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. 

Reach Out - Leave the Echo Chamber

Last week, a special issue of the American Chemical Society Infectious Diseases journal focusing on antibiotics was published.  This issue is a great collection of science, research efforts and opinions that will be of interest to all. It was guest edited by Mark Blaskovich. The articles are all open access – I contributed two viewpoint papers.  One drawback, once again, is that the special issue is laser-focused on those already interested in antibiotics, the pipeline of new drugs, and the crisis of emerging resistance. It does not, and probably cannot (given the journal’s raison d’être) draw in those readers we need most – those in fields of medicine outside of infectious diseases. We need interest and action from internists, oncologists, pulmonologists, intensivists, transplant specialists, surgeons, emergency medicine docs and their respective professional societies. I have blogged about our echo chamber in the past, and things seem not to be changing. If we cannot convince our colleagues that there is a serious and growing threat to their ability to continue to treat bacterial infections, then we cannot expect governments to believe us either. 

Why is this so hard? In one of my viewpoint articles, I discuss some of my own experiences caring for patients with various infections - from those that responded dramatically to penicillin to those completely refractory to everything in the toolbox. But these patient encounters are not isolated to infectious diseases physicians and microbiologists. They involved surgeons and intensivists. I can think of myriads of other patients with challenging bacterial infections that I did not discuss where I interacted with a host of other specialists and subspecialists.  All of them will probably remember those very difficult cases whether the end was tragic or not. I certainly still remember them. 

Of course, one reason it may be difficult to recruit those in other areas of medicine to our cause is the matter of patient numbers.  Us infectious diseases specialists see these challenging patients all the time.  It’s our job. But surgeons, for example, only see those for which they consult us. And those numbers, hopefully, are small. Therefore, it is more difficult for them to see today’s need and the looming threat of tomorrow. We must rise to the occasion to help them see that the rare difficult to treat patient they saw this year will become the one they see every month then every week in coming years if we don’t act now. They must unite with us in common cause.

Today, we are struggling with a pandemic viral infection. Those of us who are ID physicians will recognize the failure of all of the effort that went into pandemic planning at least at the beginning of the pandemic. Now that we are catching up (I hope), will we be able to recognize this failure?  Will we learn that sometimes those with special expertise and knowledge can provide useful guidance in preventing catastrophes that threaten our future health and that of generations to come? Our failure to deal with the antibiotic market crisis and its inevitable consequence of a failing pipeline of new and useful products does not have to be the end.  We can still alter the future by investing now as we should have done to prepare for a pandemic like covid. This, however, is a lesson that I am not sure that we have learned. For short term thinkers, investment in the future is a severe challenge. But this is an argument that we must make and do so in the strongest terms. To do that, we need the help of colleagues outside of our infectious diseases bubble. 

This is a job for the infectious diseases professional societies. In perusing the IDSA website, I find precious little in the vein of outreach to other professional societies. There are guidance documents established with other societies, but they are often years in the making and without the kind of outreach that we are discussing here today. 

In the absence of sufficient efforts from our own professional society, I am going to ask that all of you in our echo chamber discuss the problem of the antibiotic pipeline, the market and emerging resistance with your non-ID colleagues. Explore with them the possibility of joining our cause. Reach out to IDSA as well – I can’t be the only one preaching this line of argument. 

If we are not successful soon, we may be dealing with years of drought in the face of emerging resistance. 

Now Will Europe Pull it Together?

Could Europe’s recent moves to provide bailout monies Europe-wide have implications for incentives for antibiotic R&D? A few months ago, Christine Ardal and colleagues published a paper discussing the European approach to these incentives. In their paper, they noted that decisions around drug pricing and everything related to drug reimbursement were the responsibility of the various national authorities and not the European Commission. They did suggest that the European Medicines Agency, the European regulatory agency from drugs, could identify products that would qualify for any incentives that might be available. They suggested that individual countries could contribute to the European Investment Bank to support a regional incentive. Ardal et al also pointed out that Europe assumed that their responsibility for such in incentive on a global scale would be about 30% based on antibiotic market data. I wrote an editorial response to their paper where I suggested that incentives for antibiotic R&D would have to be a European responsibility since that was the only authority with enough financial clout to provide effective incentives for the region. Relying on the contributions of individual countries, I suggested, would not be sufficient. Ardal et. al. did note that transferable exclusivity vouchers would be possible in Europe, but that any “guardrails” that might be required to limit the size of the reward would still be a decision of the national authorities. This, in my view, renders that approach impossible. Further, I noted that even if Europe could agree to provide an incentive that amounted to 30% of what is required, there might be no point since the participation of countries outside of Europe and outside Europe’s control would also have to agree to participate. I suggested that Europe as a region could take the lead in providing a more substantial incentive for antibiotic R&D if for no other reason than to protect their vulnerable populations.



