2013 in Review

2013 was an eventful year in the antibiotics world – not all good but not all bad either. 

Both the FDA and Europe released new guidance on developing anti-bacterials for highly resistant infections and other unmet needs.  The EU guidance is much more user-friendly than that from FDA – but both provide feasible ways forward for very small trials for antibiotics targeting limited populations of patients with such unmet needs.

In the context of the FDA reboot, we began a discussion in earnest and with payers around the necessity for value-based pricing for new antibiotics active against resistant strains.  These new antibiotics would be developed along the lines of what the FDA calls anti-bacterials for unmet needs in their guidance released in July. The trials would be very small and the clinical data would be supported heavily by preclinical data and both clinical and preclinical PK/PD. Because the populations targeted by these drugs would be small, the industry would need to charge a high price for each treatment course in order to make a return on investment.  This will be true in spite of the smaller, less expensive trials required for achieving market approval.  The reduced expense will not be enough to allow sales at currently accepted prices. The meeting at the Pew in January confirmed that payers are willing to take on these high prices for products that can be shown to work.  Payers seem used to this idea based on their experience in oncology where drugs offering very little in terms  of value are already given high prices.  Further support for the concept comes from a paper published by Rex and Spellberg analyzing the cost-benefit of this approach and clearly showing that even very high prices can be supported by the benefits of new antibiotics that work where others don’t (if you don’t have a subscription to Nature – check my blog).

The development of feasible regulatory pathways for small, rapid and less expensive trials to register antibiotics targeting resistant infections plus value based pricing for such drugs provides the boost we need to get large pharma interested again in antibiotics.  Since these events, Cubist has purchased both Trius with its tedizolid being submitted to FDA and EU and its preclinical programs and Optimer with dificid for C. difficile infections. The two deals amounted to up to $1.6 billion. Roche entered into a licensing agreement with Polyphor for their new peptimomimetic antibiotic that is highly specific for Pseudomonas aeruginosa. This represents the first real venture into antibiotics (with one minor exception) for Roche since 1999 when they were the first large pharma company to announce they were quitting the field.  I fully expect this trend to continue in 2014 with increased investment in antibiotic R&D from venture capital and other private sources of funding as well as additional large pharma companies re-entering the field. 

In spite of all these activities, Astra-Zeneca, which has been the stalwart company for antibiotic R&D over all these years, announced that it would limit its investment in the area while awaiting further developments.  Basically, the CEO does not believe that value-based pricing will occur to the extent required for his company to make a sufficient return on their investment. Going forward, I am optimistic and believe that the CEO will realize the error of his ways – but nothing would surprise me from AZ at this point.

The low point of the year for me was the loss of John Quinn.  I hope to have more to say about this in 2014. But I know that John lives on and, like me, awaits the awakening of the sleeping giant that will be a new era of antibiotic R&D to provide the medicines that we need now and that we will need in the future.

The blog will continue.  I am retiring from my consulting business (see below), but not from blogging.  2013 and 2012 were both big years for the blog.  Since its inception, the blog has seen 138,000 page views from 38,000 different visitors. 2012 and 2013 were the biggest years for the blog with around 23000 page views each year compared to 12,000 in 2011. The most popular blogs were Lew Barrett’s piece on the market for a limited use antibiotics (4500 page views), the tribute to John Quinn (3800 page views), the FDA and CABP (3600 page views), rebooting hospital acquired pneumonia (3500 page views) and my piece on antibiotics in 2012 looking forward from 2011 (3028 page views).  

I’m looking forward to 2014 and my retirement from consulting.  I apologize to all those of you who wanted me to work with you this year and in the future – but all good things must come to an end sometime. I am hoping, though, as I noted in a previous blog, to be able to work more closely with the FDA to continue to implement their reboot of antibiotic development in a way that makes sense. I hope to be able to tell you more about that early in 2014. I’m now working hard on my next book, my guitar, and the blog, but I also have time to spend with my family and for travel that does not involve work.

To everyone out there in blog-land – many thanks for your continued support! Have a great New Year!

The Supplement Threat

The New York Times has recently published two articles on the use of so called nutritional supplements. Nutritional supplements are not regulated as drugs, but physicians and hospitals should, and usually do, treat them as drugs.  What does this mean? Supplements do not have to prove that they are efficacious and safe before they are sold.  The FDA can only regulate them in a retrospective way – when they find that there may be a problem. It’s like the FDA and food safety, at least until recently.  Only after the problem occurred, when it was too late, could the FDA crack down on a malfeasant food supplier. Same deal for supplements.

The FDA is now spending a great deal of its enforcement time dealing with supplements that have unlabeled active ingredients like steroids or Viagra-like drugs or amphetamines. Some have high quantities of things like arsenic or heavy metals like lead and selenium.  Some are just mislabeled so instead of getting gingko, you’re getting green tea or just twigs and leaves. All of these can be harmful to your health.  And – you don’t know that you’re taking them because you think that the supplement you are taking for your joint health or whatever is safe and effective.  You believe all those advertisements on TV.  Or you mistakenly believe that somehow the FDA has your back here.  You’re wrong on all counts. By the way – the FDA is not alone here – same problems in Europe.  My impression is that supplements are even more popular there than in the US.

Steroids in supplements can lead to masculine traits in women like beard, mustache or chest hair.  They can lead to breast enlargement in men.  But, in the worst case, they can lead to liver failure as noted in the second article in the Times. Liver failure can sometimes be treated with medication and watchful waiting, but sometimes a liver transplant on an emergent basis is the only alternative.  Sometimes, you die.

