Editor’s Note: The U.S. Transhumanist Party publishes this article by Sedeer el-Showk, originally featured by our allies at Lifespan.io, in order to highlight the fallacious nature of many media outlets’ responses to a recent study about the “invariant rate of aging”. As Mr. el-Showk eloquently explains, this study does not refute or undermine the possibility of pursuing the reversal of biological aging, but simply suggests that this needs to be done through medical and technological means, and that without such means, overcoming the limitations of the current maximum human lifespan would not be feasible. Many of us in the longevity advocacy community have known this for a long time already, but it is important to spread accurate information to prevent an unjustified decline in public confidence in the feasibility of radical life extension.
~ Gennady Stolyarov II, Chairman, United States Transhumanist Party, July 25, 2021
Aging is not unstoppable, despite misinterpretations of the new study.
The study shows that “immortality and everlasting youth are the stuff of myths,” according to The Guardian. The article goes on to say that “an unprecedented study has now confirmed that we probably cannot slow the rate at which we get older because of biological constraints.” Other outlets published similar conclusions, with Futurism saying that the study shows “an ‘invariant rate of aging’ that won’t slow down”.
These reporters seem to have gotten tripped up on the idea of an ‘invariant rate’, which has the key implication that biological constraints determine the rate of human aging. This led to the conclusion that aging is fixed, inevitable, and immutable, but that’s not at all what the study shows, as the paper itself directly says.
What the study actually says
The study aimed to investigate the ‘invariant rate of ageing’ hypothesis, which proposes that the rate of aging is fixed within a species. The idea is that aging has evolved in concert with a suite of other traits, such as birth rate and metabolic rate, and this concerted evolution has led to the rate of aging being relatively fixed within a species.
In this context, ‘fixed’ is used as the opposite of ‘plastic’. It doesn’t mean ‘set in stone’. It means there’s relatively limited variation in this trait within a species because biological factors have a stronger effect on it than environmental factors. A good example might be the number of digits on a limb – environmental factors don’t really affect it, and there’s very little (but some) variation.
To test this hypothesis, the researchers created a statistical model of the age-specific risk of death in species from seven primate genera. They used data from various studies to set the parameters of their model, which is how they tested the amount of variation.
The model included parameters for infant and juvenile mortality, age-independent mortality, and senescent mortality. Variation in the biological rate of aging would be reflected in the senescent mortality parameter, since it captures what we normally think of as ‘aging’, while the infant and juvenile morality parameter reflects the misfortune of dying young.
The study’s first finding is that most of the gain in human lifespan so far has come from reducing mortality at younger ages. There’s also variation in the infant and juvenile mortality parameter, both between societies and at different times.
This also shows up in the relationship between life expectancy and lifespan equality. Media reports generally got this part of the study right, and you can look at the report on SciTechDaily to get more details about these findings.
Unlike the infant and juvenile mortality parameter, the senescent mortality parameter varied very little within each species. In fact, changing this parameter in their model shifted the mortality and demographic data of one species to look like another.
Changing the other parameters led to minor shifts in age distribution, but changing senescent mortality made it look like data from a different species. What this means is that within a given species, biological factors are the ultimate determinants of longevity.
Changing the environment to reduce mortality at younger ages (as we have in most parts of the world) affects demographics, increasing life expectancy and lifespan equality. However, accomplishing more than that will require tackling the evolved biological constraints on lifespan.
This study, therefore, doesn’t show that the rate of aging cannot be changed; it shows that there’s a limit to how much change can be realized without biological interventions, which is precisely the challenge that longevity research aims to overcome.
The paper itself closes on that note, though you wouldn’t know it from the way it’s been covered: “It remains to be seen if future advances in medicine can overcome the biological constraints that we have identified here, and achieve what evolution has not.”
Is it possible to slow the rate of ageing, or do biological constraints limit its plasticity? We test the ‘invariant rate of ageing’ hypothesis, which posits that the rate of ageing is relatively fixed within species, with a collection of 39 human and nonhuman primate datasets across seven genera. We first recapitulate, in nonhuman primates, the highly regular relationship between life expectancy and lifespan equality seen in humans. We next demonstrate that variation in the rate of ageing within genera is orders of magnitude smaller than variation in pre-adult and age-independent mortality. Finally, we demonstrate that changes in the rate of ageing, but not other mortality parameters, produce striking, species-atypical changes in mortality patterns. Our results support the invariant rate of ageing hypothesis, implying biological constraints on how much the human rate of ageing can be slowed.
Ultimately, this wasn’t a study about longevity or the inevitability of aging. It was research to understand what affects the rate of aging – how much it results from evolved biological processes versus the effects of the environment. That’s important science not only for longevity research but also for evolutionary biology. It’s undoubtedly valuable, but unfortunately, its message has been misconstrued.
Far from showing that aging is inevitable, this research instead demonstrates that, ultimately, we’ll run out of environmental improvements and will have to turn to biological interventions to affect aging.
 Colchero, F. et al. The long lives of primates and the ‘invariant rate of ageing’ hypothesis. Nature Communications (2021), doi: 10.1038/s41467-021-23894-3
Sedeer el-Showk became a professional science writer after finishing a degree in biology. He also writes poetry and science fiction and fantasy, and somehow juggles an ever-growing list of hobbies from programming to knitting to gardening. Eternal curiosity and good fortune have taken him to many parts of the world, but he’s settled in Helsinki, Finland for the moment. He hopes he’ll never stop learning new things.
The Unnatural Objection to Life Extension – Article by Arin Vahanian
Of all the objections to life extension, perhaps the most banal one yet is the argument that it is not natural for humans to want to live longer and healthier than they currently do. Of course, not only does this actually go against human nature itself, but it is also an insult to the immense progress we have made in improving the human condition throughout the course of history. In fact, this opposition to life extension also flies in the face of the entire medical industry, which is focused on keeping people alive, and any other industry that contributes to the betterment of the human condition, of which there are many. The fact is, opposing life extension is what is unnatural, because it is a natural human desire to want to survive, and to continue living in a healthy manner.
And let me be clear – just because something is natural does not make it good. It doesn’t take a genius to understand that getting poisoned by a plant, mauled by a wild animal, drowned by a tsunami, or crushed by a landslide are scenarios that are to be avoided at all costs. That these sorts of events are now relatively rare speaks volumes about the progress we have made in battling the destructive forces of nature.
Similarly, cancer, heart attacks, and strokes are natural too, yet no one would say that these conditions are desirable or good. In fact, many billions of dollars and resources are spent on finding a cure for these diseases, and for good reason – these diseases are deadly and contribute to massive suffering and pain.
