Here They Come!

It looks like the European and (with any luck) the US regulators will just about make it in time . . .maybe.  

An interesting news article just popped up from Edmonton, Canada where officials are investigating an outbreak of  Gram negative bacterial infections resistant to all of our most effective antibiotics.  These bacteria were introduced by a patient who had received medical care abroad, but who was not placed in isolation upon admission to the hospital in Edmonton.  The patient apparently died of her infection. Several other patients subsequently became infected. An investigation is ongoing and it made the local press and television.

Another  article  also caught my eye.  Dr. Huttner and colleagues examined the use of certain so-called last resort antibiotics between 2005 and 2010 within the 152 hospital VA system in the US.  They clearly showed an increasing use of polymyxin (up about 30%) and tigecycline (up over 5 fold) during the years of study.  Polymyxin is an antibiotic of questionable efficacy and is associated with frequent kidney and nerve toxicities.  Tigecycline (dear to my heart) is limited in the dose that can be used because of gastrointestinal intolerance and it has been shown to work poorly at recommended doses in very seriously ill intensive care unit patients. Nevertheless, both these antibiotics are on the upswing.  Why – because more and more patients are being infected by highly resistant Gram-negative pathogens – similar to those causing the outbreak that caught the news in Edmonton Canada.  For these infections, there are no other choices. 

There is hope.  There are antibiotics in the late stage pipeline that will address at least some of these pathogens – but unfortunately not all.  The question is – how quickly can they be brought forward?  That is the question that the regulators must decide and decide now.  And what about those pathogens for which there is little in the current late stage antibiotic pipeline?  There are some at earlier stages of development that might be useful.  How quickly can these be tested in infected patients?  Here again – regulators and sponsors will have to get together and move things along quickly. But the time for infeasible trial designs and a long FDA reboot process is over.  The time to act is NOW!

FDA REBOOT!!

In nothing less than a remarkable presentation to the Brookings Institution yesterday, Janet Woodcock, Director of CDER at FDA, stated that the FDA will reboot its approach to antibacterial development. Rachel Sherman, the Associate Director for Medical Policy at FDA remarked that Dr. Woodcock had said to her FDA colleagues that she would not preside over the demise of antibiotics – not on her watch! With these words, the non-FDA audience in the room – and I suspect some of the FDA audience both in the room and on the phones – were flabbergasted. During the last 15 years of interacting with the agency, this was the most positive, even exhilarating set of statements I have ever heard regarding antibacterial development from the FDA.  We have come a long way from the day when Bob Temple announced to a group from PhRMA back around 2000 that infectious diseases developers had been “getting away with murder for years.” 

Dr. Woodcock, in her presentation, reviewed how we had arrived at this point.  She emphasized the role of telethromycin (Ketek).  Safety concerns on a drug with a controversial and complicated history that was finally approved led to demands for “more rigor” in the clinical investigation of antibiotics – specifically around the non-inferiority trials that are always used as pivotal studies to support marketing approval for these drugs.  In their re-examination of non-inferiority trial designs, their search for justification for the margins used for these studies combined with concerns over the objectivity of the usual outcome measure – “cure” – led to tighter margins requiring higher patient numbers and new outcome measures. The new trial designs proposed in draft guidance were, mostly, simply infeasible.

In another surprising statement, Dr. Woodcock acknowledged in a way the loss of trust in the agency.  She stated that this reboot would not affect the FDA’s current agreements with sponsors on the design of ongoing trials.

What does this proposed reboot look like?  It is hard to say from the conversation during the daylong meeting.  But it is clear that the agency wants to focus on areas of unmet need – those patients where current therapy is inadequate in terms of efficacy or where efficacy is at least questionable and where toxicity may be an important consideration (e.g. colistin).  Dr. Woodcock mentioned the possibility of pathogen-specific studies instead of indication-specific ones.  She agreed that for these patients a tradeoff in certainty around the data vs. potentially efficacious and less toxic therapy would be worthwhile. The words “historical controls,” “natural history studies,” “Bayesian designs” and “orphan drug status” were all used.  Clearly, for these patients, everything is on the table for discussion.