Another recent study looked at the utility of those vitamin pills many of us take every day.  Guess what!  They don’t do anything. But, in some cases, like the other supplements, they can be harmful or contain unlabeled contaminants.  Admittedly, the problem of unlabeled or mislabeled ingredients seems to be less urgent for vitamins – at least our risk of dying from taking them seems to be less than for other supplements – but they don’t seem to do anything to benefit us either.

What does all this have to do with antibiotics and why is this topic appearing in this blog? Well, supplements have always been a pet peeve for me and the latest spate of lay news articles has given me the opportunity to vent a little. But, some “natural” practitioners are recommending that one way to cut down on inappropriate antibiotic use – a noble goal – is to use nutritional supplements of various sorts instead. Obviously – I think this is a very bad idea.  If you don’t need an antibiotic because you have a viral infection that antibiotics won’t treat – don’t take them.  But if you have a potentially serious bacterial infection and you try to treat it with some supplement – you’re playing Russian roulette.

Education vs. Advertising in the Pharmaceutical Industry

 A series appearing in the New York Times this week on the explosion in prescriptions for Attention Deficit Hyperactivity Disorder (ADHD) that is occurring in the background of an exponential increase in diagnoses of this disease in both children and adults and aggressive direct to consumer marketing campaigns for medications by the pharma companies. Of course, ADHD has nothing to do directly with antibiotics and infectious disease per se but direct to consumer advertising is a topic that touches all areas of medicine.

Sometimes, believe it or not, when a pharmaceutical company discovers something truly innovative where no therapy or no vaccine has existed for the disease before, in order to provide appropriate information for physicians, education about the disease and the product are required.  I can give you a great example from my own experience at Wyeth.

Invasive disease caused by Streptococcus pneumoniae is not common in children – but is dangerous and costs society a good deal of money every year since the morbidity and mortality robs society and the children themselves of years of productive life. Prior to the introduction of Wyeth’s first Prevnar vaccine back in 2000, the World Health Organization calculated that over 5 million children under the age of 5 years died every year of this infection. Many more suffered serious sequelae from these infections. Five million seems like a big number, but back in the 1990s, Wyeth carried out a survey of pediatricians to ask how many cases of invasive infection caused by S. pneumoniae they saw every year.  The answer was one or two or less. Wyeth asked whether the physicians thought that vaccinating children against this disease would be worthwhile – only about 2% thought that such vaccination should be routine in the United States. Wyeth recognized, though, that the epidemiology of the disease and potential cost savings to the healthcare budget even in the US would be substantial.  They also recognized that death and suffering could be prevented for many thousands of young children if such a vaccine were safe and effective and were widely administered. Wyeth set out to convince the world that this was true.

To carry out their education campaign, Wyeth partnered with the Centers for Disease Control in the US, the World Health Organization, with pediatric infections diseases specialists and others.  They carried out epidemiological studies showing the incidence of disease in the US and around the world.  They sponsored presentations at pediatric and infectious diseases meetings. Prior to the launch of Prevnar in 2000, something like 70% of pediatricians thought that routine vaccination against invasive pneumococcal disease was a good idea. The advisory committee for immunization practices of the CDC recommended that Prevnar be given to all children in the US. Since its launch, it is estimated that there was a decline of over 90% in the disease caused by pneumococcal strains included within the vaccine.  Because some pathogenic strains were not included within the vaccine, Pfizer, the current manufacturer of the vaccine, has added a number of strains.  This allows the inclusion of less common strains causing infection in children, as well as more common strains causing infection in adults.

The story of the conjugated pneumococcal vaccines has been one of the great success stories of the last century.  Without a pharma-driven educational campaign to increase physician awareness of the problem of pneuomoccal disease, I’m not sure that the success would have been as rapid or as dramatic as it was.  

One could imagine that in order to encourage parents to comply with the CDC’s recommendation to obtain this vaccination of their children, some education would be required.  If pharma collaborated in sponsoring such an educational campaign – I don’t see anything wrong with that.  But I agree with some of the comments in the New York Times indicating that there is a fine line between education and outright marketing and that the latter is less beneficial at times than the former.

The Cost-Benefit of Value-Based Pricing for Antibiotics

Several weeks ago, Brad Spellberg and John Rex published a fascinating analysis of cost and benefits of a pathogen-specific therapy for highly resistant infections.  They used carbapenem-resistant Acinetobacter baumannii as their case study. There are a couple of different ways of looking at this as I see it.  First – how much is a so-called Quality life adjusted year worth? Apparently, the number accepted by most is something like $50,000.  If that’s true, its hard to understand how cancer therapies that prolong life, frequently without much quality benefit, for a few months are worth up to $100,000.  But maybe I’m missing something.  That said – who decided that $50,000 is a correct price for a year of quality life? The other way of looking at this is based on overall cost savings to the healthcare system.

Based on these sorts of considerations, Spellberg and Rex clearly demonstrate that if therapy costs $10,000, the cost per quality life year is only $20,000 (much less than $50,000). At prices of $4-8000 per course there were clear savings in health care costs overall.  In a sensitivity analysis, the authors show (Table below - click to enlarge), that even costs of therapy as high as $30,000, depending on the excess mortality caused by these resistant infections and the efficacy of the new therapy in preventing mortality, the costs could still be below $50,000 per quality year of life.

As I have argued previously, costs of antibiotics like the example chosen by Spellberg and Rex will have to be high in order to provide sufficient return on investment for the companies that market these products.  Given the potential for this return on investment plus feasible regulatory pathways for getting to market, we can expect to see more and more large pharmaceutical companies like Sanofi and Roche getting back into the antibiotics field of research.  With this movement, the private investment in antibiotics will once again flourish.  So – overall – the development of these therapies is a win-win-win for patients, physicians, societies and private industry and their shareholders.