To be sure, the environment is precious and should be protected. After all, to be able to walk through a forest and appreciate the flora and fauna is refreshing. Being able to visit a beach and feel the cool ocean breeze on one’s skin on a late summer afternoon is lovely. However, we should also be very wary of romanticizing nature, mostly because nature is entirely indifferent to the human condition. Indeed, nature does not care one bit about our happiness or fulfillment. Earthquakes, tornadoes, tsunamis and hurricanes are part of nature, but no sane person would argue that these events are positive or that we should experience more of them.
Just because something exists in nature does not make it desirable or good. Conversely, just because something was developed outside of nature does not make it undesirable or bad. In fact, more often than not, science and technology have contributed to massively improving the quality of life for human beings. Imagine how much worse life would be without electricity, life-saving medicines, medical procedures, and computer technology.
How many people now would say that the tuberculosis vaccine, stents, or pacemakers are bad and should be abolished? Of course, all these discoveries were “unnatural,” but no sane person would wish to be inflicted with a deadly infectious disease or suffer a heart attack.
But going back to talking about the environment, climate change is a very real threat to planet Earth and humanity, and we should do all we can to protect our planet, the human race, and members of the animal kingdom. However, the solution to climate change is not going to arrive automatically as part of a natural process. Neither is the answer to stop evolving as a species or to stop all technological innovation and progress and revert to the Dark Ages, and in turn have humanity experience economic collapse and widespread suffering. In fact, humanity’s best hope for battling climate change will likely come from science and technology.
Further, attempting to control nature is what has allowed us to come up with inventions such as indoor plumbing, safe and comfortable shelter, and weather forecasts, all of which have improved the quality of life dramatically. Suppose that we had just let nature run its course in these scenarios. I don’t think I need to spell out what would have happened to humans had we allowed that to happen.
But even after we have thoroughly debunked this ridiculous objection to life extension, critics may then move on to other objections, such as the idea that a human life is already long enough, or that we may become bored if we were to live longer, or that the Earth will become overpopulated. Fortunately, we have answers to these objections as well. And what about the argument that sickness and death are inevitable and that we should just accept things the way they are? This topic deserves its own discussion, but for the moment we can respond by saying that catching an infectious disease and dying at the age of 20 or 30 was once the way things used to be, but it is fortunately no longer the case.
The fact is that it is entirely natural for humans to want to live longer and healthier. Indeed, it is what we have been trying to do since the dawn of time. It is human nature to want to survive and thrive. For the first time in human history, we have the potential to overcome nature itself. Limiting ourselves to what is natural means we deny ourselves the opportunity to be better and to do better. Dying at 20 years of age due to cholera, measles, or malaria wasn’t our destiny as human beings, and therefore we overcame infectious illnesses and significantly increased our life expectancy. Now, we are at a crossroads where we get to decide if we wish to continue suffering for years and then dying due to aging-related illnesses such as dementia, heart disease, and cancer, or, whether we will dedicate this next stage of human development to overcoming these horrific illnesses.
Of course, even after admitting that aging-related illnesses and natural disasters are devastating and should be avoided at all costs, opponents of life extension may still argue that they are entitled to oppose life extension. Of course, they are entitled to their beliefs, no matter how faulty their reasoning and logic may be, but we supporters of life extension are also entitled to advocate for the defeat of aging-related illnesses and to improve the human condition through advancements in science and technology, even if these advancements are not part of nature.
I would urge those who oppose life extension technologies because they are unnatural to revisit their stance after burying a loved one who dies from cancer, or after witnessing a calamitous natural disaster that destroys entire towns and kills thousands of people.
If nature held all the solutions to life, then we would not need to build earthquake-resistant buildings, we would not need to develop anti-cancer drugs, and we would not need spend money, time, and resources on reducing human suffering and improving the human condition.
Nature is how we started as human beings, but nature is not where we need to end.
I had an unfortunate encounter with a friend of a U.S. Transhumanist Party member who was conducting on his page what I call an “anti-vaxxer drive-by”: shooting out some quick chart with poorly interpreted data that seemingly supports the idea that vaccines make you sick / don’t work / are Bill Gates microchips, etc.
The graphic in question was this one:
The chart in question shows a rise in infection at equal rates from those who got both vaccines, and those who did not receive a vaccine at all. The green bar shows amount of cases where no vaccine was received, and the blue bar amount of cases who again tested positive two weeks after the vaccine. What is the implied conclusion, then? The creator of this graphic wants to convey the message: “Why even get the vaccine, if the rates of infection are just as high 20 days after getting it as they are if you don’t get one at all?”
This post is about why his conclusion is wrong, why his analysis is wrong, and why his ilk are not to be trusted.
I was very lucky to find myself with several free hours of time today, as digging into this took some time. I had to type the source link into the browser a few characters at a time, since it was from an image, and the site itself was in Hebrew. I was pleased to find though, that the site did have the data available for download in a CSV format, which is easily importable into Google Sheets.
The data showed weekly stats on 9 age groups, and how many cases there were in three time periods: one to six days from vaccination, seven to thirteen days from vaccination, thirteen to twenty days from vaccination, and cases from vaccinations more than twenty days ago. This sequence is repeated for cases after dose two of the vaccine. Here is the spreadsheet:
I’ve included the last two weeks in this screenshot, and would like to direct the reader to notice a few things that should stick out sorely after a few moments’ study.
1. For the age range 0-19, the number of youths who reported cases was forty times as high as those who did not.
– Were children perhaps just 40 times as susceptible to infection? This would have been interesting for the person looking at the chart to know.
2. The age range 0-19 actually makes up one-half of the total amount of cases reported.
– Maybe it was just that those who signed up for this study all happened to be children who needed pocket money? That can’t be right…
3. For week the week of June 27 (2021-06-27), excepting the youth group for vaccine 1, not a single case was reported during the weeks 1-20 for any group. The next week never had more than five cases for an age group.
– Ah, good news! Perhaps the vaccine was super effective, if only for 20 weeks.
4. It is not reported how many people total got the vaccine who were NOT sick after 20 days.
-Perhaps the data account for all cases, and all those in the study eventually got reinfected?
There are some big problems with this chart, and the first is that this is a HUGE instance of what we call “self-selection bias”.
Unlike lab rats who have no choice in the matter, humans get to choose whether to participate in studies or not. Adults can easily choose to not report when they are sick; people had to voluntarily “select” themselves to be included in this dataset. Children have less choice. Children are in school, and vaccine testing can be conducted just the same way standardized knowledge testing is: get all the students in the same building, line them up, assign each a number, and have every single one tested. I think this is why youth aged 0-19 outnumber those aged 20-90 combined.
Even more important than that, we do not know how many people got the vaccine who did NOT get sick vs those who did not get the vaccine and did not get sick. Assuming Israel gives out 9,000 inoculations a day, the 30-39 year olds in week 07/04 could have been 248 vaccinated people infected out of tens of thousands who received the vaccine. We don’t have a way of knowing and don’t have that data.
