Tuesday, May 26, 2015

Antibiotic Opportunities

Since the appearance of Jim O’Neil’s last report, there has been a surge of international (virtually all ex-US) thinking about how to approach the problem of antibiotic resistance. Most recently, the WHO approved a plan to combat antibiotic resistance that included a plan to develop a plan to support new investment in antibiotic research – if you see what I mean. Germany, holding the presidency of the G7 Summit this year, will introduce a plan to provide international funds to support the development of new antibiotics to combat resistance. Part of this plan will be to designate these antibiotics as orphan drugs – a topic they have already raised with the European Commission and upon which I reported recently in this blog.

All of this is nothing but good news. But I still have a problem with seeing, in a practical way, how any of these good intentions will turn into the effective use of dollars (or more likely Euros) as an incentive that will attract companies (back) to antibiotic R&D. Whatever the plan is, it must be crystal clear and must lack the usual bureaucratic intricacies of the usual WHO and EU funding mechanisms. It must also involve large sums of money as noted in the O’Neill report - $1-3 billion per antibiotic aiming for around 10 new antibiotics over the next twenty years.  That’s a lot of money.  Of course, compared to O’Neill’s worst-case scenario of no working antibiotics and a $100 trillion hit to the world economy, it’s a drop in the bucket.

It seems likely that something involving actual funding will come out of all this. How it will work in reality right now is anyone’s guess. 

If I were a pharmaceutical company who was not active in antibiotic research today, I would be making plans to be there tomorrow. A couple of companies that come to mind are Vertex and Gilead – especially Gilead.

Vertex has dabbled in antibiotic research in the past and finally gave up the ghost several years ago.  Bad timing in my view – but, given their lack of productivity, maybe it was not the wrong decision at the time.  Maybe now is the time to rethink. 

With the entry of Gilead’s high-priced drugs for Hepatitis C to the market place over the last two years, their earnings have soared.  Analysts and investors are asking how Gilead will be able to continue to grow?  Will this require an acquisition?  And if this were to occur – in what area of pharmaceuticals should it focus?  Well Gilead, here is your answer – antibiotics. Of course, this is not so easy since the only large antibiotic franchise that might still be available for “partnering” if not a complete takeover is that of AstraZeneca.  But with their pipeline around the novel B-lactamase inhibitor avibactam, this would be attractive.  That is, it would be attractive if AstraZeneca is reasonable in its demands. Of course, AstraZeneca could do with some rethinking as well, as I have been saying for the last two years.

So, I remain skeptical that organizations like the G7, the EU and the WHO can actually get their acts together to come up with the kind of monies we are targeting. And importantly, a clear pathway to those monies must also be provided. Nevertheless, I believe that something good will happen in the near future. This is not the time for indecision in the industry.  This is the time for bold, pre-emptive action such that you are positioned to take advantage of the coming opportunities.

Friday, May 15, 2015

O'Neill's Latest - Antibiotics in Neverland

The latest installment of Jim O’Neill’s report for the UK government on securing a future for antibiotics has just appeared.  Like the other chapters of the report, there is much to like here.  But when it comes down to the key next step – money – his shot is wild.

Entitled, “Securing New Drugs for Future Generations,” it suggests three interventions to get us across the goal.  (1) Create a more predictable market for new antibiotics. (2) Provide focused funding for early research into new antibiotics. (3) Create centralized platforms for the efficient clinical development of antibiotics targeting resistant pathogens.  There is nothing new in any of these proposals – but its good to get confirmation from a task force with the stature of this one. In fact, we are already doing (2) and (3) – jut not enough and not very well.  Partly, this is a problem of training, something O’Neill does not discuss. What we are not doing at all is (1).

O’Neill suggests a global buyer provide somewhere in the range of $1-3 billion as an upfront payment for an appropriate new antibiotic.  The global buyer, by such a purchase, would immediately provide a significant return on investment to the company that developed the antibiotic.  The buyer would then distribute the drug according to demand and need and would monitor usage. Such a payment would immediately de-link marketing from sales or use of the antibiotic since the buyer would be the distributor. The obvious problem with this is to try and designate such a global buyer who could actually coordinate distribution and use on a global scale. The only entities I know who come close to this are pharmaceutical companies and they are not so good on the stewardship side of things. Governments are notoriously useless here to say nothing of WHO or the UN or the EU.

A hybrid approach includes an upfront payment that reimburses costs of development including prior failures – still in the $1-3 billion range – but that allows the company to sell and make its profit in that way.  But here, the price would remain low since the company no longer has to make up its research investment.  The de-linkage and stewardship components would not be the same, but would be much easier to manage since sales pressures would be lower.