Enter the coronavirus pandemic. According to the New York Times, “The European Commission, the bloc’s executive branch, on Wednesday proposed that it raise 750 billion euros, or $826 billion, on behalf of all members to finance their recovery from the economic collapse brought on by the virus, the worst crisis in the history of the European Union.” “’This is about all of us and it is way bigger than any one of us,’ Ursula von der Leyen, the commission president, told European Parliament members in a speech in Brussels. ‘This is Europe’s moment.’”



In my editorial, I cited Flora Lewis’ book, Europe, A Tapestry of Nations, in discussing the balance between lines of national sovereignty and European union. Since the establishment of the European Union in 1993, and its precursor, the European Economic Community back in 1958, all aspects of finances and health including taxes, health insurance, drug pricing and others were responsibilities of the national authorities. This changed little with the introduction of the Euro to a portion of European Union countries in 1999. But here we are today, 27 years after the formation of the European Union, with the first steps of Europe into federalism. And with federalism comes the ability to commit Europe, with all its member nations, to common financial activities for the good of all. Incentives for antibiotic R&D should be one of the first European priorities of this new federalism.

Back to the Future

I want to return to my favorite topic, antibiotics, viewed through the lens of the covid-19 pandemic. Of course, as is probably true for all of us, my perspective is colored by my own history and experience. I want to share that with you before proceeding further. 

Back when I was working as a microbiologist and infectious diseases specialist at the VA Medical Center in Cleveland, the head of the pulmonary department asked me if I would attend (supervise) on our medical intensive care unit for one month a year. I thought this was because he admired my ability to diagnose infections combined with the fact that I also understood blood gas data. In retrospect, I wonder if it wasn’t that he couldn’t find anyone else to take the job. This was before there was a recognized specialty in critical care medicine in the US (boards were established in 1985). Luckily, I was supported by pulmonologists so that I had backup on decisions involving the proper use of mechanical ventilators among other issues. The work was . . . .intense. Often, on arriving in the morning, I could tell which patients had gotten into trouble the previous night by the number of antibiotic orders written for them. There seemed to be a correlation between the number of antibacterial, antifungal, and, for those truly desperate, antiviral drug prescriptions and the severity of their acute illness. I spent a great deal of time trying to hone the diagnosis of infection, if there was one, and, in the light of day, to “adjust” therapy to something more appropriate. 

The US CDC estimates that about 50% of hospitalized patients receive at least one antibiotic during their hospital stay. A study from New York hospitals treating seriously ill covid-19 patients showed that 89% received antibiotics. A recent review showed that about 8% of patients hospitalized with covid-19 infections had a complicating bacterial or fungal infection during their hospital stay, but that a striking 72% of all hospitalized covid-19 patients received antibacterial or antifungal therapy.  This reminded me of my own ICU experience. Given the numbers of such patients overwhelming our hospitals, this could represent up to a 50% increase in hospital antimicrobial use.

One thing that we know for sure is that the “you use it, you lose it” law of antimicrobial resistance rules. This means that the use of antibiotics, whether appropriate or not, will select for the emergence of resistant pathogens. Therefore, we can expect an increase in bacterial resistance in our hospitals – globally. The CDC recently reported that there about 3 million antibiotic resistant infections occurred every year in the US resulting in 48,000 deaths. Several years ago, the Review on Antimicrobial Resistance (I call it the O’Neill Commission since it was led by Jim O’Neill ex of Goldman-Sachs) estimated that there were 700,000 deaths worldwide annually due to resistant infections.  They predicted that given the trajectory of resistance, by 2050, 10 million lives will be at risk annually along with a $100 trillion-dollar loss to world GDP. No one imagined, I guess, that this might be accelerated by a global pandemic – but here we are. 

This unexpected acceleration of resistance will occur at a time when our 95% of our completely inadequate new antibiotic pipeline is supported by small and fragile biotechs. Will it occur during a time when we have learned at least one key lesson from covid-19 – to invest in our future health? Will we finally realize that we have to support the antibiotic marketplace to prevent further bankruptcies of antibiotic biotechs?  Will we find a way to encourage investment in our antibiotic pipeline again? Or will we ignore the counsel of untold experts and just wait for the next disaster to strike?

The Keystone Cops vs. Coronavirus

It sounds like the US Department of Health and Human Services has become completely dysfunctional. The Secretary, Dr. Azar (ex-lobbyist and President of Eli Lilly), apparently can’t get along with his administrator of Medicare, Seema Verma. He led the FDA and CDC (HHS agencies) as they failed to protect the US population because of their disastrous early approach to coronavirus testing. And on and on . . . .

