What if . . . ?

First, I need to apologize to my readers.  I took almost the entire month of February off to escape the New England winter – hence the lag in blogs. I promise to make it up to you in the next few weeks.

There have been a number of developments in clinical trial design issues and, at the same time there is a continuing failure to develop novel trial designs as well.  I’ll discuss this in my next blog.

Today, I want to speculate on incentives for antibiotic research and development. As I have mentioned, I recently joined the Drive AB effort to help design effective incentives.  The Drive AB effort is very well described on their website. The purpose of the Drive AB effort as they clearly state is to “develop new economic models to incentivise antibiotic discovery and development activities while safeguarding the efficacy of antibiotics by researching and advocating their appropriate use.” On the surface, this sounds simple – but as most of us know – achieving this will be incredibly challenging.

As I have been thinking about incentives, a single question keeps popping into my thoughts. Who, exactly, are we incentivizing? I think the incentives required will differ depending on the answer to this question. The Drive AB private partners are large pharma companies.  The first stakeholder meeting of Drive AB focused on European small to medium sized enterprises. (My view is that these companies and investors are far less numerous and experienced than those found in the US, by the way).  But the concerns of large pharma are entirely different than those of small pharma. Lets try and dissect this out a little.

Large pharmaceutical companies are mostly worried about a return on their investment in antibiotic R&D. Because of the high risk of such research, high margins are required for any successful products to provide a reasonable return.  In today’s markets, these high margins have been impossible to achieve with antibiotics – which partially explains the abandonment of the area by most large companies.  For these companies, a large incentive that provides for a rapid return such as the incentives discussed in the O’Neill report is best.  So called “push” incentives where upfront costs are defrayed by funding for research and development are also helpful since this ultimately reduces the amount of money required during sales in the marketplace in order to provide a return.

The situation for small companies may be somewhat different.  Here, push incentives are probably even more important as this reduces the amount of money that must be raised from investors (like VCs). Other advantages like tax breaks will also be more important for the small company than the large one. But, when it comes to marketing, we come to another fork in the road. Some small companies like Theravance, The Medicines Company and Allergan are willing to or even prefer marketing the antibiotics themselves. For them, more push and somewhat less pull (post-market) incentives would probably work well. Other small companies are funded by investors, especially VCs, who strongly prefer an acquisition as an exit.  While this can occur via a small company like The Medicines Company, VC investors more often target large pharma companies.  This then takes us back to incentives for large pharma and to the following question.

If a large incentive paid at the time of approval were to be made available for new antibiotics active against resistant pathogens, particularly on the large pharma side, what would be the result?

1.     Would Astra-Zeneca re-start their antibiotic discovery effort?  Would they be less likely to jettison their antibiotic development and sales group?

2.     Would the commercial and development group at Novartis be more welcoming to new antibiotics?

3.     Would companies on the edge like Pfizer and J&J jump at the opportunity to re-engage in antibiotic R&D?

4.     Would companies who abandoned antibiotic R&D over a decade ago like Lilly, BMS, Bayer, Abbott etc. be convinced to get back in the game?

I would like to get answers to these questions before we go ahead and design proposed incentives. What about you?

Big Pharma and Antibiotic R&D - An Update

Today I went back to the book I wrote back in 2010 – Antibiotics – The Perfect Storm.  In that book I had a table showing the number of large pharmaceutical companies (>$10B in revenues) pursuing antibiotic R&D and those who were not.  I then updated that table as it stands today.  It is shown below. 

Guess what!  The names have shifted, but the numbers are the same.  Since I wrote the book, Pfizer and J&J dumped their antibiotics research programs, but Roche and Sanofi restarted theirs. I put AstraZeneca and Novartis in parentheses this time since AZ recently spun out their discovery group and is now entirely a development organization while Novartis remains schizophrenic (as far as I can tell).  Novartis has an active and dedicated antibacterial research group, but a hesitant development and commercial group (unless something has dramatically changed recently).

