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. 

 

What Happened to the CDC?

Last week, Tom Frieden, the former Director of the US Centers for Disease Control in the Obama administration, wrote an editorial in the New York Times. In his article, he praised the professional staff at the CDC emphasizing their scientific acumen, skill, experience and expertise. I have come to know many scientists at the CDC to one extent or another over the last 40 years and I agree with Dr. Frieden’s assessment.  At the same time, Dr. Frieden points out that the CDC has to do better in our current pandemic. That must be the understatement of the century. 

The botched CDC attempt at providing testing for public health labs around the US was clearly a major roadblock to establishing the kind of robust testing we would have needed early in the US outbreak.  As I noted in a previous blog, what we needed to do at the beginning was to identify infected individuals, get them quarantined and then identify all their contacts, test them and quarantine them as necessary. By the time we had any sort of access to widespread testing, limited as it has been, it was too late to carry out this basic outbreak control measure and we were stuck with our current situation – everyone and everything locked down.  This critical misstep may have led to the fact that the CDC has been shunted aside. 

Dr. Frieden says that the CDC website is the best place to get information and guidance on the outbreak. I respectfully disagree. I look at the CDC coronavirus websites every day.  Compared to the John Hopkins site, worldometer, and others, I’m ashamed at the lack of utility of the CDC site for understanding the current covid-19 epidemiology in the US. 

Recently the CDC released guidance for allowing employees at essential businesses to work follow an exposure to a known covid-19-infected individual. This guidance suggests that as long as the individual is asymptomatic, it is OK for them to be at work. But this guidance flies in the face of clear evidence suggesting that pre-symptomatic or asymptomatic individuals are responsible for up to 25-30% of covid-19 transmission to others. I queried the CDC as to the scientific basis for this recommendation.  They responded without actually providing the kind of scientific data I requested. They do recommend that workers be screened for fever and that they maintain a distance of 6 feet from others . . . .

Currently, the CDC is relying on death certificates (with many caveats) to tabulate coronavirus mortality. But they know that this is entirely unreliable. We will probably have to resort to a statistical approach looking at excess deaths be geographic area, age and other variables to estimate covid-19 mortality rates. Where is the CDC leadership on approaches like that? (In fairness - they say they are working on it). 

Dr. Frieden is again correct when he says that the CDC has the expertise to validate the various tests we need to be using including the current ones used to identify infected patients and the antibody tests we need to determine who has already been infected and who might be immune to the virus. Where are these analyses – especially of the many antibody tests that are currently on the market in the US without having been formally validated by FDA? 

He notes that the CDC does have funds to distribute to public health facilities around the country. But this funding is woefully inadequate and has been decimated by successive administrations and congresses for years.  

To open the country up to anything resembling normal activity, we still have to be able to go back to our basic outbreak control measures of case finding and contact tracing. Even with access to testing way beyond what is currently available (based on lack of reagents and swabs), we will still need an army of contact tracers.  The requirement for tracers could be reduced by using smartphone technology as was done successfully by South Korea, Taiwan and Singapore to name a few. Those countries also enlisted police and army reserves to help with contact tracing. Massachussetts and California are gearing up for this task with or without smartphone technology. But, in my view, the CDC should be leading the charge here.  Where are they?

I have wracked my brains trying to understand what could have happened to the professionals at CDC. One example might be Dr. Nancy Messonnier who tried to warn Americans of the coming epidemic at the end of February. We have hardly heard from her since. I’m tempted to speculate that the CDC, similar to what happened at FDA a number of years ago, came under severe political pressure with the result that career scientists are keeping their heads down. If so, I find this to be incredibly unfortunate since the CDC is one place where we have the expertise we need to face this epidemic.  It just seems like the CDC experts have been missing in action.  

While I recognize CDC’s missteps in handling this epidemic, I also understand that the CDC could still provide critically important leadership in getting us out of this mess. I miss the CDC I used to know. 

In a future blog, I’ll discuss my thoughts on how we get back to some semblance of normality. 

 

 

Covid-19 - The US Debacle (Part 2)

In spite of study after study and the writings of expert after expert over the last 25 years, we, as a society, have failed to provide for our own security in the face of a potential public health threat.  We have failed to supply and maintain our strategic national stockpile, we have consistently underfunded our public health infrastructure and we have underfunded our hospitals' preparedness. 