At the same time, the FDA clearly would like to link these approvals with a label including a limitation of use.  It is here that things get dicey since it is not clear that they would have the authority to actually enforce such a label. This, I think, is the basis of their desire for the LPAD legislation now being considered in Congress. On the other hand, if such a drug were approved for such a narrow indication that only a few patients would be treated with the drug, the high price and perhaps even the spectrum of the drug would automatically enforce restricted use. This could easily be confirmed through a use registry. 

It also seemed to me that the agency was committing to reboot its entire approach to guidance for the more usual indications such as hospital acquired and community acquired pneumonia and others. The importance of this was emphasized by a number of other speakers during the meeting – notably Helen Boucher of the Infectious Diseases Society of America. To reboot industry, we need to have a way for all new antibiotics to get to the market – not just those that can treat very small populations of patients with specific types of resistant infections.  We need an armamentarium of antibiotics for the future since resistance is hard to predict and many of our antibiotics have been around for a long time and resistance to most is already increasing.

As in all things in regulated industry – the devil is in the details. And the details need to be worked out BEFORE guidance is released this time.  Towards that end, the FDA understands the need for competent external advice outside the usual advisory committee mechanism.  Their approach to getting this advice should be to use small FDA teams equipped with specific questions meeting with small groups of advisors (the Brookings meeting was too large to really get anything concrete done) in a non-formal setting.  The Brookings meeting was a good start to identifying the specific areas of inquiry.

For industry - For those companies planning to negotiate designs in Europe first – I think the FDA will be more open now.  Consider a simultaneous advice session.  In general, for those companies reconsidering antibiotic R&D – I believe that the US will be open for business – when I am not exactly sure.  The water is at least warming – but its not summer yet.

Culture Wars and Antibiotics

Two weeks ago, a well conceived article was published in Forbes. It discusses the problem of the lack of productivity of large pharma. The problem is very real.  Just look at the number of patent expirations threatening this industry and the state of their pipelines.  A great example is Pfizer – a company that is shrinking as fast as it can to offset their loss of revenue from Lipitor sales. Another good example is Astra-zeneca – a company that is also fighting loss of market exclusivity with layoffs. Obviously, a better way to deal with the problem is more productivity either from in-house research and development or from external sources. So why is this not happening? 

There are multiple causes for the poor productivity of the pharmaceutical industry overall.  These include scientific issues – its just plain getting harder to find new, safe and effective drugs.  Another contributor is the increasingly stringent and risky regulatory environment affecting products from obesity and diabetes therapies to antibiotics (don’t get me started!). But I think Bruce Booth, in his Forbes piece, has really hit on another underappreciated factor – the increasingly bureaucratic and metrics-driven approach to R&D within the pharmaceutical industry.

At Wyeth at one point, the Discovery group was asked to produce 15 clinical candidates per year (IND ready).  Did this increase their late stage pipeline? What do you think?  What it did, probably, was decrease the quality and increase the risk of the compounds entering phase I development. As described by Bruce Booth, Wyeth R&D was run by committee(s).  But each committee member had their own particular agenda.  Each functional area had their own constraints and concerns – work load, not wanting to be blamed for project failure, etc. So they would try and either block a project or at least make their reticence known to the committee so they could at least say, “I told you so” later.  In the industry, it is always easier to say NO at the beginning than it is to take a risk and support a potentially costly project that, 80% of the time, will fail anyway.

When you layer committees one on top of the other – business development, safety, R&D, the problems compound more often than they are solved. 

Bruce Booth’s solution is similar to one I have been pushing.  He would create geographically localized therapeutic area units with all the critical support required (I presume this is what he means) like toxicology, manufacturing, clinical development, regulatory, etc. He suggests giving them five years of budget and then leaving them alone.  The therapeutic areas would then report directly to the “top” (whatever that is) rather than to a committee. My suggestion has always been to shrink the companies altogether by giving each therapeutic area its own P&L.  That might be achieved by providing a budget (instead of profits) from the mother company or it might be (better) by allowing them to live within their P&L based on profits from revenues derived from marketed products. Essentially, what I am suggesting is taking the Centers of Excellence in Drug Discovery of Glaxo one giant step further towards independence from the leaky, unstable giant mother ship.  

I have said in multiple previous blogs that this would be a great strategy for improving the situation of antibiotics within the pharmaceutical industry. 

Antibiotics - Go East!

