The stuff of nightmares: Why drug approval is so damn difficult now

How the biggest pharmaceutical mismanagement resulted in one of the greatest tragedies of the 20th century and the regulatory tightening that followed. Remembering Dr. Frances Kelsey.

Greetings friends and comrades, I take it you have all had a stellar start into the new lunar year of the tiger. 2022, let’s see what this year has in stake for us all. Hopefully it will be a step toward ‘normality,’ whatever that word means to you and your loved ones. Have had several people reach out to me over the last two weeks asking where my posts have gone and I must say I felt humbled and flattered that you guys miss me so (though to my defence, my last post was not even 11 days ago - sheesh!). But hey, I haven’t been lazy and ignoring this newsletter, I have just been waiting for the right topic to come my way. Which it now thankfully has. 

Next week will see the publication of my long anticipated interview with Pebbles Hooper, designer, artist, oft misunderstood social commentator and indeed the first person in New Zealand to have been indicted under the Harmful Digital Communications Act. We have a very candid discussion about everything from her recent trial to religion, science and all things beyond. I think people will be surprised at the depth of her thinking and also the clarity with which she defends her case. I have also been commissioned to make a documentary film for Stuff about the pandemic and its implications for living in Golden Bay, a powerhouse bastion of antivax worship in New Zealand. So we have been busy writing the script and filming interviews, the release date for that will be late March. Exciting times. Our aim is to capture “both sides” of the debate and give people a sense of what is on people’s mind during these trying times in the pandemic. 

I also penned an article about Neil Young and his recent protest about Joe Rogan and Spotify’s position to continually broadcast his antivax rhetoric unencumbered. I wrote this for Dave Cowen on his genius Shuffle Synchronicity substack, which can be found here. Dave gives an excellent rebuttal to my piece that invokes the lyrics of Joni Mitchell. Have a read, am sure you’ll be amused!

Unsung heroes

So now to today’s topic. The Federal Drug Administration. One of the main talking points of vaccine skeptics has to do with their supposed sinister view of the FDA as a corrupt shadow organisation for big pharma, that the fact that there seems to exist a sort of “revolving door” between people employed in the pharmaceutical industry and people working at the helm of this misaligned and misunderstood organisation. A cornerstone of life as we know it. 

To understand the FDA and its current role in drug development and approval, we must delve back into its past, particularly the time after the second world war.

If you may recall the 1950s were a bad year for pharmaceuticals and indeed, drug regulation all over the world. All over the world yes, but not in the United States. Thanks in particular to the FDA and the prudence of one diligent woman, Frances Oldham Kelsey. A name that many of you may not know, but that after reading this article I hope you tell everyone you know about most importantly your children. 

The biggest wake-up call in history

Thalidomide was originally developed in the 1950s by the German company Chemie Grünenthal GmbH. Intended as a sedative initially, it soon rose to the status of a wonder drug and was prescribed (often without doctor’s note) for the treatment of a plethora of other medical conditions, including nausea, the flu, colds and most importantly, and tragically, morning sickness in pregnant women. What stood out with thalidomide was that early preclinical testing found that it was nearly impossible to decipher a maximum tolerable dose (MTD) in animals.

It may come across as macabre but one of the requirements of drug approval is to identify the MTD in animals first, by establishing a dose that will kill them. I know, horrible, but nonetheless an important prerequisite of drug development before it is even considered dosing humans. Because of this unidentifiable dose in animals, researchers (erroneously) concluded that the drug would be safe for humans in all dosages and as such was classified as harmless. In 1956 in Germany the compound was given the green light and was even awarded a status that allowed it to be sold over the counter at pharmacies without prescription. The rest of Europe soon followed suit, as well as parts of Asia.

It was so effective at combating nausea that soon pregnant women were taking it daily for morning sickness. What followed was the stuff of nightmares as I assume most of you are aware of the term “thalidomide baby.”

The FDA was created in 1930 as a follow on to the 1906 Pure Food and Drugs Act, which mainly analysed food products and assessed faulty marketing claims. In her first week at the FDA, Dr Kelsey came across the US drug company Merrell’s application to get thalidomide registered in the US. Born in Canada, Dr. Kelsey earned both a PhD in pharmacology as well as a medical degree, and her specialty was toxicology. And she was a meticulous researcher as oe of her former professors attested to

“Never before have I met a student who questioned me or exasperated me more than Frances”

So it was perhaps luck, fate or a bit of both that Merrell’s thalidomide application perchance across her desk. With the eyes of a hawk she began trawling over all of the toxicology reports and preclinical and clinical trial data from Germany. 

She famously wrote on one of the pieces of the application note, referring to one specific section of the application that described the efficacy of the drug as 

“an interesting collection of meaningless pseudoscientific jargon apparently intended to impress chemically unsophisticated readers.”

During her due diligence, Dr Kelsey came across a letter that had been sent into the British Medical Journal, where a medical doctor in the UK had reported cases of peripheral neuritis, a condition that caused nerve damage to particularly the hands and feet of patients. She then famously confronted the scientists at Merrell, requesting “absolute proof”that thalidomide would not not cause undue harm to a developing foetus. You may call it serendipity or luck or instinct that she happened upon this paper and made the deduction regarding pregnant women taking the drug - as in “luck favours the prepared mind” - but either way she inadvertently predicted the birth of the tens of thousands of babies born with severe physical deformities and worse, all over Europe and Asia. 

The FDA responds and the world follows suit: Tighter regulations. Kelsey is vindicated.