The real plot twist though, comes after one digs into the “README” file attached to the study data right next to the CSV file. Here is the relevant excerpt Google translated:
“vaccination_without_positive_Sum – number of verified people detected per week and age group Relevant, and who did not receive any vaccine dose. It should be noted that vaccinated who received the vaccine dose The first on the same day that a positive result was obtained are included in this column.”
What does this mean? It means that the “unvaccinated” group were those who ran to the doctor after they got sick, got the vaccine themselves, and were only THEN added into the dataset. They got the vaccine too!
The charlatan that made that chart was trying to make it seem like he was comparing data from two groups in a randomized controlled trial, and concluding that the data showed you were equally as likely to get sick when taking the vaccine as not. What the data really showed is that it is very easy to test children who are stuck doing what their teachers tell them for eight hours a day, and also that when the chips are down and the unvaccinated finally do get sick, they change their mind and run to the doctor to get the vaccine anyway.
As Director of Publication for the USTP, I would like to reaffirm the Transhumanist Party’s strongly-held pro-vaccine stance. There is far too much of this junk science flying around, and I certainly can’t spend the better part of the afternoon each day playing “debunker”, but you can be sure to expect a series of pro-vaccine material to be republished under the Infinity Banner.
Zach Richardson is Director of Publication for the U.S. Transhumanist Party.
Why Transhumanism Needs More Positive Science Fiction – Article by Rykon Volta
In the modern Age of Accelerating Returns, more commonly known as the Information Age, technological growth is accelerating at an unprecedented rate. Never before in the history of humanity has technological growth shown itself so clearly to the human race. As noted by famous futurist Ray Kurzweil, the trend of exponential growth in technology follows a double exponential curve.
One famous example of this exponential growth that you might be familiar with if you are into the world of tech is, of course, Moore’s Law, but in The Singularity is Near, Kurzweil demonstrates that other technological fields, including medicine, have been accelerating as well. Ray Kurzweil shows that technology has actually been accelerating since before the Stone Age, although a man in the Roman Empire would not have noticed any ramifications of progress considering that his grandchildren would not live in a very different society from the one his grandfather and he inhabited. For the first time in recorded history, we are commonly thinking about where we will be in 100 years, where we will be in 50 years, and now we are even thinking about where we will be in a decade as technology progresses into the 21st Century. If Ray Kurzweil is right, machines will have sentience, and AI, or artificial intelligence, will be greater than human intelligence, resulting in a hypothetical event known as an “intelligence explosion” or “technological singularity”. After this point, machines will be much smarter than average human beings and will be able to carry on progress much faster than we can even begin to comprehend with our natural brains.
In the wake of the recognition of these future possibilities, many science-fiction authors and script writers have created a plethora of media to warn us that AI and future genetic augmentation pose many existential threats to the human race. Examples that now dominate the mainstream media include Terminator, 2001: A Space Odyssey, The Matrix, and many more that warn us that AI might kill us all. Gattaca expresses the great fear of an unfair society of elitism in a genetically enhanced world where a man who was born naturally is unable to get his dream career because he wasn’t born with genetic modifications. In parallel, people demonize the idea of genetic modification by ruthlessly attacking GMOs and saying that they’re bad for us when GMOs have in fact solved famine in some parts of the world due to higher yields. People are always fearful of something they do not understand.
In the Golden Age of Science Fiction, a period during the mid-20th Century that saw many sci-fi works hitting the stage, spreading optimism and futurism, science fiction had a brighter outlook on the future. Isaac Asimov imagined future Spacer societies and a Galactic Empire in his Robot Series and Foundation Series. Gene Roddenberry took us on fantastic voyages across the stars in the Enterprise alongside Captain James T. Kirk and Spock. Other authors inspired visionaries to have a brighter outlook on the future as the Space Race sent the first humans to the Moon.
Today, we have, in a way, a form of cultural stagnation. While some still see the future in an optimistic light, it seems much more popular today to look at the future as a dystopia, and New Age movements all over the place actually act like demonizing technology is some kind of “morally right” position. Despite the trends of growth continuing to accelerate, mainstream culture seems to be propagating more fear of the future than hope and inspiration. Why are we doing this? While I agree that dystopian sci-fi has it’s place and that we should in very deed analyze and contemplate existential risks in our future that we might steer clear of, progress is going to happen and we are going to try everything we can to “play god”, as the enemies of transhumanism like to say transhumanists are trying to do. To them, of course, I say, “Were we not created in God’s image? Did God not give the Earth to mankind? Were we not meant to achieve our full potential, to subdue the Earth and conquer it, bending it to our will?” Indeed, this phrase in Genesis seems to be divine permission to modify our bodies and accelerate a brighter future. However, this is mainly an appeal to my fellow religious folks who may be averse to progress. We are not playing God because, quite honestly, God would not even make that possible. We are just using our God-given talents to hack our own genetic code and modify the machinery of our initial, still quite wonderful creation. To those Christians who say that we are insulting God and telling him “You didn’t make me good enough”, the beauty of mankind is that we were in fact created with the ability to modify ourselves. Don’t modify yourself with the intention of insulting your creator, but with the intention of becoming closer to your creator. Why would he give us the ability for self-modification if he didn’t intend for us to use it? It’s like saying that we shouldn’t work out because self improvement is some kind of blasphemy against God. Do you really believe God wants us to intentionally limit ourselves from our full potential?
Others may fear the coming of AI as a usurping of humanity as the apex predator upon this planet, and they may be afraid of a Skynet scenario where a rampant AI destroys us all. I argue that the solution is to merge ourselves with the machines, allowing us to cause ourselves to evolve. Ray Kurzweil and many other singularitarians would make the same argument. By evolving our own bodies and replacing our cells with nanobots whereby we can enhance our brains to the point where neural signals travel at light speed, we will be able to keep up with AI in the evolutionary arms race to come. You can choose to live in fear in the face of the Singularity that is coming, getting left behind in its wake, or you can step boldly and bravely forward into the new world that it will create, surpassing all your physical, mental, and morphological limitations and ending your mortality fully.
As I have written before, mainstream media is overwhelmingly sending out negative signals and warnings about the future, painting into the memespace, or ideaspace, of mainstream culture the notion that technology is a negative influence and that it should be contained and controlled. Society is largely crying for a return back to the caves because many people are fearful of what they don’t understand. This trend needs to cease. People need to see that the light of the future is much brighter than they think. AI is coming, and the technological Singularity is coming, and it’s going to be better than anyone can imagine. This is a call to arms; artists and sci-fi writers who see the ramifications of the future and how it can create an abundant, prosperous utopia, I urge you to write science fiction that portrays AI not in a negative, but rather in a positive manner. Show AI in a benevolent form and show how it can aid humanity in its future quest for survival. Show how it can solve global problems like hunger and global warming and cure disease. Stories that put the Neo-Luddites in their place, and show that the pseudo-religious zeal of anti-progress-minded people is ultimately a negative factor only holding us back from creating a better world in the long run. Know and understand that the content in the mainstream media has a huge effect on the minds of the people, and indeed much of culture is shaped by what is put out there and consumed by the masses. Transhumanism needs more positive science fiction to help gain support for the movement and to inspire the next generation of scientists and inventors to design the future we all desire!