Asia - Satellite image - PlanetObserver (Photo credit: PlanetObserver)

Where will we find new markets for antibiotics and other pharmaceuticals?  Asia and other emerging economies – that’s where!  According to Bayer, China was their third largest market globally last year.  Asia overall accounted for 7.8 billion Euro (over $10B) in sales for Bayer – a whopping 21.5% of their sales globally. The sales in Asia were very similar to that for North America.  Bayer is a great example since, on the antibiotics side, they sold their North American business to Schering-Plough (now Merck) a number of years ago.  This shows where their thinking was then and how this perception has now been vindicated.

In a report published last year and freely available to all, the Economist notes that pharmaceutical sales in Asia have more than doubled since 2001.  Projections going out to 2016 suggest an annual growth rate of 13% is sales with total sales hitting an astounding $386B. A number of factors are driving this growth and include a growing population (shown below and taken from the Economist report), an aging population with longer life expectancy and a growing middle class able to afford to pay for quality health care.

The resulting projections for increases in health care spending, taken directly from the Economist report are shown below.

Of interest, the profitability index has been rising more slowly and in an erratic way.  This can be attributed to sporadic rises in wages and other costs.  Thus, sales volumes and cost savings will have to combine to maximize profits in Asia.

These observations can be used to explain the surge in antibiotic sales in Asia.  Shown below from IMS data kindly provided last year by Astra-Zeneca, are sales of antibiotics in the years 2006-2010 comparing Asia-Pacific with North America.  If you were a pharmaceutical company wanting to maximize opportunities for antibiotics, where would you place your bets?

I believe that these trends will lead to an increase in the number of large pharmaceutical companies pursuing antibiotic R&D.  Evidence that this is already happening comes from the Bayer-Trius deal largely driven by Bayer’s Asia division, the recent re-entry of Sanofi-Aventis into the antibiotic R&D game and statements by large pharma executives like Mark Mallon from Astra-Zeneca as quoted in the Economist report. 

The corollary to this is that if the FDA continues to make the development of antibiotics infeasible in the US, as I have been saying for a long time now, companies now have the option of developing their antibiotics under European aegis, ignoring the US market and looking to the East to sell their wares.  And this is exactly what will transpire.  You read it here first!

Limited Population Antibacterial Drug Approval (LPAD)

I am posting this very brief blog today to encourage you to support congressional approval of LPAD. The legislation calls for extended authority for the FDA to approve antibiotics based on a limited data set for use in populations with high medical need.  This has been reviewed briefly in a couple of previous blogs. Although I remain unconvinced that the FDA actually needs this legislation from a purely statutory point of view, I have become convinced that they need it to provide cover from congressional criticism when, after approval of a drug based on limited data the inevitable problem emerges. This means that without such cover, it is not clear that the FDA will have what it takes to do the right thing and go forward anyway.  I am also completely convinced that for some new drugs, like  those active only against Pseudomonas or those active against metallo-beta-lactamase bearing organisms like NDM-1, such a new development pathway is absolutely essential.  Luckily - the back-up plan is to seek approval under the auspices of Europe if we cannot under the FDA. Of course, if this occurs it will mean that Americans will be left without access to these new and needed antibiotics.

So check out the summary of the legislation as proposed by IDSA, then write your senator and congressman - please!

Shrinking Pfizer is Good for Antibiotics

Logo of Pfizer Incorporated. (Photo credit: Wikipedia)

Pfizer stock price over 10 years. (Photo credit: Wikipedia)

There has been more talk in the news lately regarding Pfizer’s plans to spin off various businesses.  I have discussed the general issues I will cover today in two previous blogs. The recent news that Pfizer, in addition to spinning off its nutritionals and animal health franchises, is considering selling off its generics business. Talk of this breakup was spurred by Jami Rubin’s report a couple of weeks ago based on a briefing of Goldman-Sachs by Pfizer.  Some analysts suggest that this plan could increase the value of Pfizer by over 50%. But all will depend on Pfizer’s ability to advance its pipeline to marketed products.  And that remains to be seen.

