David's New Book

Monday, May 7, 2018

Standard of Care Antibiotics?

One of the major arguments against the use of superiority trials for antibiotics goes as follows. Once a new antibiotic has been shown to be superior to a comparator, the new drug must then become the comparator for all subsequent trials. There are probably two assumptions that underlie this argument. There is an ethical concern about treating patients in a trial where the comparator has been shown not to be the “best available therapy.” The other assumption here, I think, is that the world of physicians will immediately turn to using the superior drug and therefore that the new superior drug will become the “standard of care”.  But, in fact, this last assumption appears to be completely wrong!

As I noted in a previous blog, ceftazidime-avibactam has been shown to be superior to other “standard of care” antibiotics in the treatment of carbapenem-resistant infections.  The standard of care frequently included colistin. Meropenem-vaborbactam is also superior to “best available therapy” (frequently including colistin) in the treatment of carbapenem-resistant infections. In spite of these data, colistin and polymyxin are still used in commonly in the treatment of carbapenem-resistant infections.

The figure shows use of ceftazidime-avibactam from its launch in April of 2015 until November 2017 compared to the use of colistin and polymyxin for carbapenem-resistant infections. Clearly, the superior antibiotic is not being used clinically.  There are probably two major reasons for this behavior. Ceftazidime-avibactam is very expensive – around $8000 for a course of therapy – while colistin/polymyxin is cheap. The other reason is that in spite of being launched in 2015, most automated susceptibility testing devices used in hospitals are still unable to test ceftazidime-avibactam (don’t get me started!). 

Based on these data, there is no reason why a second or third antibiotic cannot be compared to colistin/polymyxin-containing regimens in a superiority-design trial since these regimens continue to be “standard of care” in spite of data suggesting that they shouldn’t be. If physicians see no ethical concern in treating patients with an inferior drug in their everyday practice, should we force them into another behavior in the setting of a clinical trial? 

Personally, I think the ethics of continued use of colistin/polymyxin for most CRE infections is highly questionable. But if these drugs continue to be standard of care – then using them as comparators seems reasonable. 

Wednesday, April 25, 2018

Education for Antibiotic Researchers

The Global Antibiotic Development Partnership (GARDP) has teamed up with CARB-Xto provide training to current and future antibiotic researchers and developers. I have been pushing this since 2004 when I recognized that the continued consolidation within industry and the abandonment of antibiotic research in industry was going to leave us without experienced antibiotic hunters in the near future.  That future has arrived! My experience in reviewing hundreds of grant requests from biotech and academia clearly demonstrates the lack of basic understanding of the fundamentals of drug discovery among today’s generation of would-be antibiotic researchers. A number of us experienced antibiotic researchers are retired, have been fired, or are now working on oncology or autoimmunity or in neurosciences or in diagnostics. Our expertise will be lost if we don’t do something to pass it on to a new generation. I have been trying to find a way forward for this for the last 15 years without success until now. GARDP and CARB-X are stepping up to the plate!

Before I get to the great work by GARDP and CARB-X, I ask – where is the National Institutes of Health here in the US on this? For more on this see one of my blogs from a few years ago. NIH (in spite of their “in kind” participation in CARB-X) is still very much on the sidelines in this educational effort as far as I can tell.

The GARDP-CARB-X effort kicked off last fall at the ASM-ESCMID meeting in Boston with three “bootcamps” for antibiotic researchers (entire talks via the links below). 

Antibiotic Bootcamp: What Makes a Good Hit? Why and How Do You Write a TPP? - https://www.youtube.com/watch?v=FwOtawrQjBs.


Antibiotic Bootcamp: Clinical Microbiology for a Development Program - https://www.youtube.com/watch?v=xfkuFhvOXsg.


Antibiotic Bootcamp: How Does a Molecule Become a Physical Medicine to be Given to a Human - https://www.youtube.com/watch?v=0IUan9LuDBQ.


GARDP and CARB-X just sponsored a symposium at the ECCMID meeting in Madrid, Spain (slides only).


Marco Cavaleri (EMA): EU regulatory tools for expedited antibacterial development programmes


Sumati Nambiar (FDA): US regulatory tools for expedited antibacterial development programmes

William Hope (Liverpool): PK-PD in support of accelerated programmes: how much is enough?

John Rex: Alternatives to (classical) antibiotics: what will it take to convincingly develop a virulence inhibitor or similar indirect agent?

