactam active against MRSA isn’t even studying hospital-acquired pneumonia.  But hospital acquired pneumonia is the one place where we most need a B-lactam for MRSA infections. Now, Europeans will have access to the only other B-lactam around for the treatment of these infections.  Plus – the drug was approved for community-acquired pneumonia at the same time – providing some competition in Europe for ceftaroline in this indication. What about us Americans?  Sorry – but the best kind of drug to treat MRSA pneumonia acquired in the hospital is not approved for use in these infections by the FDA. So Londoners, Parisians, and actually virtually everyone else in the world will have access to a B-lactam to treat MRSA infections.  Since ceftobiprole is not approved for any other indication in the US, the drug is not sold here.  Ceftaroline is approved, and, in theory, could be used for hospital acquired pneumonia off label – but the approved dose for skin infections and community acquired pneumonia is probably too low for hospital acquired pneumonia – a more serious infection. 

Why, you might ask has ceftaroline not been studied for this indication?  Why has cetobiprole not been approved for this indication in the US?  I would let you guess – but you already know the answer.  The FDA’s requirements for approval for hospital acquired pneumonia are still, as stated in their latest draft guidance, completely infeasible. So there is a good chance that companies will simply not even bother with the FDA.  Basilea says that they will apply for US approval – but unless the FDA gets its head on straight – I’m not optimistic. Of interest, another drug, ceftazidime-avibactam, probably the most important antibiotic for Gram negative infections in the late stage pipeline, is carrying out trials in hospital acquired pneumonia.  But those trials are designed with endpoints accepted by Europe, but not the US FDA.  My interpretation of this is that Astra-Zeneca, who is developing the drug, have decided that the FDA requirements are so unrealistic that they chose the European requirements and are going to put the US in a take it or leave it situation when it comes to approval. It looks like Basilea has done exactly the same thing.  

So, Americans, do you want the best drugs for superbug infections or do you want to stick with something less? If you want the best – either move to Europe or move the FDA!

Saturday, October 19, 2013

John P. Quinn - In Memoriam

Fishing on Long Island Sound
It is with the utmost regret that I write today of the death of my good and great friend John Quinn who passed away at the age of 62 last night, October 18, 2013.  While I want the world to know what an important contribution John made to the fight against antibiotic resistance, today I want to share a more personal view of this wonderful individual who I will greatly miss. John, like me, was a professor at a great school of medicine in the Midwestern United States. He dedicated himself to the study of antibiotic resistance and to the care of his patients.  Like me, he realized that to make an even greater impact on the lives and health of patients, a turn to the dark side – the pharmaceutical industry – was going to be the best way to bring new and needed therapies forward.  So he accepted a position at Pfizer in 2008. 
Breakfast before wine tasting - France

I knew John as a colleague.  We would run into each other at meetings and advisory boards and we even collaborated on papers from time to time. But we were not really friends. At the 2008 ICAAC I ran into John and saw that his name badge showed him to be from Stonington, Connecticut.  Of course, John spent his whole life and career in Chicago – so I was surprised to say the least.  I live in Stonington.  Stonington is small. It turns out that John was living about a mile away from us in a small rented house on the Long Island Sound shoreline. From that moment on, John was a frequent visitor at our house.  He would come once or twice a month for dinner, wine and cigars – not necessarily in that order.  My wife, children, grandchildren and even the dog fell in love with John.  His quiet humor, his modesty and his ability to listen seduced all of us. We would sit on the deck watching the sunset while enjoying cigars and wine and talking.  We spoke about our families, our work, the pharma industry, academia, and all those things we had in common and not so much.

Pretty soon, John’s family began to arrive.  We had the opportunity to get to know and love Virginia, John’s wife, and his children – especially Chris and Veronica. They became part of our own family. We traveled to Columbia to spend time with them around a CIDEIM meeting in Cartagena.  John and Virginia came to visit us in France where we engaged in a favorite activity – wine tasting.

Then, in early 2011, John noticed difficulty swallowing those Columbian steaks.  He was diagnosed with cancer of the esophagus.  Being John – he quickly became an expert on the disease and went to Mass General/Harvard for therapy.  After almost dying from his first round of chemotherapy, he was able to undergo surgery to remove the tumor.  He knew that his chances were 40/60.  A year later – when the tumor recurred – he realized he had lost the coin toss.  By that time, Pfizer had shut down their antibiotic research program and John had accepted a position at Astra-Zeneca.  After the recurrence, John left AZ to live his life.  He moved to his home in Cali, Columbia to be with Virginia. He traveled extensively to Chicago, Dallas and New York visiting children.  And he packed in as much living as he could.  John went salmon fishing in Alaska, scotch tasting in Scotland and wine tasting with us in France. He kept busy in Cali helping Virginia and her students with their research programs.
All this time, John calmly and pragmatically faced the inevitable.  He managed his own illness with the help of his physicians, but studiously avoiding therapy that would further sicken him and diminish his chances of fully living the time he had left.   He did well until suddenly last month when he began having severe loss of appetite, weight loss and pain. After that, things went quickly.

John was an inspiration to all of us.  In his professional life, he was dedicated to bringing therapies to patients with resistant infections. And in his struggle with death, he faced his fate head on. He led the way for us all to live with him and put aside thoughts of what we all knew was to come.