Rykon Volta is the author of the novel Arondite, Book I of The Artilect Protocol Trilogy. Arondite is available on Amazon in hard-copy and Kindle formats here. Visit Rykon Volta’s website here.
Watch the U.S. Transhumanist Party Virtual Enlightenment Salon of July 19, 2020, when Rykon Volta was the guest of honor and discussed science fiction, his novel Arondite, and the ideas surrounding it with the U.S. Transhumanist Party Officers.
Author’s Note: This article is cross-posted from my Substack.
Preface: It’s well known that stories of people who suffer while waiting for drugs to be approved rarely get attention, while the stories of those who suffer from unexpected side effects often end up in the news and congressional hearings. There are many reasons for this. One of them is the act-omission distinction. Intuitively people tend to place much more blame on actions that result in harm rather than omissions that result in harm. Rationally though, the distinction doesn’t amount to much — a doctor that withholds a life-saving medicine, while processing knowledge that it is likely to help a patient, still commits a grave ethical injustice even if they didn’t directly cause harm. Another reason is that patients are often not aware of drugs in the pipeline that have a good chance of helping them.
It doesn’t have to be like this, though. I strongly believe those who have suffered under FDA regulatory delay should have their stories heard and appreciated. That’s why I’m so happy John Bennett attended my second #ApproveAstraZeneca #UnclogTheFDA protest outside the FDA. When I heard John’s story, I knew it deserved to be told to a wider audience. So, I had him retell the story to me so I could tell it to you here. I really appreciate John taking the time to tell me his story and proofread my writing.
When John was only around nine years old, he started experiencing joint pain. Initially his doctors thought he might have juvenile autoimmune arthritis. Around age ten, however, he was diagnosed with Crohn’s disease. Later his doctor would tell him that after that initial diagnosis he estimated his life expectancy was only nine more years.
Crohn’s disease is not just “digestive problems”. The disease affected all aspects of John’s life, and he spent much of middle and high school in and out of a wheelchair. In 2001 he started receiving infusions of the monoclonal antibody Remicade every six weeks. Due to Remicade, he started to be able to walk again and was able to live a mostly normal life. That all changed suddenly and unexpectedly in 2005 when his throat closed up after his injection. Unfortunately, as happens to many long-term Remicade patients, his body had developed an immune response to the drug. In response doctors switched him to a similar monoclonal antibody drug, Humira. However by 2013 his immune system had started rejecting the Humira as well. In response his gastroenterologist tried several general immune suppressors but at this point John was running out of good options.
Fortunately there was a new drug with a lot of clinical trials data to support it, Entyvio. Unlike Remicade and Humira, which are TNF-alpha antagonists developed for rheumatoid arthritis, Entyvio was developed specifically for Crohn’s disease and a similar disease called ulcerative colitis. Entyvio was specifically studied in Crohn’s disease patients like John who either could not tolerate or did not benefit from conventional therapy and TNF-alpha antagonists. A peer-reviewed Phase II study from 2008 showed a dose-dependent beneficial effect of Entyvio. Four Phase III studies followed. By February 2013 enough studies had been completed on Entyivio that a review article in Expert Opinion on Biological Therapy concluded the drug was “an effective and well-tolerated drug that is an important advance for the treatment of Crohn’s Disease.” Takeda Pharmaceuticals filed the paperwork for approval with the European Medicines Agency on March 7th, 2013 and filed with the FDA on June 21st, 2013.
This is where the story starts to get really dark. Throughout the summer and fall of 2013, John suffered from fatigue, joint pain, and stomach pain. His symptoms came and went in unpredictable waves, so he was never sure if he would be able to attend any social events or be able to go into work. He had to start taking a lot of leave from work, some donated from co-workers, and some unpaid. Eventually the pain got so bad he started going to a pain clinic every two weeks, which started him on Vicodin and Percocet. His intestine was so inflamed it was shot through with holes. A persistent infection developed. His neck felt like it was in a vice and was so difficult to turn he had trouble driving.
Given John’s condition, his doctor knew he was in a race against time and that he needed Entyvio as soon as possible. As a member of the FDA’s Gastrointestinal Drugs Advisory Committee, John’s doctor had an inside view on the agency and predicted he should be able to get the drug by the end of the year. Indeed, on December 9th, 2013 the Committee voted 21-0 in favor of approving the drug for Crohn’s disease. Under normal circumstances, an approval would follow shortly thereafter. Unfortunately for John (as well as many other patients), this isn’t what happened.
Even though the FDA had granted Enyvio Priority Review Status, for the next five months the FDA kept John (and undoubtedly many others) suffering as they debated the wording for the warning label. Since the approval of earlier monoclonal antibody drugs such as Remicade and Humira, scientists learned that in the long term some patients can develop allergic reactions to treatment. The FDA wanted to put a warning about the possibility of a severe allergic reaction on the label. The problem was that the drug had been designed specifically to avoid the allergic reaction rejection problems that occurred with Remicade and Humira, drugs which did not contain such a warning. A warning about allergic reactions would make Entyvio look less safe, something that the company rightly took objection to.
Another possible reason for the delay might be related to the fact that the FDA claimed that Entyvio put patients at risk for progressive multifocal leukoencephalopathy, (PML) an often fatal brain virus. In over a decade of trials however no patient who had taken Entyvio had ever developed PML. Still, the FDA pointed to a similar drug, Tysabri, which carries a “black box” label warning of the risk for PML. The company disputed this – pointing to established mechanistic differences in how the two drugs worked, but the FDA wasn’t convinced. In the end, the FDA decided to include a warning about PML on the label and require post-market surveillance.
By April 2014 John’s condition had gotten so bad that John’s doctor started filling out compassionate use paperwork. The FDA told him not to bother and to wait for the approval. In retrospect, he probably should have tried anyway. When the drug was finally approved on May 20th, 2014, the initial doses the drug company had made had expired. The company had to manufacture new doses, leading to a delay in commercial availability. It wasn’t until September 2014 that John got the drug. By that time John was in precarious health. Although he now had the drug in his system, it was too late to help. In January 2015 his doctor sent him to the ER where he stayed in an ICU for several days fighting an infection. John had to have two major surgeries that ultimately removed his large intestine altogether.
The story illuminates many areas for improvement in the FDA approval process. First, it took five and a half years after promising Phase II results for the drug to become available to patients. Other different regulatory approaches like Free to Choose medicine or adaptive licensing could have made Entyvio available to patients faster and at lower cost. But even if you remain convinced that pre-market Phase III trials are a necessity, there are still major areas for improvement highlighted by this case.