GARDP has started providing a series of webinars. The first three webinars (presented by me) are on Clinical Development and they are specifically targeting scientists and others who are not clinical developers.  The idea is to provide an understanding to discovery researchers of the various development pathways available for new antibiotics and the risks that might be entailed for given types of products. The first webinar, focusing on traditional development pathways (Tiers A and B) has been prerecorded and is available here. A live version will take place on June 13, 2018.  You can preregister to listen and ask questions here.  Two additional webinars in this series will include one on the development of antibiotics targeting specific pathogens and another on enhancers and non-traditional approaches.  The dates for those have yet to be established, but both of them will include a panel of experts to provide information and answer questions. 

GARDP and CARB-X also plan symposia for the ASM Microbe in Atlanta and for the ASM-ESCMID meeting in Lisbon, Portugal later this year. 

I attended the first two bootcamps last year in Boston. I was incredibly impressed with the quality of the presentations, the speakers and the slides.  I am also extremely grateful that all of this is publicly available for anyone who wants to view the program now and in the future. I believe that all of the programs coming from GARDP and CARB-X will provide a similar high level of quality.  What I do not guarantee is that all of the experts will agree with each other on all topics. It’s going to be your problem to work your way through any controversies.  But at the very least, we will all start with a more advanced understanding of the subject.  

Many many thanks to GARDP and CARB-X for taking up this gauntlet and meeting the challenge head on!




Monday, April 16, 2018

Generic Antibiotics on the Edge

Many thanks to Lew Barrett for pointing me to this article

In the struggle to control drug prices, the rapid entry of new drugs into the generic marketplace is a key step.  This was emphasized by the National Academies of Science, Engineering and Medicine in their recent report on drug prices and shortages. 

Lets talk about generic medicines (even though I’m not an expert here). My understanding of the commercial aspect of selling generic drugs is basic. You work hard to identify the cheapest route to manufacture that you can. You set a price to maximize your margin.  You understand that as more manufacturers enter the field your sales volume will drop. So you keep working on that chemical synthesis and on your suppliers and supply chain to maximize efficiency.  This allows you drop your price while still maintaining enough margin to compensate for your decreased volume of sales. Is there a limit to this strategy? Apparently. 

A 10 day supply of trimethoprim-sulfamethoxazole (Bactrim, Septra, generic) costs from $.4.00 to $15.00 depending on your pharmacy.  That is $0.20-.75 per pill. A “Z-pack” of generic azithromycin runs $7.00-25.00 for the six tablets. According to the article by Cynthia Koons of Bloomberg Business, 90% of drug prescriptions in the US are filled with generic medicines. Generic drug prices are falling about 11% a year according to Koons. This is partly fueled by the domination of only a few giant drug purchasers in the US.  These large purchasers continue to pressure generic manufacturers on price. The generic manufacturers are, in turn, forced to compensate by selling drugs where margins are higher.  Antibiotics are apparently not among this group. Brendan O’Grady noted that Teva, where he is Executive VP for their North American business, still makes antibiotics – but Teva wonders why.

At the same time, drug pricing has become a hot-button political issue here in the US. The price gouging by Mylan for their Epi-Pen and, of course, that of the now infamous Mr. Shkreli and his $750 per pill price for the antiparasitic pyrimethamine used to treat opportunistic infections in immunocompromised patients, have inflamed public opinion.  Congress is not in the mood to support higher drug prices. Yet some reasonable strategy for drug pricing is required and this strategy might involve assuring some minimum value-based price for important drugs like, say, penicillin. This recommendation was, in fact, one of many from the National Academies.

Unfortunately, though, if Congress does not take this seemingly counter-intuitive step, we will continue to suffer more and more drug shortages. As the National Academies report notes, “drugs that are not affordable are of little value while drugs that do not exist are of no value.”  

It’s the triple whammy! Congress needs to provide financial support for new research and development of new antibiotics, money to fix the broken antibiotic marketplace, and support for pricing of generic antibiotics. Wow!  And Congress still seems unable to tie its own shoelaces . . . .

Thursday, April 5, 2018

Reflecting on Antibiotic R&D and Pull Incentives

Today I would like to reflect with you on what I have heard from investors, Pfizer, J&J and various biotech company executives concerning antibiotic R&D, the antibiotic marketplace and the potential role of pull incentives.  

One major problem is that pull incentives remain hypothetical.  Even in the hypothetical, the value of any potential incentive remains completely unknown.  Because of this, investors are essentially ignoring pull incentives, but are very focused on non-dilutive funding via push incentives. I am hearing that we are now experiencing another down cycle in antibiotic biotech investing in spite of the increasing opportunities for push incentives (CARB-X, Novo, Wellcome, BARDA). A recent survey of biotech investments shows that among the top ten life sciences investors, only Entasis, Spero and Nabriva among antibiotic R&D biotechs were recipients of their investments.  Most money pours into oncology and immunology biotech. A recent conversation with a top antibiotic investor confirms this current down cycle for me.

