The 21st Century Cures Act and Antibiotics

It looks like congress is finally going to pass the 21^st Century Cures Act. Its 996 pages long!  Please read it yourself (just kidding). Of course, this doesn’t even come close to France’s labor laws at 3500 pages – but its still impressive. The bill contains over $6 billion in funding most of which will go to NIH for work on opioid addiction, cancer and Alzheimer’s disease. There is no doubt that the NIH needs more money since funding has been flat for years – therefore, corrected for inflation – we’re on a downward spiral. But targeted funding like this tends to take money and attention away from other areas of need – like antibiotic research for example.

So – what’s in it that’s good for antibiotics? Lots!

Limited Population Antibiotic Development (LPAD). There is a clear pathway spelled out for the FDA on antibiotics for use in limited populations where approval is based on smaller data sets than would normally be expected.  Of course, we all know that the FDA is already doing this under existing regulations – but this puts Congress on record as supporting this approach.  The FDA apparently thinks that this law will help them do more to bring new antibiotics to market quicker – and if the FDA thinks this will help then so do I. (OK – I changed my tune . . .). The best example of what the FDA can do is their approval of cetazidime-avibactam based mainly only on phase II data.  Hopefully, more drugs can now be approved more quickly in this way.  One also hopes that pathways will now appear for the rapid approval of pathogen-specific antibiotics (see my last blog on this).

Novel Clinical Trial Designs.  The Secretary HHS is ordered to convene a public meeting providing input to the kinds of novel clinical trial designs and statistical methods that would be required to implement LPAD.  This would then be followed by guidance from FDA in this regard. I suspect this is already in the works and the infectious disease group has already held public meetings on this.

 

The role of BARDA is clarified and expanded. But BARDA probably still does not have the funding to provide a business model for pathogen-specific antibiotics.

Antimicrobial susceptibility testing.  The FDA is ordered to establish a website with interpretive criteria for susceptibility testing that will be frequently updated and that will start upon approval for each newly approved drug.  The FDA will have the authority to rely on outside organizations for help here – similar to the way this works in Europe. I don’t see anything here that will speed the availability of automated testing to laboratories and physicians in the US. This is still desperately needed and I don’t see a way forward here as yet. The most important aspect of this part of the Act appears to be the updating of information on already marketed antibiotics. But that, in and of itself, is a major advance.

Breakthrough Diagnostics.  There is a section on the rapid development and approval of new diagnostic devices.  This is an important section that might make it more feasible to bring new rapid diagnostic testing devices to the US market.  We have been way behind Europe in this regard.

Recruitment and Retention at FDA.  There is an entire section spelling out the skills that will be required for new hires in the clinical review roles at FDA. This includes provisions for justifying higher salaries and other areas that would allow more efficient recruitment and better retention of FDA employees.  This is obviously needed based on what I have been reading. I didn’t see anything there specifically on conflicts of interest and making exceptions although the Secretary of HHS is to report back to congress as to needs in this area.  There is also nothing related to getting more expertise on advisory panels by waiving some conflict of interest criteria.

As I noted, there are obvious areas where the bill could still be improved. Hopefully the bill will pass without amendments to defund Planned Parenthood for example.  

My congratulations and thanks to Pew Charitable Trust and to the Infectious Diseases Society of America for their tireless efforts to get this passed over the last 3-4 years.

But, at the end of the day, until we have a business model that works for antibiotics, our pipeline will remain dry in spite of this legislation.

Pathogen-Specific Antibiotics - Business Models

I just returned from giving a talk to microbiologists on the issues surrounding the clinical development of antibiotics with activity against specific pathogens – that is – the opposite of so-called broad-spectrum drugs. I used as an example an antibiotic that targets Pseudomonas aeruginosa, Polyphor’s POL 7080.  

Microbiologists play an important role in constraining the use of antibiotics in both the hospital and community settings.  They are interested in the development of antibiotics that are more specific and therefore less likely to engender antibiotic resistance as collateral damage.  What I mean is – when treating someone for a Pseudomonas infection with a carbapenem antibiotic, you may select for resistance in Klebsiella since the carbapenem kills indiscriminately.  At least with a drug that targets only Pseudomonas, you only have to worry about selecting resistance in Pseudomonas.

I pointed out that, at least today, from a regulatory point of view, we still don’t know how to run a feasible trial that will result in marketing approval for such a drug. While I am confident that this problem will ultimately get solved, I am not so sure about the business model for such a drug.

The problem for this sort of antibiotic is that it will be used, at best, only sparingly. From the stewardship point of view – this is the ideal situation. But, if the company marketing the product has to depend on sales volume, it will be even more difficult to provide a return on investment for this sort of antibiotic compared to a broad-spectrum agent that can more easily be used on an empiric basis. Since companies are not in the business of providing for the public health in some sort of charitable way, why would they spend their limited resources on developing this sort of product? We, as a society, need to provide a business model that will work.

In Europe, where most countries already have a form of socialized medicine, the models being discussed all include some sort of market entry reward. In all these models, when a company gets approval to market an antibiotic that meets pre-determined criteria, they receive a payment of some sort.  How this payment is distributed is the basis of the debate on which model to use. Regardless of the model, the payment would be such that it would provide a return on investment for the company. While such a model was about to be put into use, I understand that everything is now on hold awaiting a better understanding of what Brexit will mean for payers in Europe. 