Ideally, after the company reached their endpoints in their Phase III trials the drug would be rapidly approved within a month or two. In reality, John suffered for well over a year waiting for Entyvio to be approved by the FDA. Even after the FDA’s board unanimously voted in favor of approval, John suffered for another five months waiting for approval (the FDA could have figured out the proper warning label much earlier, for instance in the five years during which the Phase III trial was running). Even after approval, John had to wait another four months before he finally got his first dose since the initial doses had expired.
As a result of over a year of completely unnecessary delays, John became dependent on opioids, ended up in the ICU with a major infection, and had to undergo several risky surgeries. In the end though, he was lucky to have survived the ordeal. One wonders how many patients like John there were who also suffered from the delay, and how many died as a result.
Dan Elton, Ph. D., is Director of Scholarship for the U.S. Transhumanist Party. You can find him on Twitter at @moreisdifferent, where he accepts direct messages. If you like his content, check out his website and subscribe to his newsletter on Substack.
My Path to Transhumanism and Becoming the First Transhumanist Party Member to Hold Political Office in North America – Article by Gerald Shields
In 2016 I changed my political party membership to Transumanist on my voter registration card. Then, I became a town councilmember of the Town of Berwyn Heights in Maryland. I served in that role from October 2016 to May 2018. I believe I am the first Transhumanist Party member to hold a political office in North America (during the time period of the U.S. Transhumanist Party’s existence).
My path to Transhumanism has been varied and interesting. I changed my voter registration for a variety of reasons. During the 2016 election cycle, I was disappointed in the various election platforms of the major parties. I thought that pushing the goal of making humanity a two-planet species was a more important goal than what was listed in those parties’ platforms. After some research for alternative parties, I discovered Mr. Zoltan Istvan’s campaign for the U.S. Transhumanist Party. Mr. Istvan called for a medical Moonshot program. Even though it was not a direct step to a two-planet species, it was a step in the correct direction to long-term colonization of other stars. I contacted the campaign, and I saw that there were no campaign posters for an internet-based campaign. I realized that without visual legitimacy, the transhumanist ideas will not get much traction. A visual will look good on television, blogs, and YouTube. A visual aids in the message. I helped create campaign posters with Ms. Chelsea Gilbert. It was my idea to use vector graphics in orange and black with classic Americana political phrases to illustrate some transhumanist ideas. The idea is to tap into the Americana meme under the banner of the Transhumanist Party without causing future shock. The goal is to stir the passion of our members as discussed during the various transhumanist conversations on YouTube.
The phrases I proposed were:
“The Future is here. The Transhumanist Party.”
“We can do it….With the Transhumanist Party.”
“The Transhumanist Party builds the Future.”
“Wake up America with the Transhumanist Party.”
“Reclaim America. Join the fight for the future and the Transhumanist Party.”
During the campaign, I attended several Washington, DC, and Seattle, Washington, transhumanist meetings, during which I met Zoltan in person.
On October 3 2016 at Berwyn Heights Town Office, Gerald Shields (left) was sworn by Mayor Jewitt (right) in an a member of the town council. Photograph from Gerald Shields.
Then, as part of my political path, I was on the Town Council of Berwyn Heights, Maryland, from October 2016 to May 2018. The competition was nonpartisan between a total of three people. I filled an empty position on the Town Council, and this was done via a special appointment, not a general election. However, in normal times, this is a nonpartisan, general-election position. I believe I am the first Transhumanist Party member to hold a political office in North America (during the time of the U.S. Transhumanist Party’s existence). During the special appointment, I campaigned on a very local and non-glamorous issue of improved storm drains. Storm drains are important because, in Berwyn Heights, there was a 100-year storm that flooded the basements of several houses. On a town or even county level, there really is no way to have a longevity Moonshot in my view. I am a very practical and nuts-and-bolts (no transhumanist pun intended) type of person, who wants this Party to be a success. However, when I was on the Town Council, my political portfolio was Parks & Recreation, Education, and Civic Affairs; not Public Works. I laid the foundation for the town’s policy on non-governmental organizations. During my term, Berwyn Heights achieved the title of Banner City for the first time and attained other objectives due to my efforts. At the end of my term, I achieved my Parks and Recreation goals, so I decided not to run in the election.
Right now, the public view of transhumanism is characterized by cyborgs and other scary things. We must adapt and put forth the benefits of increased medical knowledge and increased energy resources in a beneficial way while addressing the general public’s concerns. That is why I suggested to Zoltan to emphasize the Good Neighbor Next Door policy. The Good Neighbor Next Door policy would focus on volunteering on local committees, such as Neighborhood Watch, the State Government’s official State Defense Force, Green Team, or other local small-town groups, as well as just saying “Hi” to one’s neighbors, to show that one is a normal person who cares about local matters. Also, I suggested that Zoltan post photos of himself and his kids because this would make him more relatable to other fathers. Then, as time progresses, Transhumanists who follow this approach would show that they are ready, willing, and, most importantly, able to lead in political positions.
That is my varied path to Transhumanism and becoming the first U.S. Transhumanist Party member to hold a Town Council political office.
Gerald Shields is a member of the U.S. Transhumanist Party and was a Town Council Member in Berwyn Heights, Maryland, between October 2016 and May 2018.
To the FDA: Approve Leronlimab Now for Critically Ill COVID-19 Patients – Article by Dan Elton
Author’s Note: This article is cross-posted from my Substack.
How does Leronlimab work?
Leronlimab is a humanized monoclonal antibody that antagonistically binds to the CCR5 receptor to block activation of immune cells and lower the release of cytokines. The development of Leronlimab started with mouse antibodies that bind to CCR5. Unfortunately, mouse antibodies can’t be directly imported into humans since they are attacked by the immune system as foreign invaders. That’s where next-level genetic engineering comes in. Researchers looked at the genes for human antibodies, identifying ones that were closest to the genes for the antibody that the mice produce. They then took the segment of DNA from the mouse antibody that coded for the antigen binding site and stitched that into the human antibody gene. (The antigen binding site is the key part of the antibody allows it bind to the CCR5 receptor). The result is a chimeric or humanized antibody which can be mass-produced in bacteria.
As alluded to, the specific place where these antibodies bind is the CCR5 (Chemokine Receptor Type 5) receptor, a “G Protein coupled” receptor that resides on the surface of cells, in particular immune cells such as macrophages. When the receptor is stimulated, calcium channels open up and Ca++ ions move into the cell, causing activation (movement) of the macrophages.
Leronlimab was originally developed to treat HIV, because the HIV virus uses the CCR5 receptor to get into cells. (By blocking the receptors, the HIV virus could be blocked.) Despite being under study since 2007, Leronlimab is still not FDA-approved for HIV, although it appears to be getting close. To treat HIV, it is given as a once-weekly at-home injection. Researchers have found many other uses, however. For instance, when Leronlimab blocks the CCR5 receptors on breast-cancer cells, it prevents them from moving around so that the cancer can’t move to other parts of the body, which makes the cancer easier to treat. Note that Leronlimab is not yet FDA-approved for any of these possible applications, so off-label use for COVID-19 is impossible.