Biotech executives tell me that pull incentives play no role in their plans nor are they discussed in any serious way by their investors. Non-dilutive funding, however, plays an important role in their considerations. All agree that without more successful antibiotic launches, the investment future for antibiotic R&D will be bleak. Where they disagree is on what type of product will be required for a successful launch. Some say that the only way to go is with a relatively broad-spectrum antibiotic that can be used in empiric therapy.  Others say that a pathogen-specific antibiotic can garner a high price and also be successful. My personal opinion is that the high price strategy has, at least so far, been a dismal failure. (See my blog on price perversion). 
From large PhRMA, I have two opinions.  Actually, there is only one opinion and one obfuscation. Pfizer was quite clear. They look at antibiotic investing like any other potential portfolio opportunity. They are clear that they view the scientific risk of antibiotic discovery as simply to high to justify investment even with available push incentives at least given the current state of affairs. They are also clear that a substantial pull incentive will be required for them to invest in late stage antibiotic assets if the assets are to survive their portfolio review process. 

J&Jwas anything but clear. They start with their scientific expertise.  Although I know a number of antibiotic R&D experts who remain within J&J, I am not sure that they have the internal expertise to evaluate antibiotic opportunities.  They seem more interested in “global” needs such as treatment for resistant TB and gonorrhea. And they have demonstrated their commitment to TB with actual products from which they will gain no profits (their priority review voucher notwithstanding). Of course, this is nothing but laudable.  They would not really address any specific issues around what a pull incentive would need to look like for an antibiotic program targeting say resistant Gram negative pathogens to be adopted at J&J.  This makes me believe that such a program has little (but perhaps not zero) chance at J&J regardless of any pull incentive.

The events of the last several years leave me believing that we are standing on a cliff looking into the abyss. Astrazeneca’s spin-off of its antibiotic research assets into Entasis and its sale of marketed antibiotic assets to Pfizer was a beginning. This year we have seen the loss of another large PhRMA company from antibiotic R&D – Sanofi.  This is all the more ironic since they had reentered antibiotic R&D after having jettisoned their assets to form Novexel – the company that ultimately gave birth to avibactam. Once again, Sanofi spun out their assets (while retaining some rights) – this time to Evotec.  Nevertheless, every loss of a large PhRMA hurts because we lose their deep pocket support for the area.  The loss of the Medicines Company, a small pharma company, was especially discouraging since this occurred just after they had won approval for their meropenem-vaborbactam combination antibiotic. I firmly believe that the availability of substantial pull incentives would have altered at least some of these corporate decisions.

I have reason to believe that more losses are coming. Only the successful launch of a new antibiotic or the implementation of substantial pull incentives can keep us from the abyss. 

Friday, March 30, 2018

J&J, Antibiotic Resistance and Pull Incentives

 Before getting into the topic of today’s blog, I wanted to wish everyone a happy Passover and Easter. I hope that our thoughts of renewal this weekend will extend to the impending antibiotic resistance crisis.

Today I spoke with Dr. Adrian Thomas, an Australian physician, who is now the Vice President of Global Public Health for Johnson & Johnson.  As you may know, J&J has performed yeoman work in the area of tuberculosis and, more recently, Ebola. The company has a major investment in medical devices especially around surgery.  They recognize the implications of antimicrobial resistance for their device business.  Surgical implantation of devices in orthopedics, both electively and emergently, and, in the future, from the use of robotics in surgery are areas clearly at risk from emerging antimicrobial resistance.

As I did during my interview with Pfizer, I tried to get Dr. Thomas to provide me with a specific incentive or even a specific monetary amount as to what J&J would expect from a pull incentive in order to invest either in antibiotic discovery research or in the development of a late stage asset.  The reply I received was not what I expected.  Dr. Thomas pointed out that J&J is a science-driven company.  Therefore, that any opportunity they might explore would depend on whether they had the scientific expertise to maximize the opportunity. (I wonder if J&J still has the internal scientific expertise to evaluate antibiotic assets).  Only when that criterion was satisfied would commercial considerations come into the picture. He also noted that the requirement for the size of a pull incentive might be quite different depending on the specific product and its spectrum of activity. The most difficult of the products might be those where the smallest numbers of patients would be treated.  Therefore, one would be developing a product that would, essentially, be used only very sparingly.