BARDA (an HHS agency) director Rick Bright was transferred to NIH after warning in January about the potential of a pandemic hitting the US and then hesitating to release large supplies of chloroquine and hydroxychloroquine without more evidence that this treatment for coronavirus infection was safe and effective. He accuses the HHS of a disregard for science and for cronyism in the award of BARDA contracts.  He states that his transfer to NIH was retaliation.

Some of the CDC guidelines on dealing with coronavirus defy logic and science. A good example is the guideline on essential workers stating that they should be allowed to work after a known covid exposure unless they are symptomatic.  This in spite of our knowledge that at least 25% of transmissions occur via presymptomatic or asymptomatic individuals. 

The CDC’s most recent detailed guidelines for re-opening the economy were rejected by the administration for being “too prescriptive.” There are guidelines on criteria for re-opening from the CDC posted on the Whitehouse and CDC websites. Many states that are re-opening are ignoring them. 

The federal government planned to screen airport travelers for fever to instill confidence that flying was safe again.  The CDC refused to participate saying the effort required was too costly and that the screening was ineffective anyway. 

The Whitehouse eschewed masks even though they were recommended by the CDC only to reverse course after several positive cases among their staff.  The President and Vice President were, of course, to be excepted from the requirement to wear masks in the West Wing. 

Dr. Deborah Birx, the White House Coronavirus Response Coordinator, recently said that she had no confidence in the coronavirus case and death statistics being provided by the CDC. While she (apparently) was complaining that the numbers were inflated, I (along with many experts) believe that the CDC was significantly undercounting both for lack of testing and because our methods of attributing deaths to the virus are antiquated. 

The NIH recently revoked a grant, renewed under the Trump administration, that supported a research collaboration between a US non-profit called Eco-Health Alliance and laboratory studying bat viruses in Wuhan, China. Apparently, the cancellation of funding was related to a debunked conspiracy theory that the Wuhan lab was the source of the covid-19.  This has been disproven many times over by now. The head of Eco-Health, Peter Daszac, had warned of the coming SARS pandemic back in 2003 and researches the animal origins of human viral infections. His collaboration with the Wuhan lab was key to identifying the anti-coronavirus activity of remdesivir – currently the only specific anti-viral therapy approved by the FDA for treatment of the disease. 

This is a living nightmare.  Who could have imagined what is happening to US science during the worst pandemic since the 1918-1919 influenza? 

If anyone is still optimistic that the US will be funding the incentives that we need to restore our antibiotic pipeline in the near future, just look around you. 

 

What Have We Learned?

Those who cannot remember the past are condemned to repeat it. (George Santayana).

Never let a good crisis go to waste. (Churchill?, Emanuel?).

It’s tough to make predictions, especially about the future.  (Y. Berra).

We are still at the beginning of a tragic, horrible pandemic that is both robbing us of lives, of our livelihoods, and disrupting the very fabric of daily life. Sometime, hopefully in the not too distant future, we will need to look at how this tragedy unfolded and come to grips with what we could have done to make it, at least, somewhat less tragic. The fact that several countries and societies were able to escape the worst of the pandemic provides us with opportunities to learn and to act. So does our long history of scientific warnings that just such a thing could occur along with years of guidance on how to prepare – all of which were ignored – for decades.

So, it is with something less than optimism that I try and understand whether we, as a national or even global society, are capable of changing in a way that will alter our approach to public health. The problem I see is not new.  Its old.  Its usually green. And it’s made of paper (and cloth). We need to invest money now to prevent or manage a public health threat that might occur sometime in the future. Our history in this regard is not encouraging. 

My lack of optimism is fed by our recent experience with the problem of emerging antibiotic resistance and our failure to provide the financial incentives required to address this public health threat. Anyone who has been reading this blog for the last several years will be familiar with the issues.  Ditto for anyone who follows John Rex’s publications and blog. Mainstream media even picks up the topic from time to time. But to summarize – bacterial resistance to antibiotics is a growing problem worldwide. While relatively small numbers of patients have infections that are so resistant they are difficult to treat, these numbers are growing.  At the same time, our antibiotic pipeline is dismally inadequate to provide for new therapies for these resistant infections. One major reason for this situation is the fact that there is no real market for new antibiotics because, luckily, the numbers of patients with highly resistant infections are too low to support sufficient revenues from new therapies.  This has discouraged both large pharma and investors from research and development of new antibiotics.  Our meager pipeline today is provided almost entirely by small biotechs.  So far, almost all of those who have successfully developed a new antibiotic active against resistant infections have gone bankrupt (or the equivalent) shortly after commercialization. 