In the case of COVID-19, infection by the SARS-CoV-2 virus induces stressed endothelial cells to produce CCL5. When CCL5 reaches T-cell and macrophage cells in lymph nodes and binds to their CCR5 receptors, it induces those cells to become activated and then move towards the source of the infection along the CCL5 gradient. Unfortunately, in severe COVID-19, the immune response can be so strong that it leads to tissue damage. CCL5 also induces the production of inflammatory cytokines including TNF and IL-6.
What do we know about the efficacy of Leronlimab?
CytoDyn Inc. published a press release on January 28th, 2020, announcing that it was beginning to evaluate Leronlimab’s use for COVID-19. In that press release, CytoDyn clearly explained the mechanism of action described above, noting that clinical experience in China found that many patients who died from COVID-19 did not die from the virus but from an overactive immune response causing inflammation and the infamous “cytokine storm”.
A study published in preprint form on May 5th, 2020, looked at 10 terminally ill COVID-19 patients on ventilators at the Montefiore Medical Center in Manhattan. The experimenters administered 700 mg of Leronlimab to each patient. Within three days they found that found that IL-6 had decreased in all of the patients, reaching healthy levels in two weeks. After two weeks six patients had recovered while four died (a 40% mortality rate). At that time the mortality rate for ventilated patients was said to be “as high as 88%” in New York City. So, while there was no control group in this study, one can argue there was an observed reduction in mortality here. While the results on reduced mortality are weak due to a lack of a suitable control, the biomarkers studied all showed a reduction of immune response. The researchers found a reduction of new immune cells manufactured in the bone marrow and a return of platelet cell counts towards normal levels. The researchers also found that the concentration of virus in the blood (viremia) decreased. In a TEDx talk, one of the authors, Dr. Bruce Patterson, claims that Leronlimab was responsible for the drop in blood virus concentration. He said this:
“Leronlimab restored CD8 T-cells and increased Granzyme A to better clear virally infected cells. It also inhibits Treg cells and repolarizes macrophages which both enhance the immune response against infected cells.”
I honestly do not understand these details or know how well they are empirically supported by this or other studies.
The mild-to-moderate trial did not meet its primary efficacy endpoint, but in a post hoc analysis in the subset of subjects with more severe disease, a higher proportion of Leronlimab-treated subjects (50%; 24/48) versus placebo-treated subjects (21%; 5/24) showed improvement in National Early Warning Score 2 – a risk score for “rapid clinical deterioration requiring critical care intervention” (p = 0.0223).
The severe-to-critical trial also did not meet its primary endpoint — considering all patients, the difference in Day 28 mortality between Leronlimab and placebo was not statistically significant (N=384, 2:1 split, p > 0.05). (Update: a commentor pointed out that the placebo group ended up being younger and was small, so unfortunately they missed statistical significance. You can see all the details here.).
However, the researchers then analyzed patients on invasive mechanical ventilation or ECMO. They found that if Leronlimab was added to the standard of care, then on the 14th day there was a reduction in mortality of 82% (p=0.0233, N=62) and an average reduction in the length of stay of 5.5 days (p=0.005, N=62). They also found a 400% improvement on a 7-point ordinal scale for COVID-19 severity when compared with standard of care.
There have been several clinical reports and anecdotes about patients on ventilators or ECMO who rapidly recovered after receiving a single dose of Leronlimab (see here (N=1), here (N=4), here (N=1), and here (N=1)). A somewhat larger observational study with N=23 patients reported that after 30 days, 74% no longer required hospitalization. Six out of the seven patients that required ventilation survived. The biomarker results were somewhat mixed – while the researchers found evidence of reduced immune activation in the patients who received Leronlimab, they also found that the inflammatory marker CRP didn’t decrease until after two doses were given. Another small study on N=3 lung transplant patients with COVID-19 found a decrease in CRP after one week.
On March 29th, 2021, the Phillippines’ FDA began issuing compassionate use authorizations on a per-patient basis and for up to one year. Incidentally, one of first two patients was a former President of the Phillippines. In April compassionate use authorizations were given to 28 critically ill patients.
Why hasn’t the FDA acted?
CytoDyn’s failure to reach either their primary or secondary endpoints in their Phase II/III trial on critically ill patients is undoubtedly a major blow. The company has not yet applied for an Emergency Use Authorization (EUA), and it seems this failure is the reason why. (News reports from August 2020 saying that company had applied for an EUA turned out to be incorrect.) CytoDyn is moving forward, however, and has filed a new protocol with the FDA that will study four doses given over four weeks to critically ill COVID-19 patients.
The use of any immunomodulator like Leronlimab is clearly a double-edged sword. It makes sense that it would only be helpful in the most severe cases. This is what the two clinical trials showed – they showed a significant effect on mortality for patients on ventilators and no statistically significant effect on other patients. Unfortunately the analysis of the patients on ventilators was a post-hoc analysis, which is frowned upon in science due to the possibility of data dredging. So clearly the science is not settled here.
Let’s consider this from an ethical point of view. Patients who are in ICUs and on ventilators have a high chance of dying. Inflammation macrophage activity, and excess cytokines are implicated in many COVID-19 deaths. There is strong evidence, going back over a decade, showing that Leronlimab decreases inflammation, macrophages, and cytokines. Leronlimab is known to be a very safe drug (prior to 2020 no serious side effects have been found in nine clinical trials with more than 800 patients). Even if Leronlimab only saves 20% of those to whom it is given, then one can argue we have an ethical obligation to do so. It is a somewhat expensive drug (for HIV patients getting weekly therapy, it costs about $2000 per dose; another source suggests it would cost about $1100). However, keeping someone in the ICU costs around $3,000-$10,000 per day. So in addition to saving lives, Leronlimab could also save money as well by reducing the amount of time patients need to spend in the ICU. This could lead to second-order life-saving effects in places where ICU beds are in short supply.
“I believe that if there is a drug that can help someone who is on a ventilator or ECMO and it can save them, then whatever small population that is, it is useful — that is my opinion. I have no financial interest or commercial interest or any other interest of any sort with them (CytoDyn).”
I agree. While the evidence is not conclusive, we have good reason to believe Leronlimab can help very critically ill COVID-19 patients such as those on ventilators or ECMO. There are likely gains from receiving Leronlimab for such patients and very little downside, especially if the patient is considered terminally ill. So not allowing doctors access to Leronlimab risks many unnecessary deaths. The drug should be an especially impactful tool in places like Brazil and India, where there are currently shortages of ICU beds and ventilators.