I also asked what kind of pull incentive would be preferred by J&J.  Once again, he responded saying that it would depend on the specific product and that this is a complicated topic.  He pointed out that different pull incentives might be required in different markets globally. Dr. Thomas provided an example of a priority review voucher that they received upon approval of their TB drug in 2012.  They used this voucher to accelerate approval of a drug to treat psoriasis – a particularly competitive area. For them, this was an important pull incentive. This pull incentive was then ploughed back into public health related research according to Dr. Thomas.

In discussing pull incentives generally, Dr. Thomas pointed out the importance that J&J would place on innovation in the award of such incentives. He also pointed out than any such incentive, according to J&J, should be accompanied by appropriate guardrails.  But when I asked what they would look like, he demurred suggesting again that such questions could only be answered on a case-by-case basis. There is no specific answer here from J&J, he said. The other need he emphasizes is that companies need to be able to recoup premium pricing on drugs that are rarely used.  (Recent launches have not been encouraging in this regard - my thought here).

Dr. Thomas also expressed some skepticism around the regulatory process that might be adapted for approval of rarely used antimicrobials targeting resistant pathogens. He noted that the pivotal trials for their TB drug took 3-5 years to complete.

Finally, Dr. Thomas noted the concern that I think all of us share.  In the absence of defined pathways not only for approval, but more importantly, to success in the marketplace, investors are hesitating.  My recent conversations with key investors in this space confirm that this is a real concern. Dr. Thomas noted that there is a dearth of potential partners for drugs acting against resistant pathogens (partners that would interest J&J, I presume he means).  

In summary, like other large pharmaceutical companies such as Pfizer, J&J believes that pull incentives as well as premium pricing are a necessary part of fixing the broken market for antibiotics targeting resistant pathogens.  Dr. Thomas would not provide details on preferred pull incentives or the amount of compensation that would be required.  He maintains that it all starts with the science and with J&J’s internal expertise and that commercial needs would have to follow on a case-by-case basis. That said, he noted that J&J was pleased with the priority review voucher they received for their TB drug.

Monday, March 19, 2018

Duke Margolis FDA Conference on Rare Diseases

Today the Duke Margolis Center and the FDA held a workshop to discuss how to approach clinical trial designs for rare diseases. Full disclosure – I mainly watched the summary discussion session. Much of the earlier discussion on the details of Bayesian statistics escaped me. The rare diseases that were the subjects of this meeting were mainly things like muscular dystrophy and inherited metabolic diseases in children. Bacterial infections and targeted therapies were mentioned, though. Most of the discussion, therefore, revolved around superiority trials.

I know that some antibiotic developers have very strong negative feelings about superiority trials.  I am not among them. I do not agree that once a drug has been shown to be superior to a given therapy, that drug then must be used as the control in further superiority trials. I am also not sure that non-inferiority trials are even feasible for pathogen-specific therapies even with a wider non-inferiority margin. As I mentioned in a previous blog, in spite of the fact that ceftazidime-avibactam is available to treat resistant infections, our old, inferior drugs, polymyxin and colistin are still being used very frequently. This suggests that clinicians and pharmacists are not convinced of ceftazidime-avibactam’s superiority to the polymyxins. (How this could be true escapes me!) Therefore they continue to use the cheaper product.

Key concepts included the use of Bayesian designs where non-trial data is used to established “priors.” Questions that many of us have asked in the past revolve around exactly what kinds of data can be included here. I would think that, for antibiotics, in vitro data, in vivo animal models and both preclinical and clinical PK/PD could be useful in establishing priors. Such data could even lead to modeling of response in the clinic.  Could these models be used as well? Other useful prior data might include early clinical trial data that might have been generated before embarking on pivotal trials.

In this regard, clinical trial networks could be extremely useful. Data that might be used in the to streamline the trial itself might include natural history data from registries.  A clinical trial network that participates in late stage clinical trials might also be able to provide this registry data.  Such a network might also be able to utilize a master protocol for various new antibiotics targeting smaller populations. 

Data from prospective observational studies might also be useful to help establish control levels of response and to provide a better understanding of contemporaneous natural history of the infection of interest. Such data could also come from the network, but does not necessarily have to be from the network.

These concepts fit well with the latest draft of the FDA’s unmet needs guidance.  This guidance discusses the use of superiority trials, external controls and the use of Bayesian approaches. They even state that a statistical finding for superiority for a pathogen specific antibiotic targeting patients with unmet needs might be less stringent than the usual standard.   

