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.