O’Neill, for the most part, dismisses high prices as a way forward.  My own belief is that his other proposals are simply not implementable on this planet today.  Therefore, a model including high prices in some markets (US, I’m talking about you!) is inevitable.  Further, a global buyer is off the table.  Funds from governments where individual markets then work out their own distribution systems - probably involving the pharmaceutical company - is a much more realistic way forward. 

The report also includes a proposal on funding early research and here O’Neill takes a page from the Innovative Medicines Initiative in Europe and suggests that the pharmaceutical industry fund these efforts. Well . . . .I think maybe too much beverage from the northern reaches of the UK was available when the committee was thinking about this one.  There is a dearth of funding for research largely because the pharmaceutical industry has abandoned the area.  Why we think those companies who have abandoned antibiotics will now fund research in the area is beyond me.  Of course, if large, upfront payments become a reality, this might happen – but not before.

The final portion of the report is dedicated to centralizing the clinical development of antibiotics using centers designed to provide patients to participate in such trials.  There is also the requirement that regulatory requirements for trials be harmonized.  This, currently, is mostly the case for the US and EU – even though trial endpoints differ in the two jurisdictions.  But this issue is relatively easily handled through the use of two different statistical analysis plans, one for the EU and one for the US.  Its outside of these jurisdictions where things are getting stickier these days and O’Neill’s report does not go into those issues.

So, while I think that the report is a good one in terms of the monetary figures proposed, in terms of practical implementation, we seem to still be in Neverland. Sorry, Jim, but the UK is actually going to have to put up real money, as will its European (for now) colleagues.  I think the US will remain the land of high prices.

Sunday, May 10, 2015

Infection Control in a Small US Hospital

Today’s blog is related to something quite different than the discovery and development of antibiotics – sorry.

It may also sound like a familiar plaint to anyone involved in infection control.  I expect to hear a lot of “suck it up, buddy” out there.

According to CDC data, almost 80% of US hospitals have less than 200 beds and over 50% have less than 100 beds, like the hospital where I volunteer.  I am helping their infection control committee on a consultant basis since they do not have an ID physician on their committee. My hospital is on the border of two states and has recently been acquired by a larger hospital in the neighboring state. The morass of state and federal regulations imposed on this hospital is a nightmare in terms of trying to provide the services that patients and physicians need to prevent and control infections and at the same time fulfilling various agency bureaucratic requirements.

The state where the hospital is located is mandated to supply hospitals with influenza vaccine.  But for the last several years, they have either been unable to fill orders on time or have substituted inferior vaccines (trivalent instead of tetravalent) without notice or warning.  Also, our state will not pay for vaccine administered to out of state patients.  But because we're close to the border, we have a lot of those.  We have to track who is from out of state to make sure we do not charge the state for their vaccine. The hospital, wisely, finally decided to buy their vaccine on the market this year rather than rely on the state and they were able to obtain the vaccine they ordered on time and in adequate supply.

Recently, with my help, the infection control committee instituted an antimicrobial stewardship program.  The goals were to decrease antibiotic resistant infections and healthcare-associated infection with Clostridium difficile. A major stumbling block to implementing the program as envisioned by the committee has been the inability of pharmacy personnel to track antibiotic usage using daily defined doses – the standard required for best practice. There has been no budget for software nor has there been budget available for additional pharmacy staff help to analyze usage manually.

This year, the state conducted practice drills and carried out inspections of our hospital to assure that we could handle Ebola patients should they show up on our doorstep. While this might have been necessary – at least as far as assuring the safety of hospital and emergency personnel is concerned – it was a major distraction to those involved in the routine of everyday infection control in the hospital.

Then there is the requirement of reporting to the National Health Safety Network (NHSN) of the CDC. We report certain surgical site infections, all intravenous catheter infections and all urinary catheter infections.  We also now report something called “ventilator associated events.”  We used to report ventilator-associated pneumonia – something I thought I understood.  Now we’re reporting the changes in pressures on the ventilators used to support patients in our small ICU as well as changes in patients’ ability to oxygenate their blood and other parameters. But I don’t know what we as a hospital are supposed to do with this information nor do I understand exactly why it falls within the purview of the infection control committee.  I do understand what we are supposed to do about ventilator-associated pneumonia and I also understand why that would fall within the role of infection control.  But now, the CDC requires that a patient have a bronchoscopy for the diagnosis of this infection – something that almost never happens at my hospital.  As such – we virtually never see ventilator-associated pneumonia anymore.  Pretty good progress – huh?