Let’s first discuss the Strategic National Stockpile (SNS). The Department of Defense maintains its own stockpile and has done so since the 1930s. The thinking that led to DoD’s preparedness ultimately led to the formation of today’s SNS for the US population at large.  In 1998 Bill Clinton signed a law forming the National Pharmaceutical Stockpile.  In 2003, after 9/11 and the anthrax attacks, the role for the stockpile expanded considerably and became the Strategic National Stockpile managed primarily by CDC under the Secretary of Health and Human Services and the Department of Homeland Security. The stockpile is kept at various regional locations around the country. It stocks a wide variety of pharmaceuticals and vaccines as medical countermeasures against biological attack.  A summary of these holdings can be found here. Many of those countermeasures were purchased by the stockpile under BARDA. The NIAID and BARDA were responsible for a large fund called Project Bioshield established in 2003, under President George W. Bush, to support research into these medical countermeasures.  NIAID, with over $5 billion in funding for Project Bioshield, established a number of regional centers of excellence to study dangerous pathogens that could potentially be weaponized.  This funding established sites that were equipped to handle these pathogens under strict security – physical and biological. The research yielded important basic scientific understandings of these dangerous pathogens and toxins, but little in the way of actual vaccines and countermeasures.  The latter came mainly from small biotechs who believed that the SNS might serve as a business model for their R&D. (In my view, they were, in the main, disappointed).  

The Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) is the organization that decides what goes into the stockpile. They have expanded the stockpile over the years to cover needs for other situations such as hurricanes and earthquakes for example. They have also stocked key hospital supplies like masks, gowns and ventilators in preparation for a pandemic like Ebola, Zika or influenza. In their budget, maintenance of inventory is an essential item.

Funding for this overall effort began with an infusion for a 10 year period in 2003 ending in 2013. After that, congress moved Project Bioshield to BARDA and funded it on a reduced year over year basis. In spite of the reduced funding, BARDA has been a stalwart in our effort to find and stockpile medical countermeasures. Early on, BARDA was constrained to funding antibiotic R&D only for those products that clearly had an application as medical countermeasures. That expanded later to include antibiotics active against resistant infections. This was clearly appropriate given the public health threat of these infections. Initially, BARDA was also constrained to focus only on those products that were entering late stage clinical development. Now, BARDA has become a key funder of CARBX – focused on early stage research of antibiotics. They have also been able to support “portfolios” of antibiotic research within companies encompassing late stage as well as early stage R&D. In a recent move, perhaps to address the suffering antibiotic marketplace, BARDA has entered an agreement to fund Paratek’s omadacycline as an agent for the treatment of drug resistant anthrax with a commitment to ultimately purchase the drug for the national stockpile. It is clear that without BARDA, our antibiotic pipeline would be in even more disastrous shape than it is currently. It is also clear that with additional funding, BARDA could do so much more.

In addition to the SNS, there are funds distributed by the CDC to local public health authorities and to hospitals for preparedness. A history of funding for these various programs is shown in the figure below. If you focus on funding for hospitals, you will see a drastic decrease over time. Funding for these programs has decreased by 30-50% not counting inflation. The years cover both democratic and republican administrations and congressional majorities. Apparently, in spite of strident warnings by both experts and two of their own – Tom Daschle and Judd Greg – government was not willing to invest sufficiently for our future security. (Although the Trump administration proposed cuts to both the hospital preparedness program and to the emerging zoonotic diseases program, congress maintained or even slightly increased funding for these areas in 2018 according to Politifact. Obviously, this was still not sufficient.)

As we slowly emerge from this horrible pandemic, will we learn from our missteps?

 

Vaccines and Therapies for Coronavirus

I thought that this would be a good time to review the various vaccines and therapies being studied to combat the coronavirus pandemic. In such a short article, it will be impossible to review them all.  Additionally, the number under study grows substantially every day so this article might well be out of date when its published.

First, without trying to throw cold water on all your hopes, we should take a look at the odds. A vaccine or therapy that is found in a laboratory has only a tiny chance of making it all the way to approval by a regulatory agency. Once a vaccine enters the earliest stages of clinical trials (phase 1), usually in healthy volunteers to study safety and get an early read on possible immune response, the chances of ultimate approval are only around 15%.  For a therapeutic (like an antiviral drug), those odds are more like 10%. But, if a vaccine or drug makes it all the way to the last stage of clinical testing (phase 3), chances of ultimate approval go up to 75%. 