Dan Elton, Ph. D., is Director of Scholarship for the U.S. Transhumanist Party. You can find him on Twitter at @moreisdifferent, where he accepts direct messages. If you like his content, check out his website and subscribe to his newsletter on Substack.
For an overview of the possibilities of Leronlimab to save the lives of critically ill COVID-19 patients, watch this brief video by Random Ryman.
20 Cutting-Edge Biotechnologies in Development Today – Article by Logan Thrasher Collins
I have compiled a list of some of today’s most exciting, cutting-edge biotechnologies! Some of these technologies are emerging, and some of them are already prevalent in a translational context.
1. CRISPR-Cas systems: revolutionary for gene editing, gene therapy, fundamental biology, diagnostics, and more.
2. Gene therapy: enables cures for genetic diseases and powerful treatments for many cancers, may eventually treat polygenic disorders, ameliorate aging, and even enhance human biology (e.g., provide radiation resistance to astronauts). Synergy with CRISPR-Cas technologies will greatly aid gene therapy.
3. DNA origami: paves the way for new nanomedicines, biocatalysts, biosensors, imaging probes, diagnostics, data storage methods, biocomputing, and more.
4. Computational protein engineering: paves the way for new nanomedicines, biocatalysts, biosensors, diagnostics, biomaterials, imaging probes, and more.
5. Immunotherapy: enables cures for many cancers, treatments for autoimmune diseases, and more.
6. Computational protein structure prediction: revolutionizes drug discovery and basic biology, synergizes with computational protein engineering.
7. Spatial transcriptomics: method for interrogation of cell and tissue biology in a holistic and multidimensional fashion to deeply understand health and disease, may lead to dramatic insights on aging, cognition, and pathology.
8. Optogenetics: powerful tool for understanding cellular physiology and neural circuits, may greatly enhance brain-machine interfacing (with the help of gene therapy).
9. Expansion microscopy: physically enlarges biological samples to multiply resolution. Making major strides in connectomics, vastly enhancing study of spatial organization of cells and tissues in general, synergizing with spatial transcriptomics.
10. Longevity medicines: pharmacological, gene therapy, and other methods of treating aging may extend human lifespan and dramatically reduce the prevalence of most aging-related diseases.
11. Bioprinting: produces replacement tissue and may enable manufacturing of replacement organs. Also greatly aids study of tissue biology and provides platforms for drug testing.
12. Organ-on-a-chip systems: may greatly reduce the need for animal models in research, helping to understand organ microenvironments and organ physiology in general, serving as platform for drug testing and discovery.
13. Organoids: may greatly reduce the need for animal models in research, helping to understand organ physiology (especially in context to 3D structure and function), serving as platforms for drug testing and discovery, contributing to understanding of cognition, aiding understanding of developmental biology.
14. Cryo-EM and cryo-ET: rivaling x-ray crystallography for solving high-resolution protein structures and is much easier than x-ray crystallography (especially for certain problematic samples), giving 3D images of cellular environments at sufficient resolution to see some macromolecular structural details, preserves sample integrity better than other methods.
15. Phage therapy: enables versatile and potent treatment of bacterial infections, may save the world from antibiotic resistance.
16. Synchrotron x-ray nanotomography: rapid 3D imaging in one or two colors, may help map brain structure much more rapidly than other methods. This could lead to superior brain-inspired AI and robotics, treatments for brain disease, and whole-brain simulations.
17. Tissue clearing with light-sheet microscopy: facilitates 3D imaging of tissues and even whole organs, leading to much better understanding of biological function, aids connectomics.
18. Predictive systems biology models: transforming vast biological datasets into parameters for large-scale simulations which give valuable insights. Some key examples are kinetic signaling network simulations, molecular dynamics simulations, and biophysical neuronal network simulations.
19. Injectable electronics: minimally invasive method of delivering brain-machine interface hardware, may lead to widespread biomedical and nonmedical adoption of brain-machine interfaces.
20. Minimal cells: may transform understanding of cellular physiology, may act as a superior biomanufacturing platform, may act as a superior platform for cell therapy, and more.
Logan Thrasher Collins is a U.S. Transhumanist Party member, futurist, synthetic biologist, author, and innovator. When he was 16, he invented a new antimicrobial protein, OpaL (Overexpressed protein aggregator Lipophilic). He next developed a bacterial conjugation delivery system for the gene encoding OpaL. His synthetic biology research has been published as a first-author journal article in ACS Biochemistry: “Design of a De Novo Aggregating Antimicrobial Peptide and a Bacterial Conjugation-Based Delivery System.” In addition, his synthetic biology research has been recognized at numerous venues including TEDxMileHigh, the Intel International Science and Engineering Fair (ISEF), the International BioGENEius Challenge at the BIO International Convention, and at the American Society for Microbiology General Meeting. At Intel ISEF 2014, his synthetic biology research won 1st place in microbiology and best of category in microbiology ($8,000) as well as the Dudley R. Herschbach award. The latter included a trip to take part in the Nobel Prize ceremonies via the Stockholm International Youth Science Seminar (SIYSS). As part of the honors at Intel ISEF, a minor planet was officially named Logancollins.
As the Chief Technology Officer (CTO) at Conduit Computing, Mr. Collins is leading a supercomputing project which has allowed visualization of how the constituent proteins of SARS-CoV-2 interact inside of cells to build whole viruses.
Editor’s Note: The U.S. Transhumanist Party publishes this article by Michael Herschman to illuminate his creative idea for the development of skyships that would act as permanent human habitats and transitional platforms between Earth and space, benefiting the infrastructures and development of both of these realms. The skyship concept echoes the floating structures observed above the Earth and other worlds in the paintings of Robert McCall, and it would be an impressive feat of human progress for them to be brought into concrete reality.
~ Gennady Stolyarov II, Chairman, United States Transhumanist Party, April 17, 2021
Physics evolves, and we can soon expect our advances in engineering. They rarely come, but they never leave. Voices can evolve from turmoil or from excess: People do not often think about science in terms of moral progress… However, there is no holiness of the mind that does not seek happiness. If we choose to look into the sky rather than at the ground, we will find more area for expansion. To a degree, our economy has developed an association with buoyancy. Self-reflection will take you far, but aviation can take you further.
Individuals try to want what is right. Most people never consider human-governed celestial action. NASA, Blue Origin, and SpaceX are influences toward limitless human engineering capacity. To not engage is to hold on… We face gravity as a creative people: Skyscrapers are natural, airplanes are natural, space rockets are natural. Skyships are natural. We need to defy current electronic constraints. It is the natural imperative of every individual to understand according to their capacity the truth of climate change. We see our Earth becoming more and more deceased from carbon. And we use carbon-dioxide-emitting rockets as we leave Earth. By our current standards, the safety and integrity of life on Mars is absurd.