The players who have returned to the field since 2010, Roche and Sanofi, have yet to produce anything truly promising.  Also, I guess I should add a number of companies to the list.  Gilead had $29B in revenue in 2014, but remains a highly specialized company focusing mainly on antivirals. There may be other companies that I should have added as well – some of you will know this better than me.

This week, at the Davos conference, a group of pharmaceutical and diagnostic companies released a declaration supporting incentives for antibiotic R&D. In going down the list of signatories, the only large companies not pursuing antibiotic R&D that signed were J&J and Pfizer. Abbot, Bayer, BMS, Lilly, (Gilead), were nowhere to be seen.  As I noted for the New York Times this week, the question is, even if the incentives were to appear such that a return on investment for antibiotics was guaranteed, would some of these companies get back in the game?

The absence of signatures may tell the story.  Why? Once you have abandoned a field of research, you lose all internal expertise in that field.  Getting back in is hard and takes years.  Just ask Roche and Sanofi. Some of these companies probably feel comfortable where they are and have no desire to get back to antibiotic R&D even if there could be a return on their investment. 

The story with Pfizer may or may not be different.  I noted in November that they are pursuing a purchase of Allergan.  Allergan has the US rights to the promising AZ pipeline of antibiotics for resistant Gram negative infections and is already marketing ceftazidime-avibactam (Aycaz). This means that Pfizer would have an opportunity to get back in.  Will they take it?  Is that what their signature means? Will incentives help them decide? Who knows?

I leave the question as to whether we have made progress since 2010 or not up to you.

AstraZeneca Where Are You?

You will all remember that mcr-1 mediated resistance to polymyxin (colistin) emerged on transmissible plasmids last year.  How did it arise? Because Chinese farmers wanted their pigs to grow faster – so they fed them low doses of this antibiotic as a growth promoter.  I pointed out in my previous blog on this that the US allows use of polymyxin as a growth-promoting agent as well. This means that our very last, end of the road, toxic and poorly effective antibiotic for otherwise totally resistant Gram-negative infections is in serious jeopardy.  That means that WE are in serious jeopardy. By the way - since its discovery, the gene has been detected pretty much worldwide. 

These cheerful thoughts lead me to think about Astra-Zeneca?  Why?  Because they (and their partner, Allergan) have an antibiotic in their pipeline that could make a big difference here. Aztreonam-avibactam combines a monobactam (aztreonam) that is resistant to the metallo-beta-lactamases like NDM-1 with a broad spectrum B-lactamase inhibitor that will protect aztreonam from destruction by any other B-lactam hydrolyzing enzymes that might be (and usually are) present in the pathogen in question. This combination has been shown to be active in model systems (hollow fiber) suggesting that it will be highly active in vivo. Way back in 2010, David Livermore, myself and others were pleading with AZ to get aztreonam-avibactam into clinical trials so we could treat highly resistant pathogens like these.

Aztreonam-avibactam did not enter phase I clinical trials until January of 2012. Those phase I trials appear to have been completed according to clinicaltrials.gov. Here we are, four years later and that’s where we are folks. During that time, Astra-zeneca has spun out their antibiotic discovery group into a company called Entasis.  AZ has also turned their antibiotic development group, still within the parent company, into a separate business unit – a move I applauded then and still do. This means that they have their own profits coming in from their sales of ceftaroline and meropenem.  That should be plenty of money to finance the development of aztreonam-avibactam.  Not only that, but they recently received a large grant from BARDA worth up to $220 million and they have funding from the European Union for aztreonam-avibactam as well. So, you might ask, why is this development proceeding at such a tectonic pace?  If this keeps up, the drug won’t be available until my grandchildren reach my age if then.

It strikes me that, for an antibiotic like aztreonam-avibactam, that targets a tiny number of cases (at least today), the data that might be required to get regulatory approval for human use will probably be fairly minimal and could be accomplished quickly – especially in Europe where AZ holds the rights to this drug.

