David's New Book

Tuesday, September 26, 2017

Pull Incentives for Antibiotics - Update

There have been at least two recent developments on proposals for pull incentives.  One comes from the DRIVE-AB meeting this month and the other from the Office of Health Economics in the UK.  Both recommend “partial de-linkage” models. As I have said consistently, de-linkage is a non-starter and I think the prevailing opinion is now in agreement with that view.  De-linkage means that there would be no “marketing” spend by companies in the sense that they would not need any “sales” to support income.  Revenues would come entirely through a market entry reward of some sort. But this approach divorces the company from needed physician educational efforts and provides no incentives for generics to enter the market after the expiration of exclusivity for the product.

The recommendation from DRIVE-AB is illustrated below. It shows a market entry reward starting payments at the time of drug approval and continuing for five years. At the same time, the company is allowed to charge some price for the drug that is sold during those years.  The company can earn sales revenue both during the five years of the reward payments and thereafter. The reward remains contingent on various milestones that the company must meet including manufacturing, physician education, microbiological surveillance and other activities essential to introducing a new antibiotic to the market. DRIVE-AB predicts that this approach would stimulate antibiotic R&D to the extent that antibiotic approvals would quadruple over the next thirty years.  Personally, I think that probably does not take into account sufficiently the scientific risk inherent in antibiotic discovery and therefore that this is an optimistic prediction based on historic rates of approval. Nevertheless, I agree that this would clearly stimulate antibiotic R&D and would motivate investors and companies to continue in antibiotic R&D or to get back in that business.

The new publication from the Office of Health Economics promotes an insurance model as a market entry reward. In this model, with the approval of a new, needed antibiotic, company would receive sufficient reimbursement to provide for a net present value (NPV) of $100 million. This would cost the health system something like $262 million per year over ten years or $2.6 billion.  The question for me is, is $100 million in NPV enough? The answer from the marketing folks at Wyeth in the year 2000 was “no!”

Both of these models and a number of others, including and especially the exclusivity voucher model, could work. The insurance model is a better fit in Europe where most countries provide some sort of national health insurance already.  It is probably not a good fit in the US. I guess I don’t see anything wrong with different countries using different approaches as long as there is a clear and predictable return on investment for the companies such that they are motivated to continue or to re-enter the antibiotic research field.

I see a number of questions that are still extant. First -  how much do we really dislike and distrust the pharmaceutical industry that will be the source (in all likelihood) of these new products? During a recent lecture one of the audience members posed an interesting question. “If we are going to have to spend this amount of money, why wouldn’t we spend it on research in a government antibiotic R&D effort that would not require profits?” I’m sure this question comes, in part from a basic distrust of and anger towards a pharmaceutical industry that many see as consistently gouging consumers. And who can argue with that?  My answer was that the expertise exists today within industry.  But I suppose that could change, even though I remain extremely skeptical.

Another remaining question revolves around the numbers. How much NPV should society provide?  This, in turn, depends on how we value new antibiotics active against key resistant pathogens. It also depends on how we value the existence of a robust pipeline that is, in a way, our insurance against emerging resistance to the new agents that we are using sparingly hoping to avoid the rapid emergence of resistance.

No matter which model we prefer for pull incentives, and no matter whether we are angry at the pharmaceutical industry, we still need a robust pipeline of new antibiotics for the future.  And the only way we will get there is by assuring companies, at least for the foreseeable future, that they will have a sufficient enough return on their investment that they should, in fact, invest in antibiotic research and development.

Friday, September 15, 2017

Antibiotics and Climate Change

What do antibiotics and climate change have in common? We have our heads in sand for both.  If we can’t see it, it won’t hurt us. I was inspired by an article in the New York Times today on climate change contending that even some Republican congressmen and senators are reconsidering their hardline positions on climate change in the wake of hurricanes Harvey and Irma. I asked myself , “Is this what it takes? Do we have to suffer through death and destruction to recognize the accuracy of climate science?”  If the answers to these questions are “yes,” then I guess we also have to wait for the antibiotic apocalypse before we get a substantial change in policy.