Why do I bring this up in the context of learning from the covid pandemic? Last week the Government Accountability Office released another report on antibiotics and antibiotic resistance. This government watchdog group has written a number of these in the past looking at the FDA and its role in the use of antibiotics in animal husbandry and our lack of ability to adequately monitor antibiotic use in human populations.  The latest report, similar to previous efforts, focused on the federal approach to addressing antibiotic resistance.  They covered a number of areas including surveillance of emerging resistance, the potential role for diagnostics in detecting and treating resistant infections, efforts to improve antibiotic use, and, most importantly for me, the insufficiency of federal efforts to incentivize antibiotic research and development.  For this latter point, they highlighted the need for the very incentives we have been discussing for years – market entry rewards, transferable exclusivity vouchers, or even value-based reimbursements (as an appropriately lower priority). The GAO faults the Department of Health and Human Services essentially for failing to lead and failing to provide a strategy to achieve the needed incentives. The response from HHS - HHS did not concur with the recommendation that it develop a strategy that includes the use of postmarket financial incentives to encourage the development of new treatments for antibiotic-resistant infections, citing its ongoing analysis to understand whether postmarket incentives should be included in such a strategy. This does not inspire confidence since these incentives and the need for such incentives have been the subject of innumerable conferences, reports and peer-reviewed publications. 

Will we have learned that our hospitals must be prepared?  That they must have sufficient surge capacity? Have we learned the potential importance of our Strategic National Stockpile?  Have we learned that the ability to rapidly design and deploy diagnostic testing is critical to success for the next pandemic? Have we learned that early testing and contact tracing is essential to avoiding the kind of mitigation by social distancing that has paralyzed the global economy? 

We can only hope that the recent GAO report and the HHS response will not exemplify our willingness to learn from the covid pandemic. If we do not act, the pronoun “we” is the key.  Our government is, in fact, us. If we do not force our representatives to act, they may well ignore our history and force us to re-live it. 

 

To BARDA with Love

Yesterday we were confronted with the news that Rick Bright, the director, Biomedical Advanced Research Authority (BARDA) and Deputy Assistant Secretary in the Office of the Assistant Secretary for Preparedness and Response had been fired. He claims this was in retaliation for his insistence that all potential diagnostics, therapeutics and vaccines for coronavirus infection undergo rigorous scientific testing before they are widely used – including, especially, hydroxychloroquine. This stance is no different from mine, from any reasonable scientist’s, nor from Dr. Fauci’s. In fact, a recent, large (but retrospective) VA study showed that hydroxychloroquine is more dangerous to seriously ill coronavirus infected patients than placebo – vindicating our skeptical view of the drug. While several, large prospective trials of the drug are still underway, it is now more than reasonable to maintain a healthy scientific skepticism when thinking about using this and related compounds for prevention or therapy of covid-19. His firing, if based on his scientifically rigorous approach to testing, is nothing less than a national disgrace. 

BARDA, as an agency, has been a constant light in a dark cave of antibacterial research and development for almost the last decade. Without funding and support from BARDA, our meager pipeline of antibacterial drugs would be virtually non-existent today. BARDA evolved from being restricted to only funding those projects that could result in countermeasures for bioweapons and having to avoid funding phase 3 trials to being a key funder in the research and development of antibiotics for the treatment of resistant infection in all phases of discovery and development. And thank goodness for that. 

I don’t know Rick Bright well, although we have spoken on occasion. Based on his direction of BARDA, though, it is clear that he has a clear-eyed understanding of the issues facing us in terms of antibiotic resistance and our need for new therapies in the face of a broken marketplace. BARDA’s recent agreement with Paratek is proof of this. Rick has been an aggressive leader of BARDA’s involvement in the search for diagnostics, therapeutics and vaccines targeting covid-19. Once again, it’s hard to imagine how companies could have accelerated the testing of many of these various projects without support from BARDA. 

I want to now turn to those scientists, contract experts, lawyers and everyone else working at BARDA.  We need you. We need you to keep BARDA alive and well.  This administration will pass into the depths of history – hopefully sooner rather than later.  What you have done and are doing at BARDA will provide a living legacy of valuable products for decades to come. When I arrived at Wyeth as a naïve academic physician-scientist, one of the first things I learned was the importance of dealing with failure.  Since almost all projects initiated in the laboratories of the pharmaceutical industry are doomed to failure, it became important to show scientists how to deal with these constant blows. I counseled them to focus on the science. I told them to keep good records, write papers and put them aside until such time as they could be published. We all need everyone at BARDA to keep their focus.  This is too important a moment to allow what is happening to Dr. Bright to distract you from your goal of keeping the rest of us safe. We need you to provide us with the wherewithal to get through covid-19 – to say nothing about the importance of improving our antibiotic pipeline. 

Now I am going to ask all of you out there to write your representatives insisting that the treatment of Rick Bright get the investigation that is clearly warranted.  We cannot let this stand – at this time, in this moment – this cannot stand.