After her confronting exchange with Merrell, the scientists there protested and even subjected Kelsey and her family to political harassment, enlisting the governor to get her “to come to her senses” and release their drug. But Kelsey did not budge one bit. And rightly so, nearly a year after her refusal to grant the drug approval, German researchers started to see the link between thalidomide and entire clusters of birth defects that were being registered all over Europe. These children were born with phocomelia, a condition in which the limbs became malformed or were even missing during gestation. On top of this, many children were also blind and had majorly malformed internal organs such as the liver and kidneys. The number of children affected by this drug is still not known and it became an important warning sign for all future drug developers and the regulatory agencies that guide them. Every major country in Europe looked to the US and the FDA in particular to try to fashion regulatory bodies in the same way that the FDA worked. Stringency and diligence being the key. Never again was this type of tragedy allowed to happen again. 

So, thanks to Dr Kelsey’s courageous attitude and dedicated research, the drug thalidomide was never allowed into the US market. As a direct result of her work, the US Congress passed severely restrictive drug amendments in 1962, which made it nearly impossible to get a drug approved in the US without convincing drug profiles, safety data and assurances that all the potential eventualities of approving a drug had been considered. As a result, the average time it takes to approve a new medication in the US after an FDA application, is 12 years, and the estimated cost of taking this new medication from concept to market exceeds $1 billion.  

Dr Frances Kelsey went on to become chief of the the “New Drugs Division” at the FDA and then went on to be director of the Division of Scientific Investigations, and deputy for Scientific and Medical Affairs, Office of Compliance. On August 7, in 1962, President Kennedy awarded her the President's Award for Distinguished Federal Civilian Service, the highest award possible for a civilian in the US. She was only the second woman ever to this award. In the ceremony JFK acknowledged:

"Her exceptional judgment in evaluating a new drug for safety for human use has prevented a major tragedy of birth deformities in the United States. Through high ability and steadfast confidence in her professional decision she has made an outstanding contribution to the protection of the health of the American people."

So, how does all this fit in with the covid-19 vaccine?

In light of all this and the research being performed on the covid vaccine, specifically for its safety and efficacy in children, I would urge you to read the article I wrote a few weeks back, regarding precisely the diligence and in depth safety trials performed before allowing a vaccine such as the covid-19 vaccine to market, see The safety of age de-escalation trials and why you should get your children vaccinated. 

And yes, there is a revolving door between the pharmaceutical industry and the FDA, but this is not surprising. There aren’t many places that pharmacologists can work. The field of discipline is exceedingly small and so yes, some people who work at the FDA end up working for a pharmaceutical company and vice versa. There is nothing nefarious about this, it is just the way it goes. Yes, the former commissioner of the FDA is now an advisor to the board of Pfizer, Dr. Scott Gottlieb. This is not surprising as he headed the FDA for two years and was offered the opportunity to join the company in 2019, a year before we even knew what covid was. And yes, this may have helped Pfizer in certain parts of the bureaucratic approval process but certainly not in the scientific and regulatory aspects. Let’s not forget Dr Gottlieb is a physician and as such he has sworn to the Hippocratic oath. Just for reference sake’s here is a shorter, modern version of this oath (longer one can be found here):

“I swear to fulfill, to the best of my ability and judgment, this covenant:

I will respect the hard-won scientific gains of those physicians in whose steps I walk, and gladly share such knowledge as is mine with those who are to follow.

I will apply, for the benefit of the sick, all measures which are required, avoiding those twin traps of overtreatment and therapeutic nihilism.

I will remember that there is art to medicine as well as science, and that warmth, sympathy, and understanding may outweigh the surgeon's knife or the chemist's drug.

I will not be ashamed to say "I know not," nor will I fail to call in my colleagues when the skills of another are needed for a patient's recovery.”

The current acting commissioner of the FDA is Janet Woodcock, a physician and 35 year veteran of the organisation. She began her career in 1986, a the FDA’s Center for Biologics Evaluation and Research (CBER) as the director of the Division of Biological Investigational New Drugs. She then served as the CBER’s Acting Deputy Director for a period of time. 

She is now in charge of nearly $7 billion in funding and 20 000 hardworking employees, most of whom are scientists whose sole purpose in life is to discover whether or not a new drug is harmful to humans or not. Just like Dr. Frances Kelsey those many years ago. 

Covid-19 vaccine approval

And in light of this vaccine and people’s justified skepticism of how quickly it got approved (during a pandemic I might add,) I wanted to take the chance to echo another previous article I wrote about this topic:

“<sic> What most people fail to realise is the incredible resources now at our disposal to create these types of vaccines. The amount of computing infrastructure used to emulate the virus and every possible biochemical reaction, every potential variable in the human body, using powerful computers that we never had access to 20 years ago. The mRNA vaccine was created and tested independently in laboratories across 4 continents, it is an unprecedented example of cross border collaboration and innovation. It was scrutinised more than any other drug in history, and represents the culmination of 70+ years of theoretical and practical experimentation with DNA. We have been working with mRNA in clinical applications for at least 30 years.

This vaccine is an emblem as to how ingenious our species can be.”

In saying all this, I may now also add that this vaccine has become the most ubiquitously administered medication on Earth with nearly 4 billion people - over half the planet’s human population - having received at least one dose. 

Just take a moment to think about this?

Hope this little essay has helped you understand the drug approval process a bit better and that yes, there are still good people out there holding the fort and protecting us.

Thank you for reading. 

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