Wednesday, October 24, 2018

The UK and Antibiotic Resistance - What Happened?

 In 2016 I wrote a series of blogs on the many ways the United Kingdom was leading the fight against antibiotic resistance.  Tamar Ghosh blogged about the Longitude Prize for a new rapid diagnostic for resistant infections. I wrote two (1,2) blogs speculating on the effect of Brexit on the UK’s fight against resistance and comparing efforts in the UK to those in the US in this regard. A key personality in the UK’s approach to resistance was David Cameron.  He was supported by George Osborne, his Chancellor of the Exchequer, and Dame Sally Davies, his Chief Medical Officer. Cameron made antibiotics and resistance a top priority of his government. Antimicrobial Stewardship became a high priority within the National Health Service and used financial incentives and disincentives to achieve goals. 

So, what has happened under Teresa May? First, antibiotic resistance is no longer among the “top five” priorities in her government’s strategy – where it was in that list under Cameron. With Brexit looming, the European Medicines Agency (Europe’s pharmaceutical regulatory agency) decamped from London and opened up shop in Amsterdam. In the UK you hear very little these days about action and funding to deal with resistance. Brexit dominates the news cycle. (Of course, in the US, one might say that things are even worse than in the UK).

While there was progress in the area of stewardship, many of the other recommendations from the O’Neill Commission (as I call it), have not seen any progress.  Specifically, those recommendations dealing with the broken antibiotic marketplace have fallen by the wayside. A recent report from the UK parliament highlighted these shortcomings of the May government. According to CIDRAP, the report makes a number of key observations and recommendations.

·     In spite of lowering antibiotic usage by a relatively small percentage, there has been an increase in resistance among bloodstream infections in the UK.
·     40% of all antibiotic use in the UK remains in animals. The report recommends that this be further curtailed.
·     The report targets environmental discharge of antibiotics and other waste that might provoke or disseminate resistance.
·     Finally, and of greatest importance, the report notes that there has been a complete failure to follow the O’Neill Commission recommendations on fixing the broken antibiotics marketplace.  They parliament suggests a six month time period for government and industry to get together and provide specific recommendations for dealing with this problem. In other words, find a pull incentive that will work and then implement it! (Seeing is believing).

I don’t live in the UK and don’t spend enough time there to judge for myself whether there is any chance that this parliamentary report will result in concrete action.  (If this occurred in the US, I know exactly what would happen . . . ). But I do remember the days of the O’Neill Commission, the days when Dame Sally Davies was frequently covered by the world press as she spoke about the dangers of resistance and when antimicrobial stewardship policies in the UK grew teeth. Are those days gone?

One bright light in this story in the UK has been and continues to be the Wellcome Trust. The Trust clearly understands the importance of the resistance threat and it reacts by providing funding for a large variety of efforts to combat this threat. They do this alone and through collaborations here in the US, in China and throughout the world. But without key government action (think pull incentives), the Wellcome, even with all its collaborations, will not be able to finally deal with the threat of antibiotic resistance that is knocking at our door. 

Tuesday, October 2, 2018

Musings on the Introduction of New Antibacterials to the Marketplace

I know its been a few weeks since my last blog. A great deal of discussion around antibiotic development and pull incentives is still occurring even though the topic has disappeared underneath the continuing stream of news out of Washington. Scott Gottlieb, our FDA Commissioner, recently gave a speech where he emphasized the importance of pull incentives in revitalizing the antibiotic pipeline. The FDA and the Duke Margolis Center just held a conference on the use of real world data and evidence in regulatory considerations. 

Since our webinar a few weeks ago, I keep circling back to the differences between what we need to accomplish for regulatory approval and what is needed to convince clinicians, patients, hospitals, pharmacists, payers and other stakeholders that our new antibiotic is a valuable and important addition to our therapeutic inventory. To be successful, we must address all of these parties above and beyond any regulatory requirements. While I still believe that in spite of all our best efforts, the antibiotics marketplace is still broken, I also think we could be doing a better job addressing the needs and concerns of our most important partners in health care. We clearly need to do better to convince these stakeholders that polymyxins are never the drug of choice when drugs like ceftazidime-avibactam, meropenem-vaborbactam or ceftolozane-tazobactam are also appropriate options. What steps can we take to ease the cost considerations that make our clinical stakeholders hesitant to stock these drugs for the relatively rare cases that they may encounter where these drugs could replace the polymyxins? Should we be going to multiple local depots where such drugs can be stored such that a hospital can obtain a non-formulary item within hours instead of days?  Is that practical? Should we simply not charge for orders but only for use such that hospitals can return unused product? 
What more can we do during our pivotal trials or in post-approval studies to convince stakeholders that our new drug should actually be used instead of the older, less efficacious and more toxic options that are readily available? Will sub-population analyses really help?  Will small, unpowered superiority trials help?  Will real world data gathering such as in prospective observations studies help? I can’t help feeling that we are not doing enough talking with the right stakeholders on these and related topics.  

Are we doing enough to convince stakeholders that our new drug, in spite of its cost, is actually cost effective? Have we learned from the approach of the antiviral community in this regard? What are we getting wrong here?

Finally, what can be done to speed the availability of automated susceptibility tests when our drug is launched? Delays of one year and more are unacceptable.  It is not clear that recent FDA guidance will help in this regard (more on this in a future blog). This problem can probably best be resolved at the level of the test manufacturers. 

I know that all companies attempt to explore all of these questions with a number of stakeholders prior to the launch of their new product.  But I also know that either they are not hearing what they are being told or that they are not being told what they need to hear. 

I think that its time once again to gather all stakeholders beyond the regulators together in an objective setting to explore these and other questions on the introduction of new antibacterials to the marketplace.