Monday, August 24, 2020

Politics and the FDA

 If you are one of those who believe that the FDA is purely guided by science and that politics never has influenced its decisions or its very structure, you and I live on different planets.  By way of background, I recommend some reading.  First, there is a definitive history of the FDA written by Phil Hilts on the occasion of the FDA’s 100th anniversary in 2003. He notes that the very early beginnings of what was to become the FDA goes back to Charles M. Wetherill – a chemist in the Department of Agriculture in 1862 who began to analyze substances in foods for toxins. Then came Harvey Wiley who started to try and convince lawmakers to act against the quack remedies harmful nutritional ingredients that had proliferated during the 19thcentury. Wiley finally was appointed chief chemist in the Department of Agriculture around 1880.  At the turn of the century he established the poison squad – a group of young volunteers who tested foods and food additives on themselves (!). Wiley wrote much of the Food and Drugs Act of 1906 that was signed into law by Teddy Roosevelt. Looking back on all this early history, the laws passed after the civil war were often the result of political pressure from the obvious adverse effects of the various snake oils and remedies being promulgated at the time and that had resulted in sickness and death of US soldiers during and after the war. 


Back then, the early FDA could not actually pursue manufacturers or products until they had shown that a problem actually existed either via showing clinical harm or by demonstrating the presence of known dangerous substances. This is similar, by the way (and to the horror of many of us) to the way “nutritional supplements” are regulated (not) today largely thanks to Orin Hatch. 


This early approach changed dramatically in 1962 with the passage of the Kefhauver-Harris amendment to the Food and Drugs Act.  The impetus for this change was the devastation of birth deformities as the result of the use of thalidomide to control the nausea of pregnancy and the resulting political pressure for change.  This amendment required manufacturers to demonstrate not just safety but also efficacy of any proposed therapeutic.  


Fast-forward to the early 2000s and clinical trials to prove safety and efficacy of new antibiotics.  For years, the Infectious Diseases Society of America and the FDA collaborated in the promulgation of guidelines setting out the requirements for the design of these studies. Starting around 2000, the statisticians at FDA began to balk at the fundamental statistical foundation for the approach that had been used since the days of penicillin. That approach called for studies comparing a new antibiotic to an old, approved and standard of care antibiotic where the new drug had to be shown to be not inferior to the standard treatment.  This is quite different than other clinical domains where new therapies are shown to be superior to placebo.  As we all know, it is generally not acceptable to treat patients with a life-threatening disease (many if not most bacterial infections) with a placebo when we know that a safe and effective therapy already exists. Hence the so-called non-inferiority approach. The FDA then gradually tightened the statistical margins required resulting in increased costs of trials, lengthened time to market and decreased profits for new antibiotics. Then came the Ketek scandal of 2006 and the major involvement of politics in FDA “business.” Ketek (telithromycin) is an antibiotic developed by Sanofi for the treatment of pneumonia, sinusitis and bronchitis. It was approved in the US in a twisted set of data evaluations by the agency where, virtually uniquely, post-market safety data from Europe where the drug had already been on the market for a period of time was used to help justify the approval. After a year or two on the US market, several cases of severe liver injury were linked to Ketek and the scandal was born. Public Citizen cried foul relying on FDA insiders who objected to the way Ketek was approved to begin with. Public Citizen in turn pressured congress, especially representatives Markey and Grassley, to investigate the FDA. Markey and Grassley threatened the FDA with an investigation.  This resulted in FDA panic mode as they feverishly began to assemble all the documents and materials that such an investigation would require.  Rather than face the congressional investigations threatened by Markey and Grassley, FDA reacted by essentially carrying out their own investigation in public. There they crucified not only their own officials who led the approval of the drug, but also the clinical trial requirements for antibiotics. The latter response led to a point where it was no longer possible to carry out new antibiotic development and therefore where new antibiotics no longer had a clear path to approval. And all this was clearly based more on politics than the cold hard facts of the science. The FDA lost many dedicated and experienced antibiotic experts as a result of the Ketek scandal. This is all detailed in my book (you can just download the chapter on FDA if you want). As we all know, all’s well that ends well – but that was after at least six years of antibiotic development drought and the loss of hundreds of antibiotic researchers. 


Fast forward to covid.  OK.  Political influence might be erring on the side of less scientific stringency as opposed to more stringency – but there is no doubt that the FDA, as much as they claim to be science based, is susceptible to political pressure. And this is nothing new . . .

Thursday, August 6, 2020

Policy - Coronavirus vs AMR

The coronavirus pandemic is clearly an acute and immediate pubic health crisis. Within the space of just a few months, almost 20 million people have had documented infections and over 700,00 have perished globally. The US alone accounts for almost 5 million cases and 162,000 deaths. In response to this public health catastrophe, the US along with the rest of the developed world (including China) have cobbled together an incredible effort to identify, test and distribute new vaccines and treatments. In addition to supporting research efforts (push incentives) many countries (especially the US) have been providing market support by ordering doses (hundreds of millions) of the various vaccines currently being tested in clinical trials (subscription model of a pull incentive). There is also a great deal of support for manufacturing at commercial scale (Operation Warp Speed) at risk before trial results are known (another key push incentive). I am not sure there is anyone out there who thinks that any of this is a bad idea. 


Now lets talk about antibiotic resistance (AMR). It is thought that there are currently about 700,000 deaths annually from AMR infections globally. That is – every year, year in and year out. This number is actually probably increasing every year. In the US alone, the CDC has estimated that there are about 3 million AMR infections occurring every year in the US and 48,000 associated deaths. Most experts, including yours truly, believe these numbers are clear underestimates. These infections also have a significant cost to the global and the US economies measured in billions of dollars. 


AMR infections have been with us since the dawn of the antibiotic era. Their numbers grow slowly every year and they are often hidden from view.  They occur in hospitals, in long term care facilities and in the community. But we don’t consider this a crisis.  Why? Because it has been going on so long?  Because AMR infections are a chronic and not an acute problem? Because the victims of these infections are somehow a lower priority? Because physicians are so used to dealing with AMR infections? Why is this not a crisis? 


And if we now agree that AMR infections is a slowly growing crisis, why can’t we put the kinds of resources into fighting the problem that we are investing in coronavirus?

 While there are a number of publicly funded sources of funding for research and development (push incentives), there is virtually nothing (including the efforts by UK and Sweden) to bolster the failed antibiotics marketplace sufficiently to provide developers with any sort of meager return for their efforts. 


Like many in our echo chamber, I am horrified and discouraged at the lack of action on the part of US and global authorities to address the failed antibiotic market. I am especially discouraged in light of our robust response to the coronavirus pandemic as compared to our lackluster response to the AMR crisis. I can only hope that we will learn from this pandemic that investing in our future is a much more efficient approach than reacting to a crisis while its happening. And I must hope that we apply this lesson to the growing AMR crisis. But will we do so?