What happens with all these data?  We can get a summary of the CDC analysis of our data – but our numbers are so small that in the new CDC paradigm of accounting for various risk factors and then comparing to other hospitals in their database – the resulting data becomes meaningless.  We never achieve anything resembling  statistical significance.  And our numbers can vary wildly with the addition of a single case of say IV catheter infection in a year. 

To make things worse, CMS (Centers for Medicare and Medicaid) now punishes hospitals for having infection rates higher than the CDC-defined “norm.”  In 2013, we had a single case of IV catheter infection in our ICU for the entire year. But because our numbers of days where patients had catheters on our ICU was so low – our risk-adjusted rate based on this single case was higher than the CDC norm.  The hospital was asked to refund 1% of its Medicare payments from that year - something we could ill afford.  Of course, our goal is to have no IV catheter infections – but does this policy make sense to anyone out there at least insofar as small hospitals are concerned?  We are trapped by the tyranny of small numbers and a Federal Government who couldn’t care less.  

All this reporting to the CDC requires that someone spend hours on the CDC website filling out virtual forms. And who is that someone?  Our infection control nurse, of course. Her time might be better spent working on enforcing our hand hygiene policy – that is making sure health care providers wash their hands between patients. She could also be more useful spending her time assuring that best practices are always followed when intravenous lines are inserted and making sure that the urinary catheter the nurses want to insert in a patient is actually needed for something other than the nurses’ convenience.

OK - I’m done for now . . .we’ll just “suck it up” . .. . .

Saturday, May 2, 2015

Congress and the FDA - Show us the Money!

Well – the US Congress is at it again.  It seems like they will do almost anything except spend money where its needed. There is a very comprehensive bill called 21st Century Cures a draft of which is available here. I only paid attention to the section on antbiotics – but I will admit that in this bill, congress proposes to increase the NIH budget all of 10% over the next several years!   The antibiotics portion of the bill reflects previously proposed legislation like PATH and ADAPT and others going back maybe five years or so.

There is one useful item in the antibiotics proposal – it requires the FDA to establish a website dedicated to updating susceptibility breakpoints for various antibiotics. The idea is to accelerate the updating process and make it “FDA” official such that manufacturers of testing devices are obligated to keep up – something they do not do now since the FDA is usually years behind the curve on this.  Of course, the FDA has the authority to do this already – the only thing the legislation would do is make it a law – they would have to do this.  At the same time – is congress providing budget for this?  Of course not.

A bigger issue for me is the availability of susceptibility testing methods when a new antibiotic is launched on to the market.  Right now, there is usually a one year lag since until approval there is no official FDA designated susceptibility breakpoint for the antibiotic.  One way to change this would be for the FDA to provide a provisional breakpoint to the susceptibility testing device manufacturers before approval so that a test would be available when the antibiotic is available in pharmacies.  But that is nowhere to be found in 21st Century Cures. 

The rest of the proposal goes through establishing a rapid pathway for antibiotics meeting unmet medical needs – usually related to resistance, but also to various allergies and intolerance that might be addressed by new and efficacious alternatives to marketed drugs. But the FDA has already done this.  They just approved a new antibiotic – ceftazidime-avibactam – based primarily on phase II data – just the sort of rapid process they outlined in their guidance on developing antibiotics for unmet medical needs.  So why do they need legislation for this? Even Janet Woodcock seems to think that the FDA does not need additional authority for this – listen to her testimony from April 30 here. She does seem to like the idea that the authority they already have will be codified – but I guess I don’t understand why . . .

But if you think about all the things the FDA has to do – from food safety to the supervision of drug manufacturing to the approval of new drugs to surveillance of the safety of drugs already on the market – what they really need is money.  They have the authority to do all this (except of course for supplements – but that’s another story).  The FDA regulates products that account for about 25% of all consumer spending. What they do not have is enough budget to do all these things. A 2007 workshop from the Institute of Medicine dramatically shows the inadequacy of FDA funding.  The congressional funding for FDA as well as its user fees have essentially been flat for at least the last three years. In spite of this, if you look at FDA’s performance on drug approvals – they are the fastest regulatory agency on the planet. This is a good thing. While FDA’s responsibilities continue to increase, funding does not.  This is simply not tenable.  We are seeing this with issues of food safety, drug manufacturing and the continued problems with adulterated and fraudulently labeled supplements (that needs entirely new legislation).

So – Representatives Upton and DeGette – let’s start talking about money for FDA!