Here in the US, the model that seems to be preferred by people discussing this issue is the so-called patent voucher. In this system, a company that successfully brings a needed antibiotic to market would be rewarded with an additional period of exclusivity on the product of its choice from its portfolio of marketed products.  If, for example, the company were Gilead, it might choose extra time of exclusivity for one of its multi-billion dollar Hepatitis C drugs. This would guarantee a return on investment for the new antibiotic even if it were only used for a small number of patients every year.  The last time this model was discussed by the lobbying group from the Infectious Diseases Society back in 2004-5, the model was dead on arrival in congress partly because of the blowback from both consumers and the generics industry.  How this model will fare under a Trump administration is impossible to predict – but past experience on the Hill is not encouraging.

Some companies, like Merck, have already staked out a position here. Merck seems to want to be able to charge an appropriately high price and have that price be covered by various payers globally.  Merck and other large pharmaceutical companies might or might not be encouraged by the experience of Allergan and ceftazidime-avibactam in the US. Ceftazidime-avibactam or Avycaz was approved in the US in 2015 based on phase II data.  This antibiotic is the only alternative to the toxic and poorly efficacious colistin/polymyxin for the treatment of certain highly resistant Gram-negative infections. These infections remain, happily, relatively uncommon in the US. The label it received from the FDA restricted it to use only when other alternatives were not thought to be available.  The price was set at $12,000 per course of therapy – but payers actually provided something like $8500. This makes it the most expensive antibiotic ever marketed globally. Analysts predicted $300 million peak annual sales for the drug.  The first half of 2016 Aycaz had only $22 million in sales with the second quarter coming in at $13 million. Based on second quarter data and accounting for growth, this year could have seen $60 million.  Two events have altered this landscape.  First, the label for Avycaz has changed and was expanded now that they have an approved sNDA based on their phase III data. How this will affect the price is not yet known.  Secondly, Allergan has experienced manufacturing problems from the GSK supplier that will slow down sales in the latter half of this year.

My own opinion is that we need something beyond price and that Allergan’s experience makes a strong argument for that view. Allergan will now struggle for several years to achieve the analysts’ peak annual sales forecast of $300 million if it ever does so. And this level of sales, albeit it is only in North America, may not be enough for many companies in any case. Other pharmaceutical companies will be watching this closely and they may not be encouraged.  But we need more large companies to join the fight against antimicrobial resistance through the research and development of new antibiotics active against resistant pathogens. The experience of Allergan coupled with continued dithering on the Hill does not bode well for our goal of bringing more large companies into the field.

FDA Needs a Few Good People - But Can't Hire Them

A recent article in the Washington Post caught my eye.  The FDA apparently has over 700 vacancies in its drug evaluation group. This lack of resource is holding up drug reviews. According to the piece, Dr. Janet Woodcock complains that qualified candidates would much rather work in industry because the salaries are so much higher.  But she also goes on to explain the draconian hiring process at the FDA where all potential conflicts of interest must be reviewed and rectified before the person is hired.  And this says nothing about the lengthy federal candidate review process.

I agree with Josh Sharfstein who says the problem is not just the salary.  It’s the rest of the process.  To be hired, one has to divest all stocks or other investments in companies that might pose a conflict of interest – as in virtually all pharmaceutical companies. This probably excludes most folks with the kind of experience the FDA actually needs in its reviewers.  That is, people who have worked in industry designing and carrying out clinical trials designed to get drugs approved by the FDA. Given the devastation that’s been occurring because of pharmaceutical company consolidation, there are lots of experienced folks out there who might be interested in working for the FDA.  But who wants to go through the process, divest all of one’s pharmaceutical company stock and then wait three months for news as to whether one can be hired or not?

What is the FDA doing now?  They use contractors.  I admit that I don’t know what regulations there are for conflict of interest for contractors – but I expect they are not as draconian as those for full time employees.

And then there are folks like me.  I’m retired.  I wanted to work at the FDA on a voluntary basis – expecting that they would pay my expenses – but no salary.  I strongly believe that we need the FDA and we need it to be effective and efficient – something that the antibiotics group has not been until recently. In retrospect, the particular role I wanted to play is probably superfluous at this point since the antibiotics group is now functioning much better than it was at the time – albeit more slowly than I would like. But in my discussions with them, they noted that I would have to be a contractor and they would have to pay me. Hmmm . . ..  .As it turned out, they didn’t avail themselves of my services – probably because they thought they had things covered internally at that point (and they seem not to have been wrong).  But I’m not sure that I would have met their conflict of interest criteria either as a contractor or even as a volunteer given my experience in the pharmaceutical industry.

So who do they hire? The most likely candidates would be those coming from academia. They probably have little experience in the areas where the FDA needs expertise – so they get trained while working at FDA. The same problem exists for the FDA advisory boards where there is dearth of industry experience and key recommendations frequently lack the insight that previous industry-based trial experience can provide. It turns out that the academics on the advisory boards are probably just as conflicted as industry folks might be. The young clinical reviewers that might be hired from academia will not be at the same level of experience as those on advisory boards and hence would be free of those conflicts.  But they would also be free of experience.  Is that a good thing?  I’m not convinced that it is.

 So, while I think that increasing salaries for new hires at the FDA is a good thing, it is not nearly enough to crack this problem.  The FDA has to reinvent itself in a way that allows it to take advantage of the experience and gray hair that is now abundantly available in the world outside the federal government. Given the paranoia about conflict of interest, I expect that this won’t happen tomorrow.  But we need to at least start the conversation before this opportunity simply goes away with age and evolution to other interests.