Thursday, July 23, 2020

Infection Control - Is Medicare Helping?

Back in 2015, the Harvard group published an extensive study on the effects of Medicare’s punitive non-payment system for hospital acquired infections. The authors surveyed almost 400 hospitals or hospital systems for up to a total of over 28,000 unit-months.  They surveyed catheter-associated urinary tract infections and catheter-related bloodstream infections – for which Medicare had established punitive non-payment policies, and hospital-acquired pneumonia for which there were no punitive policies at the time. The results, shown in their figure reproduced below, show clearly that for all three infection types the, infection rates were already decreasing before Medicare implemented their policy and that the rate of decrease did not change after policy implementation for any infection type.  I concluded from these data that hospitals had realized that hospital-acquired infections were not good for patients and not good for their bottom line before Medicare’s policies and that the punitive measures did not accelerate the hospitals’ efforts to eliminate these infections. I was especially interested in these data since the small hospital where I volunteered on their infection prevention committee had incurred a punitive non-payment the year prior to the publication of the article. 


Fast forward to 2020. Authors again from the Harvard system once again examined the effect of Medicare’s punitive non-payment policies on infection rates. They specifically compared “safety-net” and non-safety-net hospitals. “In October 2014, these programs began comparing hospital performance on selected infection metrics with national benchmarks based on prospective infection surveillance data reported to the National Healthcare Safety Network (NHSN) of the Centers for Disease Control and Prevention. At present, HVBP rewards or penalizes the highest- and lowest-performing hospitals by up to 2%of the total inpatient payments the hospital received, whereas the HACRP reduces payments by up to 1% for the lowest performers.” In this case, the team examined data from 600 hospitals who submitted their data to CDC’s National Healthcare Safety Network (NHSN) system over the years 2013-2018. Once again, these punitive measures failed to improve the rates of all four nosocomial infection types studied. The authors suggest that these punitive measures have a relatively greater financial effect on safety-net hospitals for no appreciable gain in infection prevention. They also show that Medicare has learned little over the last decade of experience since implementing these sorts of punitive measures. 


I continue to believe that most hospital administrations understand that what is best for their patients is what is best for their hospitals and that they try and act accordingly.  While I am sure that there are exceptions to this, it is clear that the Medicare policies are now doing more harm than good. In order to further lower infection rates, we probably need a better understanding of the various factors that lead to increased rates, including patient risk factors, hospital staffing, and others such that we can direct hospitals to take the measures that are required to reduce rates further. It is one thing to apply a general policy without regard to the specific factors one seeks to alter and another to apply specific policies tailored to the needs of individual institutions.  I suggest that it is the former approach that is most needed.  






Friday, July 10, 2020

AMR Action Fund - a Bridge - to Where?

Yesterday, I listened to the global launch of the AMR Action Fund. The fund and its launch are also described in an article in the NY Times by Andrew Jacobs. Better yet – you can watch the launch here. In a way, this is a miraculous development that came to be under the leadership of Peter Beyer at the WHO. John Rex said he had tears in his eyes watching the launch. 

The AMR Action Fund, with pledges of $1 billion, was created by leading pharmaceutical companies and supported by the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA). Investors include large companies like Merck who still carry out antibiotic R&D efforts and those like Eli Lilly which was one of the first to abandon the area around 20 years ago. These investors recognize the constant and growing threat of antimicrobial resistance.  They are cognizant of the lack of investment in the space that is leading to an inability to bring important new therapies to market and to threaten the very existence of those companies who attempt to do so. Their intent is to provide a bridge by funding the expensive phase 2 and 3 clinical trials and attendant development costs required to achieve regulatory success and market entry. Their goal is to bring 2-4 new, high priority antibiotics to patients by 2030. No wonder John Rex was moved to tears.