I contacted my friends at AZ to let them know that I was going to be writing this blog.  I asked if they could comment on the development of aztreonam-avibactam.  I asked if at Entasis they were trying to discover even better inhibitors than avibactam that might deal with other resistant strains.  I also asked who it was that was head of the new business unit. No comment, no comment, no comment. Why is the name of the new business unit director a secret???  When I asked that question my friend replied – “you and I both know what its like to work for a large company.”

So – to those of you out there still depending on colistin to treat highly resistant Gram-negative infections, you better hope that mcr-1 does not arrive at your hospital before aztreonam-avibactam does.  Good luck on that.

2015 - Year in Review

The highlights of the year 2015 for me begin with the discovery of the iChip technology by Stava Epstein and his colleagues in Kim Lewis’ lab. This technology allows the growth of previously non-cultivatable antibiotic-producing organisms from soil by simply isolating them and placing the back in the soil environment from which they came. Its elegant and holds much promise for the discovery of novel natural product antibiotics in the future. We are all awaiting further developments here.

The output of reports from Jim O’Neill’s Review on Antimicrobial Resistance continues to amaze me even if  I don’t agree with all their conclusions. The idea that incentives for the discovery and development of antibiotics could actually become reality in my lifetime is nothing less then a breath of air after the stifling nightmare of the last 15 years. I have been so inspired that I have joined the Drive-AB effort to help make this dream come true.

This year finally saw the results of Astra-Zeneca’s efforts to sell its antibiotic research, development and business franchise.  Being unable to obtain the price they were demanding (one presumes), they adopted a different strategy.  This year they spun out their discovery group into a company, Entasis, fully funded to the tune of $40 million by the mother ship (AZ).  Shortly after that, they announced the formation of an independent business unit within AZ that would encompass their antibiotics business and as well as their clinical development group. What will happen to them is still to be determined – but I will have more to say about this in the next week or so.

A big highlight for me this year, and I hope for you, too, was the appearance of my new book – The Drug Makers.  I have been gratified by the many positive comments I have received from those within and from many outside of the pharmaceutical industry.

On a down note, Tetraphase reported that their phase III trial of eravacycline for complicated urinary tract infection failed to meet its endpoint. I was especially disappointed in this news because I helped them design the trial and thought that we had done everything to assure its success. Luckily, I own no Tetraphase stock since it crashed by about 80% with this news. I am still hoping that eravacycline will make it to the marketplace since we desperately need an effective, oral antibiotic for resistant Gram-negative infections.  Eravacycline is the only drug fitting this bill on the near term horizon.

On another low point, I discussed the effect of increasing drug prices, especially for generic drugs, on public opinion and even on pharmaceutical company stock prices and on the political campaign. I suggested that the US should adopt two simple (but politically fraught) policies to deal with this issue.  (1) We should subsidize alternative manufacturers for essential medicines to prevent price gouging. (2) The US should finally begin to negotiate drug prices nationally at least on a federal level just like virtually every other country in the world.  This is guaranteed to control prices.  While some argue that it will reduce innovation globally and here in the US, I remain unconvinced and believe we should do the experiment.

There have been important issues in the FDA reboot of antibiotic development this year related to antibiotics active only against specific pathogens. I discussed this with FDA this fall.  Their problem is that they believe that they need some sort of inferential data to approve a new drug while I think there are lots of examples where this has not been the case. They are pursuing this with the President’s Advisory Council on Combatting Antibiotic Resistance. Once again, I await further developments here and you can look forward to additional blogs on this in the future.

The recent announcement of the proposed merger between Pfizer and Allergan was the subject of a blog and a recent Lancet article. My worry is that Allergan’s key antibiotic pipeline for North America based on the beta-lactamase inhibitor, avibactam, will be in jeopardy because of this merger. Pfizer is not known for its enthusiasm for antibiotics these days.

A recent court ruling suggesting that the promotion of off-label uses for drugs was protected speech raised my hackles.  If this ruling ever becomes the law of the land, it will mean that companies can sell anything for anything. Lets not go there – please.

