Tuesday, March 31, 2015

Obama's Plan to Combat Antibiotic Resistance

There has been much press lately about President Obama’s plan to address the growing crisis of antibiotic-resistant bacterial pathogens. And I agree with many that there is much to like in the plan.  But I also find a number of key deficiencies that will lead us nowhere.

The goals of the plan are all laudable –
1. Slow the emergence of resistant bacteria and prevent the spread of resistant infections;
2. Strengthen national One-Health surveillance efforts to combat resistance;
3. Advance development and use of rapid and innovative diagnostic tests for identification and characterization of resistant bacteria;
4. Accelerate basic and applied research and development for new antibiotics, other therapeutics, and vaccines; and
5. Improve international collaboration and capacities for antibiotic-resistance prevention, surveillance, control, and antibiotic research and development.

Who can argue with that?

To achieve the first goal, the plan contains a number of key elements.  Among them are strengthening of antibiotic stewardship in both inpatient and outpatient settings including long term care. Surveillance is to be strengthened by providing regional reference centers to detect resistant strains in clinical and veterinary settings. Importantly, there is a plan to streamline the regulatory process for approving susceptibility-testing devices such that they are available when a new antibiotic is marketed instead of the one to two year delay that now occurs.  I like that one especially. Another piece of this plan is to establish a national database on antibiotic use.  That’s another one I like, but man, will that be hard to implement.

An obvious goal is to eliminate the use of medically important antibiotics as growth promoters in animal feed.  Wow.  What a surprise.  But the plan does not include an outright ban. Rather, it supports the FDA’s efforts, which could ultimately succeed, I suppose, to get the industry to back off. But why is there such consternation around an outright ban? I don’t know.

One piece of the plan calls for establishing a susceptibility-testing network for animal pathogens.  It seems like this is aimed at providing better and more focused therapy for infected animals. Good idea. What this will require is an entirely new approach to animal pathogens including setting breakpoints for what is considered resistant or susceptible in different animal species.  Right now, the assumption is that animals are humans – which I can tell you - physiologically, they’re not. Who is going to do all the sophisticated PK/PD experiments in the different species to establish these breakpoints? Is there going to be funding for this piece?  Or is there no one but me who sees this as a possible pitfall?

The there is the section on establishing rapid diagnostic testing.  See my blog on this.  I say again.  It has to be bedside and idiot-proof.  This could take a while, folks.

Finally, there is the part on accelerating both basic and applied research aimed at finding new antibiotics, vaccines and other therapeutic approaches. But the way this is worded sounds like a way to let the NIH off the hook.  For the last 50 years, the NIH has been shortchanging antibiotic research and funneling money into the study of vaccines and pathogenesis of infections.  I don’t argue that these are not worthy of study.  I just will state that antibiotic research has always gotten the short end of this stick.  And, if I read the plan correctly, this is unlikely to change in the future.

What is glaringly absent from the plan is what was recommended by PCAST in terms of providing for a return on investment for companies who pursue the research and development of new antibiotics for resistant infections. Of course, that was the most expensive part of the PCAST report.  That report would augment funding for BARDA in its effort to support applied research in academia and industry. It would also provide for various pull incentives such as an upfront purchase or so-called patent voucher system. Without this, as far as the development of new antibiotics is concerned, the plan is another piece of paper in a long line of such.  Show me the money!!!

So here we are. There is much good here.  But it is clear that the much-touted “doubling of funding” that the press is so excited about is less than it seems. Not only that, but what makes anyone think that the President’s budget, where this plan is enshrined, will pass? If it does, will it have to do so on the back of Medicare, Medicaid or food stamps? I’m sorry – but my eyes are on Jim O’Neill and the UK for now.

Wednesday, March 18, 2015

Jim O'Neill for the UK and Antibiotics!

The Prime Minister of the United Kingdom, David Cameron established a commission chaired by Jim O’Neill, an accomplished economist, to lead a review of the antibiotic-resistance crisis and to make recommendations on what to do about it by mid-2016. The commission, with help and sponsorship from the Wellcome Trust and the British Government has already published three reports.  The first was a rather exaggerated view (my opinion) of the world if resistance had become so widespread that antibiotics no longer worked.  The economic consequences of such a catastrophe were estimated in the$100 trillion range globally. Of course, this provides a wide range for the economics of proposed solutions to come later . . .

The second report – the most interesting in my view – is a survey of folks carrying out research and development of antibiotics. The commission asked small, medium sized and large pharma companies and non-profits a number of questions. Barriers to investment in antibiotic R&D were those described in my book – Antibiotics the Perfect Storm.  The most important was one of return on investment where 30% of products from the 1990s failed to provide such. Next was the scientific difficulty of discovering new products. Third was the regulatory risk where the FDA was the most often cited problem but 55% cited Europe as well.  The respondents were encouraged by recent actions at these regulatory agencies but most felt they could go farther.