 But the AMR Action Fund investors also recognize that without government action, probably on a global scale, to put in place significant pull incentives their funding will be a bridge to nowhere. And this is where my own tears of sadness and despair come in. Much of the discussion focused on the DISARM act here in the US that would provide hospitals an add-on reimbursement for high-priced new antibiotics. But as I’ve stated many times in the past, this may only be a first, sort of baby step. Senator Casey, in his remarks, spoke of the GAIN act.  The regulatory components of that legislation were welcome – especially the requirements for feasible trial designs and for streamlined development and review for priority antibiotics.  The financial incentive – five years of additional exclusivity - was never an incentive for the vast majority of products with patent lives beyond a few years after approval. The DISARM act is restricted to those patients who actually need therapy in the hospital and may not, therefore, provide for the kind of fire extinguisher approach that we need.  (We pay for firepersons and extinguishers in the hope that we never need them). In fact, the presenter from Pfizer mentioned incentives such as subscriptions and transferable exclusivity vouchers. I agree with those choices in addition to a simple market entry reward contract. 

Without government action, we all understand that the AMR Action Fund, as inspiring and generous as it is, will be a bridge to nowhere. We all need to work harder to reach out to other stakeholders and bring them in to our cause before its too late. 

Tuesday, July 7, 2020

The FDA Revisits Community Acquired Pneumonia

The FDA just published an article examining the relationship between their early clinical response endpoint for community-acquired bacterial pneumonia as compared to the late endpoint of cure at test of cure currently required by the European regulators. Accompanying this article is an editorial by George Talbot who provides an analysis of the data and, more importantly, some historical background for the study. 

For those of us who lived through the nightmare of the FDA struggles with non-inferiority trial design throughout the years 2000-2012, reading the FDA study may be difficult. During those years, the FDA struggled with how to justify the so-called statistical margins used in clinical trials of antibiotics. The FDA wanted to be sure that the antibiotic effect was not similar to placebo, the statistical assumption that underlies all non-inferiority studies. They were also justifiably worried about the effect of prior, non-study antibiotics on the ultimate clinical outcome. This worry was clearly raised during a trial of daptomycin where the drug was inactivated by lung surfactant, yet appeared to work in a late stage trial.  That false sense of success was laid at the feet of short-term antibiotic therapy given prior to enrollment in the trial. These considerations led to a complete reconsideration of trial design for antibiotics in the treatment of bacterial pneumonia. 

The FDA’s reanalysis showed essentially what we already knew. There is a huge antibiotic effect in the treatment of bacterial pneumonia.  The effect is the greatest when looking at the early response to antibiotic therapy but is still large even when looking at later cure. In this case, the treatment effect for the early timepoint seemed to vary among different studies from 30 to 77%. The FDA decided that designating 20% as a conservative treatment effect would be OK after discounting for the fact that all these studies took place 80 years ago or more. These considerations ultimately led to a 12.5% non-inferiority margin for studies of community acquired bacterial pneumonia. 

To summarize, the FDA paper, that analyzes data from six recent trials, clearly shows that the early response endpoints, improvement in at least two of four specific symptoms (chest pain, cough, sputum production, and dyspnea) without any symptom worsening, and clinical cure (the late endpoint) agreed (success or failure) 86% of the time. That this would be true was predicted by the careful studies of the FNIH team lead by Talbot in 2011 and the FDA’s analysis documented in the guidance of 2014. A detailed look at the data reveals that discordant results may be explained. Early responders who had late failures were more likely to have severe chest pain on enrollment, infection caused by Staphylococcus aureus or Chlamydophila pneumoniae, or to have received prior non-study antibiotic therapy. 

Both FDA and Europe have already recognized the potentially confounding effect of prior non-study antibiotics in these trials.  Both agencies also recognize that a total prohibition of prior antibiotic use would render trials infeasible. So both, pragmatically, limit the number of patients and the doses and types of prior antibiotics that are allowed. 