On the antibiotic-resistance front, we seem to be able to insist on antibiotic stewardship.  Initiatives from the Centers for Disease Control with enforcement through the Center for Medicare and Medicaid Services assure that hospitals and now outpatient and even long term care facilities will establish antibiotic stewardship programs in the US. But these regulatory moves (mandated by the 21st Century Cures Act) don’t cost much in terms of real government funding and, ultimately, will probably save healthcare dollars. The same thing is true for regulatory moves that will establish feasible and rapid clinical development pathways for antibiotics that target very specific, small populations of patients such as those that are only active against a single species of bacterial pathogens (Limited Population Antimicrobial Development [LPAD] in the 21st Century Cures Act) (LPAD Guidance is expected soon from FDA).  All of this and more in the 21st Century Cures Act is good and we should all be thankful that Congress was able to get its act together and pass this important legislation.
But all of this, including the critically important regulatory innovations will be for naught if we don’t fix the broken antibiotics market. Without a clear path for a return on their research and development dollars, private industry will simply not invest.  Companies that are currently investing in the area may finally give up the ghost and, like many before them, abandon the area altogether.

In thinking about the climate change article in the Times, I am reminded of the global pandemic of methicillin-resistant staphylococcal (MRSA) infections that began in the early 1980s. By the 1990s, MRSA became part of common language.  I gave a lecture at a retirement community yesterday and everybody recognized the term, MRSA. These resistant isolates grew to 30-50% of all staphylococcal infections, and in emergency rooms, up to 70% by the turn of the century.  Until 1999 there was only a single reliable antibiotic to treat serious MRSA infections – vancomycin.  By 1989 vancomycin resistant enterococcal (VRE) infections had emerged and were causing havoc in US intensive care units.  In 1999 linezolid (Pfizer) was approved and in 2003 daptomycin (Cubist) was approved.  Both these drugs became over $1B per year sellers because they offered an alternative to the only other drug available for MRSA, and they offered possible therapy for enterococcal infections as well.  But look what we had to endure before these drugs came out.

Today, we are dealing with KPC, NDM-1, Acinetobacter and other highly resistant infections.  Yes, we have drugs available today that we didn’t have just a few years ago and we have more to come in our thin but existing pipeline. The question is, will we have to wait until emerging resistance in Gram-negatives becomes like the MRSA and VRE of this century. To be assured of a robust antibiotic pipeline, we must take this last step and provide an assured return on investment for those companies that deliver such needed new therapies. If we wait for the apocalypse, it will take us a decade or more to rebuild lost abilities to discover and develop antibiotics.

There have been a number of well-considered proposals on how to fix this broken market (stay tuned for more details). All involve spending real money.  I’m talking about a total of $2 billion per year for 10 years globally.  The US share would depend on which other countries would partner with us (I assume Europe would do so. China?). And here we run into the problem.  Just like climate change, we would have to spend real money.  Of course, compared to jet fighters, nuclear arsenal maintenance, and other priorities, $20 billion over ten years is peanuts. But to our administration and to congress, this seems to be an insurmountable obstacle.

Please – lets not wait for the apocalypse. Lets do something now before we lose more companies and more expertise to denial of the inevitable.

Friday, September 8, 2017

Let's Kill Colistin/Polymyxin


Today’s blog is inspired by recent grant proposals, discussions, publications and the promise of our antibacterial pipeline today. I see many proposals where the concept of a better polymyxin is envisioned or where the structure of polymyxin is used as a lead to generate a drug that will attack the bacterial membrane to allow penetration of other, more effective antibiotics. But my view is that we should relegate polymyxin and its relative, colistin, to the trash heap of unused drugs – the sooner the better.  And I believe that we are near the threshold of being able to do just that.