Finally, the recent emergence of mcr-1, the plasmid-mediated gene encoding resistance to our very last line Gram-negative antibiotic polymyxin (colistin) scared the hell out of me. The gene has now been found in Asia and in Europe after having apparently emerged in China.  Why did this occur?  Because in China (and apparently here in the US) polymyxin can be used and has been used as a growth promoting agent for pigs and/or cattle. In an editorial, Josh Bloom and I suggested that this practice must stop and must stop globally.

With that, I wish you all a happy, productive and very safe 2016!

Infection Control in a Small Hospital

Today I want to continue talking about what its like to work in infection control in a small hospital.  About 70% of all hospitals in the US are under 200 beds and 55% are under 100 beds. I carry out infection control work on a volunteer basis for a hospital near my home with an average census of around 40-50 patients. Since I began working there about four years ago, the hospital has undergone receivership, was purchased by a larger hospital in the area, and our system is now about to merge with another huge health care system in our region. This constant series of administrative earthquakes has challenged our infection control efforts.

We have made enormous progress on a number of fronts. Our hand hygiene program has had huge success with compliance rates now approaching 100%. We have revamped our microbiology procedures to better diagnose patients with pneumonia and to better identify resistant bacteria. Our antibiotic resistance rates among key pathogens remain low. We are revamping our surgical wound infection prevention program in a way that I believe will further reduce our already low rates of infection. And we have made great strides in assuring that patients requiring isolation remain isolated during all their sojourns around the hospital for diagnostic testing and procedures.

Our hospital is one of the highest rated medical centers in our area based a number of criteria including patient safety and infection control.  We do very well on all our external audits including those by the Joint Commission on Accreditation of Hospitals. And I agree that the hospital provides high quality care. I just know that we could do even better.

We do have a number of challenges that I think are directly related to our small size.  Our digital medical records system is badly in need of overhaul. It cannot perform any of the key infection control functions such as microbiology lab surveillance, diagnostic code surveillance for hospital-acquired infection nor can it provide reporting to the National Healthcare Safety Network of CDC.  All of this must be done by hand by our infection control nurse.  Our nurse also carries out daily rounds on all the hospital inpatient units, screens the OR schedule and peruses the emergency room patient and diagnosis list in pursuit of infections that might have been acquired at the hospital and of patients in need of some sort of isolation for colonization or infection by multiply-resistant organisms. She struggles to get all this done without computer support.

Our computer systems also are unable to support our antimicrobial stewardship efforts.  We are unable to determine antibiotic dosing in standard format such as defined daily doses. This makes it almost impossible to follow antibiotic usage trends. The pharmacy staff has been cut continually since I joined such that it is difficult for them to keep up with basic stewardship functions such as assuring that patients are getting the correct doses of the antibiotics that the physician has ordered.  Other functions, like trying to get patients off of unnecessary antibiotics, have fallen by the wayside.

Every time we attempt to bring on new functionality to our system or bring in a new computer system for infection control, we are about to merge and are told that we have to wait for the merger to occur.

My hospital has a small intensive care unit.  It exists to back up our surgeons who refuse to operate (understandably) in a hospital without such a unit.  In fact, our ICU maintains a census of 3-5 patients and there is almost always at least one or two on a ventilator. The problem is that we have only one intensivist.  Obviously, he cannot be there 24/7.  Although this may work well, the reliance on trained physicians assistants, ICU nurses and frequent telephone contact makes me nervous. I would prefer to have enough intensivist coverage such that some trained physician was easily available on a 24/7 basis. To resolve this would require systematic changes that might be forthcoming with the latest merger – but in the meantime, we are still on hold. 

Some might say that we should close the hospital altogether.  But those people do not live in this community.  To the community, the hospital is very important and extremely well liked and, as I noted in the beginning, we provide high quality care for our patients.  

Having worked in a very large hospital system (I was at a university-affiliated VA for 16 years), I now understand the issues confronting both types of systems, large and small. Small hospitals have unique problems that are not appreciated by insurers and key payers like Medicare and Medicaid.  Yet small hospitals comprise the bulk of hospital-based healthcare in the US. We need to start paying more attention to them.