The FDA concludes that the data they published provide an opportunity to reach international convergence on clinical trial design for the study of antibiotics in community acquired bacterial pneumonia. I presume that they would like Europe to adapt the current FDA designation of early endpoints as definitive. But the data could also justify the FDA accepting clinical cure as definitive. As a physician, personally, I would like to put the FDA’s perseveration behind me and go back to using cure at test of cure as the ultimate endpoint.  The concordance shown between the two endpoints is a tempting reason to do so and would make the most sense (in my humble view) to both patients and providers. But I cannot help but feel that the FDA would not agree with me. 

Talbot concludes that this kind of analysis is very useful both for physicians and regulators and he lauds the FDA for publishing the data.  I cannot agree more.  

I also need to recognize the role of George Talbot in leading us through the morass of the FDA’s trials and tribulations during those critical years so that we ended up in a place where we could once again pursue the development of antibiotics. I’m not sure how long we would have been in Neverland without his steadfast leadership and insight. 

Wednesday, July 1, 2020

FDA Analysis of Antibiotic Development - with Hubris!

The US FDA just published an analysis of antibiotic development looking back over the last 40 years. The paper was accompanied by an editorial by Rex and Outterson. These papers are well worth reading and I highly recommend them for everyone whether they are familiar with antibiotic development or not. I must say that the hubris of the FDA analysis is astounding (see below). 

The FDA paper documents and quantifies a number of facts most of us already know. 

·      Antibiotic discovery and development as gone from predominantly large pharma to almost all biotech.
·      The number of approvals of new antibiotics has drastically decreased in the last two decades (with a modest increase in recent years). 
·      The success in achieving market approval plummeted by 50%.

Two observations that were of high interest were that clinical development times have increased substantially and that the antibiotic classes being developed have changed to large percentage of classes outside of B-lactams, macrolides and quinolones. The FDA notes that there has been a recent increase in the number of B-lactamase inhibitors in development (a welcome change as far as I’m concerned), as well as an increase in “others.” I think that this may be related to the biotech nature of sponsors and their willingness to pursue non-traditional avenues such as peptides, peptidomimetics, new targets, etc. This also may help explain the lower success rates since, by definition, these may be higher risk ventures. 

The prolonged development times may also be partly explained by the change to biotechs where discontinuation of development may not be reported to the FDA in a timely way. But – a KEY reason for the decreased success rates and prolonged development times lies with the FDA ITSELF. This fact is conveniently ignored both by the FDA authors and by the accompanying editorial. Let us remember that in 1999-2000 the FDA began to tighten their antibiotic trial design requirements that led to increase development costs and timelines.  This was, in fact, one of the several factors that led to the abandonment of antibacterial discovery and development by large pharma starting in 1999. Then came the Ketek scandal of 2006 where the FDA yielded to congressional pressure and essentially brought antibiotic development to a virtual halt (with just a few exceptions). They finally realized their mistake and the resulting disaster for antibiotic developers and reversed course in 2012.  But this resulted in extensive damage to the industry and our pipeline. For a complete review of this history – see my book – Antibiotics – the Perfect Storm published in 2010. 

The FDA notes that today only 8 of 25 drugs in development target critical multiply-resistant Gram-negative pathogens.  They note the increase in development of drugs on novel classes, but they also not the higher risk associated with such compounds.  They wonder if failure of a program using a novel class would doom the entire class. That is a good question and I suspect the answer will have to be provided on a case by case basis. 

The FDA also questions whether the prolonged development times translate into higher development costs.  That may be true.  But the FDA does not consider the incredible cost associate with the post-approval obligations that occur if a drug should make it all the way.  This is a topic covered by the accompanying editorial.  

Clearly, the FDA analysis confirms what we already know about the fragility of our antibiotic pipeline.  The increased development time, higher risk of failure, increased costs, and burdensome post-approval obligations all work to discourage scientists, entrepreneurs, investors and companies from entering or continuing in the antibiotic space. The paucity of our pipeline therefore is not surprising. 

As the editorial by Rex and Outterson points out, without significant pull incentives to address market attractiveness we will be doomed to a failing pipeline for the forseeable future.