My strong feelings come from an experience I had during my training.  I’ve recounted this in both of the books I’ve written. I was working in a county hospital as an infectious diseases fellow.  The hospital was a trauma center and had a large burn unit. Burn patients were regular users of the infectious diseases service.  Even today about 70% of severely burned patients will experience a burn wound infection and these infections are a common cause of mortality in this group of patients. I was called to the burn unit to see such a patient with Pseudomonas aeruginosa bacteremia. I began treatment with carbencillin and gentamicin (you see how long ago this was). But the next day the lab reported that the isolate was resistant to all antibiotics tested except colistin.  And they told me that a second patient on the unit was now also growing Gram-negative rods in blood cultures. In all, we treated maybe six or seven patients for this infection with colistin.  All but one (as I remember it) died with continuing positive blood cultures in spite of adequate (above MIC) levels of colistin in plasma (measured by bioassay). All showed evidence of kidney damage during therapy. I was never forced to use colistin again because a robust antibiotic pipeline made that unnecessary for the most part.  For those rare patients where their infections seemed resistant to all available antibiotics except colistin, since they were all urinary tract infections, I was able to devise combination therapy to get those patients through their infection without having to resort to colistin. 
Today we now have ceftazidime-avibactam (caz-avi). A recent prospective observational study of caz-avi demonstrated a 9% mortality in the caz-avi group vs 32% in the colistin group – a 23% reduction in mortality when caz-avi was used as compared to colistin. Most infections treated were pneumonia or bloodstream infections. Renal failure was significantly more common the the colistin group and overall, there was a 64% chance that caz-avi treatment would lead to a better outcome compared to colistin.

We are also about to have plazomicin – a new aminoglycoside antibiotic. In their prospective randomized clinical trials they demonstrated an all cause 30 day mortality of 11.8% for plazo treated patients vs 40% for those treated with colistin. The difference in the subset of aptients with bloodstream infections was even more dramatic in favor of plazo.  11% of plazo treated patients and 29% of colistin treated patients suffered a serious adverse event related to decreased kidney function.

Vabormere (OK – it sounds like a body of water from the Tolkien novels), a combination of meropenem plus the broad spectrum beta-lactamase inhibitor vaborbactam, was just approved by the FDA based on data in the treatment of complicated urinary tract infections where it was non-inferior to piperacillin-tazobactam.  Vabormere seems to specifically target Gram-negative infections where the pathogen carries a carbapenem hydrolyzing enzyme of a particular type such as KPC that is widespread in the US. As a side note, it was approved based on a single trial and yet its label did not restrict its use to those patients without other alternatives. Would anyone like to guess whether vabormere will be superior to colistin in its ongoing trial of treatment of carbapenem-resistant infections?

Then there is cefiderocol – a novel cephalosporin antibiotic developed by Shionogi that uses a siderophore to get into Gram-negative bacteria. It has completed a trial in complicated urinary tract infections where it was non-inferior to imipenem, a carbapenem antibiotic.  In vitro, the compound is active against many carbapenem resistant strains including those not covered by caz-avi or vabormere. A competitor for cefiderocol would be aztreonam-avibactam that seems stuck in early clinical development. But both of these drugs should also be superior to colistin/polymyxin. 

For now, for most infections, even drug-resistant infections, there is no reason to use colistin/polymyxin.  Over the next year, we will be able to treat even more resistant infections without using these ineffective and toxic drugs. The only reason to continue their use is the cost of the new drug therapies.  But when compared to the cost of kidney failure and mortality, what are we talking about?  

Monday, August 21, 2017

Pull Incentives - An Open Letter to my Legislators

Dear Readers – please copy this and share it with your own representatives.

Dear Senators Blumenthal and Murphy and Representative Courtney,

I am writing this letter with the express intent to goad you into doing more to prevent the emerging crisis of antibiotic resistance becoming an urgent public health catastrophe.  The most important problem preventing further progress towards ramping up our antibiotic pipeline is the broken marketplace for antibiotics. We have come to view these drugs as cheap and always available – almost like a right to cheap lifesaving medicine. We also like to take new antibiotics and reserve them for only those patients who absolutely need them in order to protect them from emerging resistance.  This is a good plan for the public health, but not so much for the marketplace. The antibiotic market no longer provides for even a reasonable return on investment in R&D for these lifesaving medicines. 

You may argue that the pharmaceutical companies make billions in profits every year and that they have an obligation to pay us back by continuing antibiotic R&D even though they won’t be able to make money in this area. But these companies are there to make a profit for their shareholders. They will follow the money.  There are exceptions. But in 1990, ALL of the large pharmaceutical companies had active antibiotic R&D programs. For those special companies who continue their efforts in antibiotic R&D, given the bleak market prospects, they could abandon their efforts at any time.  Some have even been discussing this possibility. Most companies abandoned the area years ago for a variety of reasons – but the lack of a viable marketplace was an important motivation.