As I have noted in the past, another approach would be to break things down further.  As it stands, there is no added value of the now almost non-existent anti-infectives effort at Pfizer.  But there are still early compounds and expertise plus Pfizer still sells linezolid, tigecycline and even piperacillin-tazobactam even though the latter is now generically available as well. These sales probably add up to about $2B in annual revenue.  Pfizer generated $67B in revenue in 2011 – so antibiotics remain a drop in the old bucket. On the other hand, a spin-off of the antibiotics business including their preclinical and early clinical assets would probably be worth much more outside of Pfizer than it is within Pfizer. Even with all the generic intrusion that will occur (linezolid loses patent protection in 2015), there will still be plenty of revenue to drive a small company.  Funding resources for such a spin-off could include both private equity as well as venture capital. The same strategy may work for other businesses within Pfizer – who knows? 

I am sure that Pfizer is not the only large pharmaceutical company where such a strategy would make sense.  I can think of several other good candidates off the top of my head – and so can you! The availability of non-dilutive funding through NIAID, BARDA or the Innovative Medicines Initiative or other sources adds to the attractiveness of the antibiotic spin-off.

But for the future of antibiotics, it is clear to me that the sales of current Pfizer antibiotics could drive new R&D in a new and much smaller company to bring new, novel and desperately needed products to patients and their physicians. What could possibly be wrong with this picture? Why can’t Pfizer bring itself to do the right thing? Is it that the problem is too small to deserve their attention?

I leave these questions in your capable hands – I do not have the answers.

Advice and Consent

The western front of the United States Capitol. The Neoclassical style building is located in Washington, D.C., on top of Capitol Hill at the east end of the National Mall. The Capitol was designated a National Historic Landmark in 1960. (Photo credit: Wikipedia)

President Barack Obama signs H.R. 2751, the “FDA Food Safety Modernization Act,” in the Oval Office, Jan. 4, 2011. (Official White House Photo by Pete Souza) License on Flickr (2011-01-12): United States Government Work Flickr tags: WASHINGTON, DC, USA (Photo credit: Wikipedia)

An interesting article appeared in the New York Times today discussing new proposed rules from the Obama administration on the relationship between lobbyists and congress.  Apparently, these new proposed rules would limit the ability of congress folks to interact with registered lobbyists under circumstances where anything free might be involved such as film screenings, cocktail parties, etc. So, it seems like it would be OK to meet with lobbyists – they just can’t pay for drinks and meals nor could they provide free entertainment.  It also seems that if the congressperson is an invited speaker at such an event – that would also be OK. I’m confused – but probably so is anyone else who tries to wade through all this.

I was struck by the article in the Times because it notes that lobbyists are complaining that they would no longer be able to educate congress on the issues important to the lobbyists clients.  The fear is that congress will become alienated and distanced from regulated industry to the point where it is no longer able to make rational decisions. It may surprise you to hear that I sympathize (within limits) with this view.  For me, a great example is the anti-infectives division at the FDA. They, through congressional pressure and through unreasonably tight restrictions on interacting with industry coming from regulations around conflict of interest, have become completely isolated from the industry that they regulate.  This has been an important contributor to the greatest debacle of our century in the discovery and development of new and needed antibiotics.  For almost a decade now, guidance documents from the FDA for the development of new antibiotics have required infeasible clinical trial designs.  This has increased the regulatory uncertainty for the pharmaceutical industry and has, in a number of cases, led directly or contributed to their exit from the field of antibiotic R&D.  I believe that if the FDA had been able to get appropriate advice (in the absence of political pressure from congress) from folks who actually are involved in the development of new antibiotics prior to releasing their guidance documents, they would have understood that their proposed designs were infeasible from the outset.  The way the process currently works, the FDA releases a guidance document requiring infeasible clinical trials.  There is then uproar from the industry and the Infectious Diseases Society of America.  The FDA then reacts (we hope – but this has not yet actually happened) with tectonic speed to revise the guidance such that required trials are again feasible.  In the meantime, more companies abandon antibiotics research. Is this a way to conduct business?  Of course it isn’t.

My nightmare is that this system becomes the way of doing business in congress. The result will be the passage of idiotic laws that then have to be modified after years of delay.  On the other hand, I don’t see why lobbyists should have to provide free meals or drinks to be able to speak to congress folks. I guess this boils down to the question of what it takes for a lobbyist to speak to a congressperson. But I agree that the complete isolation of government from regulated industry is unhealthy and may even be risky.