The most likely drivers of research according to the respondents are early grant funding (e.g. IMI and BARDA), higher prices and better hospital reimbursement.  I was surprised to see longer patent life at number 4 but I attribute this to the smaller companies and non-profits in the survey.  I was also surprised to see that patent vouchers was not a popular solution anymore.  This must be because pharma companies are rapidly running out of the double digit billion dollar blockbusters they had when patent vouchers swere first proposed back in the early 2000s. (A patent voucher would allow you to get extra years of exclusivity on a high earning product in return for introducing an antibiotic active against resistant pathogens to the market).
The first report to deal with proposed solutions is number three on O’Neill’s list of released reports. To me, one of the most important observations contained in this report is the paltry funding of antimicrobial resistance work by the NIH in the US.  Figures from the UK’s MCR are not presented (hmmmmm). One of the suggestions is a global innovation fund to supplement the obviously inadequate availability of funds from existing sources (NIH, MCR, IMI, BARDA, etc.).

The other issue O’Neill notes is related to attracting researchers into the field of antibioics and resistance research.  He suggests the establishment of centers (centres) of excellence to carry out this work.  In my view, this will only be practical if it includes training in antibiotic discovery and development with everything from preclinical to manufacturing to formulations to clinical development.  This is a tall order and it better happen soon because we are losing trained experts by the second.

All in all, the O’Neill effort will supplement  and in some ways surpass the US PCAST report in its detail and recommendations.  But, given Prime Minister Cameron's drive to austerity, we may end up with the same admonition at the end of it all.  Show me the money!!

Wednesday, March 11, 2015

AZ Spin (off)

I just came back from Boston and the annual meeting of BAARN – the Boston Area Antibiotic Resistance Network symposium held at the Broad Institute.  The meeting was interesting but the atmosphere was funereal.  Many of those losing their jobs with the closure of Cubist’s research center in Lexington, Mass were there as were many whose jobs are threatened at AZ’s facility in Waltham, Mass. One major topic of discussion during the breaks was – where will all the antibiotic research go? If, as I have been saying for years, we need to train academic antibiotic researchers in industry – what is left in Boston to address this need?  Cubist is gone.  AZ  - well – see below. Novartis has moved its team out to California where they rest in some sort of extra-dimensional limbo between their desire to find new products and their company’s desire to have nothing to do with antibiotics. This is definitely NOT the way to assure a robust pipeline of antibiotics for our future.  This is the road to oblivion.

From what I can gather from various sources, the AZ spinoff, as announced last week, was a last minute backup plan to their failed effort to partner their products, their late stage pipeline and their preclinical assets with either external investors or with another pharma company. This failure seems to be related to AZ's own stringent view of the value of their own assets and their insistence on keeping a large share of the assets. Having been rebuffed by external investors and by most of big pharma, the spin off was born mainly to provide some firm stance to employees who have been fleeing the uncertainties of AZ in large numbers.

Since I have worked with two spin-offs, Nabriva from Sandoz/Novartis and Novexel from Sanofi-Aventis, I think I can speak with some perspective here.  First, it is terribly important that the new company be completely independent from the “mother ship.” That means – no rights to current or future assets or potential products that go to or come from the new company.  It means no exclusive manufacturing agreements or obligations with the new company.  It means no board position at all or only a minority position. The board for the new company should be a balanced one with an independent chairman, a couple of independent board members and the investors who vote decisions based on their shares.

Today, I spoke with a highly placed and knowledgeable source at AstraZeneca about their plans for their spin-off. So far, AZ is providing all of the $40 million in funding to establish the new company. No formal agreements are yet in place. No officers for the new company have yet been designated. There are no outside investors. The new company will be comprised, initially, of about 20 employees derived from those remaining at AZ in Waltham. They will grow to about 30 over the first year or so. Clearly, the current structure is completely incompatible with the principles I have listed above. In spite of this, my source assures me that AZ’s goal for the spin off is as I have described above.  Are you confused yet?

AZ now maintains and apparently wants to continue to maintain an important share of the company. Their goal is to share the risk but also to share the upside.  In other words, they want their cake and they want to eat it too. In my view, AZ will be unable to attract any outside investors under these circumstances.  Their only choice at this point is either to try and sell their shares to bring themselves down to a very minority position (15-20%) or to quickly raise a second round of funding sufficient to accomplish that.  I think the latter is very unlikely as well until more assets enter clinical development. The other choice is to continue to fund the newco and retain all risks and rights.  If that will be the case – what’s the point?

While I am grateful that AZ’s antibiotics research will continue, albeit in a much more limited way, I continue to marvel at the wrongheadedness of AZ’s CEO when it comes to antibiotics and value. I understand the pressure AZ feels from investors and shareholders.  But antibiotics have value today and will produce even more value tomorrow.  They are less risky to develop and now have the same sorts of inexpensive and quick pathways to market as the more risky oncology drugs. Have I missed something here?