Why can’t the NIH or academic centers take this on?  Because they do not have the resources – but more importantly, they do not have the expertise. It would take many years of investment and education to get our academic research centers ready to take on this task. And even then there are many roadblocks to success here.

Since you have all been involved in discussions around the regulatory changes needed to assure our pipeline of new antibiotics, I don’t need to explain the importance of the problem of antibiotic resistance and its potential threat to our aging population as well as our children and grandchildren. The GAIN Act that forced the FDA to put feasible antibiotic development pathways in place was an important step. The 21st Century Cures Act that established a pathway for antibiotics to be used in limited populations with high medical need was an even more important step and I applaud you for leading this effort.

I don’t need to point out that the O’Neill Commission (as I call it) predicted 10 million deaths worldwide from antimicrobial resistance (including TB and Malaria) by 2050 if current trends continue. The cost to society globally could be as high as $100 trillion in lost GDP.

In this crisis the US, including the state of Connecticut is not spared. Nationally, the rate of highly resistant infections like those caused by highly resistant Gram-negatives called CRE has been rising as shown in the following data collected by Achaogen.

The New England area is not spared as shown in this map.

While antimicrobial stewardship and reduction of the use of antibiotics in agriculture and animal husbandry will help, even appropriate use of antibiotics will continue to select for resistance.  It’s the inevitable result of the formula – “you use it, you lose it” for antibiotics.

Improved regulatory pathways such as those already in place and those being developed by FDA will not be the entire answer either. Why?  Because the marketplace for antibiotics is broken.  Only government can fix this problem.  Without a healthy market, companies, where antibiotic discovery and development expertise reside, will not invest.  They can’t make money here – especially when compared to areas like oncology. We have seen the result of this with the majority of large pharmaceutical companies having abandoned the area starting in 1999.

The push incentives from HHS, the Wellcome Trust and others have been very powerful in helping to fund antibiotic research and development.  But they still will not be enough.  Companies need to see a viable market at the end of their R&D road.

The fix, unfortunately, no matter how it is constructed, will involve spending taxpayer money.  The funds can come from all taxpayers, from consumers of all pharmaceuticals, or from consumers of certain drugs where generic entry might be delayed by a few months. The way this will work will depend on the approach that government chooses. 

Of course, the other way to fix the broken antibiotic market is to wait for the crisis to hit. A good example of this is the global pandemic of methicillin-resistant staphylococcal (MRSA) infection that hit starting around 1982.

 By the late 80s, pharmaceutical companies were increasing their research efforts to come up with new therapies for serious MRSA infections.  They did this because they thought they saw a market opportunity in the growing number of cases of these infections.  But it took a great deal of time for them to get something on the market. The only oral drug for the treatment of these infections, Zyvox, was approved in 1999. Cubicin, discovered in the late 80s or early 90s hit the market in 2003. How long do you want to wait for the industry to get a new therapy to market after the crisis has hit? Luckily, for MRSA we had at least one other efficacious antibiotic we could use.  But in the case of these highly resistant Gram-negative infections, our choices are limited and not very efficacious.  So how long do you want to wait?

The answer is to fix the market now – with government funding. How much would this cost?  The US share (assuming we share the burden with Europe) would probably be something like $1-2 billion per year over the next 10 years. Our share would decrease if China, Japan and other Asian nations would join us. This is a paltry amount of money compared to our national budget.

So what are you waiting for?  Are you waiting for you or one of your loved ones to encounter one of these deadly infections personally?  Are you waiting for a more politically palatable moment to act? Like you, I am not getting any younger.  And I have children and grandchildren I care about. I have worked in hospitals where I have had patients with bacterial infections for which I had little or nothing to offer. Physicians and their patients should never be put in that position. And now, you, not anyone else – but you – are tasked with fixing this. Delay just increases the risk of a situation that none of us wants to imagine.

I am ready, willing, and with a little help, able, to work with you and your staffs to construct legislation that would fix the antibiotic market. It can’t happen without you. Please help!


David Shlaes

Stonington, CT