An idea that has been discussed elsewhere is  pre-enrollment or early consent.  This fits well with another concept discussed in detail at today’s conference – that of patient participation in these decisions.  Pre-enrolling patients allows patients and their families to consider a study without the urgent pressure of an ongoing severe infection where the patient is less likely to be able to be an active participant in the decision.
Finally, the FDA emphasized that they are open for business.  They want developers to speak to them. I didn’t hear the antimicrobial group at the portion of the conference I viewed, but I believe that their attitude is similar. This conference was encouraging and makes me believe that we are slowly closing in on ways to study and market antibiotics focused on limited patient populations.

I must also remind everyone that no matter how much we progress on the regulatory front, unless we solve the problem of the marketplace, we will continue to struggle to provide the robust antibiotic pipeline that we so desperately need.

Thursday, March 8, 2018

Pfizer, Antibiotics and Incentives

For this blog, I contacted three large pharmaceutical companies and two agreed to speak about how they view antibiotic research and development in light of real and potential incentives. This week, I will discuss my conversation with Patrick Holmes, Head, International Policy, Pfizer Global Policy and International Public Affairs. I have an interview with the second company scheduled for the end of this month and I will attempt to contact other companies as well.

As you probably know, Pfizer recently put their toes back in the antibiotics arena by purchasing the Astrazeneca assets.  They therefore currently market ceftazidime-avibactam and ceftaroline outside of North America. Mr. Holmes explained that Pfizer looks on antibiotics and incentives like they would any portfolio review project. For those of you uninitiated in this, the executives and others compare risks and time to success across all therapeutic areas that compete for resources within the company to choose the most promising projects for funding. One key consideration in the analysis is time.  Companies, including Wyeth when I was there, often apply a discount for the increase in costs that the company expects to incur over the years of the project including during years of marketing. This factor includes increases in inflation as well as increases in costs of research and development, marketing, capital expenses, and, of course, returns to shareholders. Generally speaking, an industry cost of capital of  is about 10% per year (similar to Wyeth’s) (inflation by itself, even in health care, has recently hovered around 3%). This means that without any other factor, by the end of 10 years, no project will provide a return on today’s investment. Therefore, it is nonsense to apply this to any preclinical project like, say, antibiotic discovery research, since that timeline is 10-15 years before there will be a product.

In addition to the overwhelming discount of increasing company costs is the discount assigned to risk of failure or, better, probability of success.  When you assume that only 10-20% of projects entering phase I will succeed in getting to the marketplace, anything prior to that such as discovery research projects again seem overwhelmingly risky. What does this mean for Pfizer? In their model, according to Mr. Holmes, antibiotic discovery research can only be supported with very substantial pull and push incentives. As I thought about this, I realized that, in fact, the time required for discovery research for antibiotics is no different than would be true for any other therapeutic area. Pfizer may simply view the scientific risk of antibiotic research to be prohibitively high. I believe that is what Pfizer has concluded.

On the other hand, the good news is that in the presence of a pull incentive, and perhaps with additional push incentives, antibiotics at a phase 3 or later stage of development look promising to Pfizer.  In other words, Pfizer is still an opportunistic antibiotic supporter. But the pull incentive has to be the right one.  Which one is that?  According to Mr. Holmes, their preferred pull incentive is the transferable exclusivity voucher where they would gain an increased time of exclusivity to market a drug from their portfolio of their choice. There are many reasons why this would be their preference, but a big one is that the reward could be much higher than the $800 million to $2 billion that has been discussed by DRIVE-AB and others. Pfizer would not be in favor of guardrails that would be too limiting in this regard although we did not get into the specifics of what Pfizer’s limits would be here. We did not discuss details of the hybrid market entry rewards or the insurance models that have also been proposed.  But Pfizer’s preference is clear and it fits with my own oft-stated views.

I am disappointed with Pfizer’s view of antibiotic discovery research as I am sure many of you will be as well. But their view is an understandable one.  Let biotech (or rarely academia) and their funders take the risks. This will mean that push incentives will more likely flow to biotech. If the resulting product is appropriate, Pfizer will reward them and, Pfizer hopes, themselves. In this way, pull incentives could actually have a trickle-down effect. Pfizer’s approach should therefore be encouraging to biotech investors.

What about those PhRMA companies that have abandoned antibiotics research?  Of course, two of them have come back into the fold – Roche and Sanofi. But have the likes of Lilly, Abbott and Bristol-Myers-Squibb reconsidered antibiotic research in the light of push and pull incentives? Lets try and find out! If anyone has contacts in public policy departments at these companies, please let me know.