Friday, October 18, 2013

FRONTLINE - Hunting the Nightmare Bacteria

October is National Breast Cancer Awareness month here in the US. Breast cancer kills about 39,000 women each year.  Antibiotic resistance probably kills about the same number (in spite of a completely underestimated number of 23,000 from the CDC recently).  Do we have an antibiotic resistance awareness day?  Do we wear red armbands and run in the parks or march in Washington or have local parades to promote research on antibiotic resistance? Do we pay the same price for antibiotics (that work) that we do for cancer therapies (that frequently don’t)?

On October 22, FRONTLINE and PBS will air a very important show called Hunting the Nightmare Bacteria.  I am hoping that this will help inspire people to do something – but I know that I am almost certain to be disappointed.  For example, in our area, the show will air at 10 pm.  I’m usually in bed by then (just kidding)!  But I would have preferred an 8 pm time slot.  But the 8-10 pm time slots are taken up with a review of shows (Just Seen It), an art magazine (Open Studio) and Julie Andrews on Great Performances.  I’m sure that we will all agree that these shows are more important than anything we could say about antibiotic resistance.

About a year ago, the Frontline folks approached me with the idea for their show.  I spent several hours with them discussing the perfect storm – not the book or the blog – but the actual problems surrounding antibiotics and antibiotic resistance today.  Early on, they were very uninformed but were clearly trying to catch up quickly.  I can report that they have mostly succeeded.  In this show that I highly recommend to any and all, Frontline takes from the bedside of patients infected with these highly resistant pathogens to the council rooms of the CDC and to those of the pharmaceutical industry.  In doing so, we see the conundrum facing patients, their physicians and clinicians. The lack of data coming from CDC is highlighted as is the fact that about half of the (human – they fail to qualify this) use of antibiotics in the US is probably unnecessary.

Left out of the show are minor problems like the use of antibiotics in agriculture, the incomprehensible approach taken by FDA for antibiotics for human use, and any kind of perspective on how to make progress in the future.  About 70% of all antibiotic use is in agriculture – mostly for growth promotion in animals where small amounts of antibiotics are added to feed to increase growth rates and get animals to market faster.  Every other country in the world (almost) has given up this practice without suffering economic hardship – but not us more advanced Americans.  This is another area where the FDA must act but has successfully avoided doing so since major reports on this topic came out in 1976 and even earlier.

The most disappointing aspect of the show is that it leaves us hanging.  The show presents only half of the key problems around antibiotic resistance, does not provide any sort of concise summary for us, and also provides no way forward.  The bottom line for most viewers will be that it’s hopeless – so why bother?  Drink and be merry! So – Frontline – good job overall but lets get it a little more together next time! I give them a B.

Thursday, October 3, 2013

I Want to Work for the Federal Government!

I want to work for the Federal Government (of the United States, that is). I think this is especially prescient of me given our current circumstances.  I also think it is a bit of nostalgia for those days when I worked for the Veterans Administration.  I fondly remember the 3 of my 16 years working there when the government actually passed a budget on time. I also always loved the last week of the fiscal year when, suddenly, a large pot of money would appear from nowhere and we would have to get it entirely spent within the week.  Do you know how hard it is to spend several million dollars (OK – maybe several hundred thousand) in a week? I have equally fond memories of the last government shutdown (which may have helped stimulate me to move to the private sector). During the last shutdown, as a physician, I was considered essential. Unfortunately, lots of other folks I needed were not – so caring for patients and continuing a research program became, shall we say, challenging.

It is in this sense of nostalgia for those good old days plus a deep appreciation for what government employees are now experiencing that I announce to the world that I want to go back to work for the Federal Government.  And – I want to be paid nothing – zero – nada. That way – I don’t have to worry about furloughs or anything else – I’ll be invincible! What can they do – fire me?  Of course, I have a specific plan. 

As you know, I will be retiring from my consulting business at the end of this year. I know those of you who are dedicated readers of my blog are depending on me to keep on keeping on – and I will try not to disappoint you.  The blog will continue.  But I would also like to continue my work in the area of regulatory policy.  To accomplish this, I need to work in a different way with FDA.  As it stands now, I speak to them – admittedly a little less this year than over the past several years – but still we speak from time to time.  I even think they listen to me sometimes and I certainly listen to them. I know a number of them read this blog.  Unfortunately, I no longer find this to be enough (I never did, truth be told).  I want to be on the inside, not the outside.  I want to try and give them a more real worldview of the implications of their policy considerations before they actually become policy and I would like to do this not just for the anti-infective division, but for those in the commissioner’s office as well. At the same time, I expect to get a better understanding of their view of the big policy picture and to try and somehow help meld these sometimes disparate and paradoxical approaches to the same issues into something that comes closer to a middle ground.

I have made my wishes known to the FDA – but I admit that I have not yet seen them gush with enthusiasm over this offer. I was hoping that my retirement from consulting would ameliorate for them, at least to a certain extent, any conflict of interest that currently exists. I was also hoping that they actually would find my experience and knowledge (such as it is) useful to them.

But, I do have a backup plan.  If the FDA isn’t interested in my offer, I’ll just spend more time concentrating on the classical guitar and my next book.

To all you government employees out there – I feel your pain!