(Disclaimer – I don’t pretend to be a vaccine expert – and I’m not trying to play one on TV. Feel free to challenge my thoughts with your own research or, if you are an expert, respond to the blog). 

I’ll limit myself to only a few vaccines either already being studied in the clinic or about to enter Phase 1 clinical trials. None are farther along, hence the long timeline of 12-18 months before anything could reach the marketplace. The vaccine by Moderna that has entered phase 1 is based on mRNA. Once we knew the nucleic acid sequence of SARS-Cov-2 (today’s pandemic virus), the scientists at Modena were able to choose a portion of that sequence that encodes a key viral protein without which the virus would be unable to attack our cells. If such a vaccine could stimulate our immune cells to target that protein, we might be protected from the virus. mRNA vaccine is a scientifically “cool” technology and has promise. Not only is this an early effort, but previous mRNA vaccines have never worked to prevent an infectious disease in humans. The risk of failure is high. The same is true of the vaccine from J&J.  It seems to be based on the use of a defective adenovirus (the technology used is not publicly available as far as I can see). Once again, this approach has never worked before in humans. Nevertheless, both Moderna and J&J (with the backing of BARDA) have high confidence in their candidate vaccines. Finally, there is the vaccine announced recently by the University of Pittsburgh. To me, this has the most promise of the three I’m reviewing for you. In this case, they have purified viral proteins and impregnated a Velcro-like device with micro-needles to deliver the proteins. The microneedles inject the viral proteins just under the skin – a target known to provide for a strong immune response. This kind of approach has a good precedent for success (micro-needles aside).  If they have chosen the right proteins in the right dosage and safety is not a problem, this might work. 

I am optimistic that we will have an effective viral therapy before we have a vaccine. The first and most promising drug being studied is remdesivir from Gilead Pharmaceuticals. This drug is an analogue of the building blocks of the viral nucleic acid and stops viral reproduction dead in vitro.  It has also worked in animal models of coronavirus infection including mice and monkeys. Because remdesivir was originally studied against Ebola in clinical trials, we already have a significant safety database suggesting that safety in humans will not be a problem. Unfortunately, the drug did not work for Ebola.  But it currently is in phase 3 trials for coronavirus looking at patients with both severe and mild to moderate disease.  There is also an expanded access program available through Gilead in various centers around the world. The drug can only be given intravenously. This will be a disadvantage since, based on our experience with other antiviral drugs, it is most likely to work when given early to those with mild to moderate disease.

Favipiravir, that is similar in concept and mechanism to remdesivir, is an orally bioavailable drug, and is approved for use in the treatment of influenza in Japan. Favipiravir is a rather broad- spectrum antiviral drug with activity in vitro against Ebola and SARS-cov-2.  Here, we have much less data.  But the drug is already in phase 3 trials for treatment of coronavirus infection based on it approved use for the treatment of influenza and a large safety database. 

A discussion of drugs against coronavirus would not be complete without talking about chloroquine, hyxroxychloroquine (plus or minus azithromycin). These are not direct-acting antiviral drugs.  All work by trying to improve the host response to viral infection. To say the least, the data here are incomplete and controversial. I have found four small studies using these drugs singly or in combination. Two suggest that there might be efficacy and two find no effect – especially in moderate to severe disease. Only one paper has been peer-reviewed so far. All studies are too small to allow for any sort of statistical comparison between treatment groups. Here I must agree with Dr. Fauci and others who suggest that these drugs should be reserved for those who can benefit from them – patients with lupus and rheumatoid arthritis. Panic buying will expose the public to counterfeit drugs and will deprive patients with legitimate needs of these drugs in order to live a normal life. 

All the other therapeutics are well behind the two drugs cited above. A number of companies are studying the use of monoclonal or polyclonal antibodies for the treatment of coronavirus disease. This is a promising approach that is generally well behind the antiviral drugs I noted above. Immunity will probably depend on antibodies and antibodies are probably mainly responsible for clearing the viral infection. Afflicted patients are currently being studied using convalescent plasma from patients who have survived infection.  If we can achieve sufficient antibody titers with this approach, it could save lives. It would be important, as always, to treat early. We should have an answer for these studies soon. 

I hope this brief and incomplete review puts some of the vaccine and therapeutic approaches to coronavirus infection in some perspective. For a recent, more complete (and more technical) review see this excellent article by Miguel Martinez.  Also see the analysis provided by Alan Carr of Needham.