Rendering a sustainable life in the sky is a real and true objective. It is a necessary structure for our next aeronautic epoch. Having a structure between skyscrapers and a space station will bring both closer. Common flying vehicles will proceed from skyship systems and intellectual scaffolding. Its existence will temper its surroundings. And its inhabitants will contribute to society. Everyone on the ship will have the goal of improving life on terrestrial Earth. It is Earth that got them there. They will serve Earth.
Skyships will come about naturally. They are a platform for energy freedoms and personal flight vehicles: so we are guided toward their construction. During the ship’s existence it will help society. Nothing onboard will languish from lack of attention or ability. The ship will be composed of givers that learn and share and provide examples for human structure. The ship will be bound by holistic healthy associations. Craft inhabitants will cure diseases.
We already have airships. A skyship is an airship that can be lived on indefinitely. They will be buoyant and provide protection and can be lived on indefinitely. They will be assisted by fuels and electricity but have no carbon footprint. They are bound to give to society.
Note from the Editor: In a conversation on Clubhouse that I hosted, entitled “Is the FDA moving too slowly with vaccine approvals?”, Willy Chertman articulated a number of nuanced points about the FDA. He had recently finished reading Reputation and Power, an 856-page book on the history of the FDA. I asked Willy to organize his notes on the book so that the USTP membership could learn his key takeaways from the book and learn more about the history and role of the FDA. Willy graciously accepted my request. I have edited his notes somewhat for length and made some minor copyedits. A few key takeaways are bolded.
– Daniel C. Elton, Director of Scholarship, United States Transhumanist Party, April 2, 2021
Reputation and Power Organizational Image and Pharmaceutical Regulation at the FDA by Daniel P. Carpenter 856 pgs. Princeton University Press, 2010
Reputation and Power is a very deep dive into the history of the FDA and the reputational universe that it inhabits and creates. The gist of the book is that reputation management is the best lens to understand the FDA, not “public interest” versus “regulatory capture”. The political and regulatory power of the FDA is bound up inextricably with how Congress, the pharmaceutical industry, academic medicine, and consumer-protection groups view it. By virtue of the size of the market it regulates and its pre-market approval power, the FDA is likely the most powerful regulatory agency in the world.
Because of the length of the book and the variety of topics it covers, I’ve split this book summary into two parts. The first half covers the history of the FDA and the second half covers the themes and lessons I learned from the book. Though Carpenter covers up to about 2010, time constraints meant that this summary only covers up to 1992. Hopefully future posts will cover the remaining material.
The origin story of the FDA in popular political mythology begins with thalidomide, but Carpenter does an excellent job showing how the FDA started as an obscure branch of the USDA, originating with the Pure Food and Drug Act of 1906. In the early 1900’s the FDA had nothing but the ability to confiscate dangerous drugs or compounds from the market. Later, in a pattern that will repeat itself, forces within and without the FDA made good use of the dictum “Never let a crisis go to waste.”
The context is that the early 1900s were a stupendous time to be a patent medicine salesman– a synonym for charlatan. Apart from aspirin, it’s not clear that any patent medicine of that time ever turned out to be effective. Medicines to lull your baby to sleep relied on opium or alcohol, and sulfonamide antibiotics were not invented until the 1930s, and even then their manufacturing process was initially unreliable . Yet the patent medicine trade was booming. In an interesting historical irony, John D Rockefeller, through his foundation’s funding of the Flexner Report, which birthed medical education as we know it, ended the traveling medicine salesman/huckster-doctor profession – which his own father had been in.
The Pure Food and Drug Act of 1908 required accurate labeling of products and also gave the FDA the power to seize and destroy products that violated the law. Importantly, this did not give the FDA the power of pre-market approval, which is its most important power today. Though the FDA was prohibited from directly lobbying for more authority, many in the agency and their Progressive congressional allies believed the FDA was weak and underfunded relative to the growing pharmaceutical industry it was supposed to regulate. In 1935, New York Senator Copeland had tried to pass legislation that would strengthen the FDA, aided by women’s political organizations and the Consumers Research group, but his attempt had failed in the House.
There had been previous small-scale pharmaceutical disasters, but the Sulfonamide Elixir stood out for scale and the media attention that it garnered. The leading role that the FDA eventually took in handling the disaster, as well as the relationship with the media that it cultivated, also made this disaster special. This is the beginning of the sidelining of the American Medical Association (AMA), which had previously been one of the centers of organized medical power.
People became seriously ill from its consumption, and by late October 1937, at least seventy-three of these had died. The FDA, assisted by state and local health officials and the American Medical Association, commenced an effort to secure as much of the compound as possible before any more was consumed.
The media ran stories of heroic FDA officials working late into the night trying to confiscate a dangerous drug, and the story re-surfaced whenever another death was reported. The cherry on top of this story was a report released by the Secretary of Agriculture, the Campbell-Wallace Report:
‘A few simple and inexpensive tests,’ the sort that would be performed by the company before marketing and analyzed in a pre-market review process by the FDA, would quickly have evinced the elixir’s “toxic properties.” Translation: with a pre-market review process, none of this would have happened.
In February 1938, Copeland’s S.3073 was again considered in the Senate. Women’s groups and public-health leagues now lobbied intensively for its passage, and their rhetoric made clear the centrality of the Wallace report in the new deliberations.
Contrary to the theory of regulatory capture, large pharmaceutical firms, who might have expected to benefit from a regulatory moat, did not advocate for the 1938 Food, Drug, and Cosmetic Act. Instead, it was Progressive politicians pressured by consumer protection groups, women’s groups, and forces within the FDA that advocated for it.
The 1938 Food, Drug, and Cosmetic Act gave birth to modern pharmaceutical regulation: The four enumerated powers—(1) pre-market review and notification, (2) prohibition (or withdrawal authority), (3) labeling regulation, and (4) compulsory disclosure of all drug contents (active and inactive)—have become assumed and core legal features of pharmaceutical markets
While the 1938 act did not contain an efficacy provision, Carpenter shows how this was effectively smuggled into drug regulation anyways, with officials saying:
It has been emphasized that there is no arbitrary standard of safety; it is a relative matter in which the toxicity of the drug must be weighed against the therapeutic benefits which its use will bring about.
In the 1940’s and 1950’s the FDA gradually raised the standards for drug approval, and its Division of Pharmacology drew many talented pharmacologists from academia. Throughout the FDA-cultivated “reputational ambiguity”.
The simultaneous ambiguity and fear-provoking stance of investigational regulation was, in part, FDA officials’ manner of expressing and maintaining the agency’s gatekeeping role, even as they did not fully comprehend…
Though a Randomized Controlled Trial was not yet an explicit requirement for drug approval, the FDA gradually raised the bar on the required toxicity, stability, and drug metabolism studies. As pharmacology refined its methodology, the FDA required more and more from drug companies, viewed amateur physician-directed trials with more suspicion, and by being the central gatekeeper of pharma, made the whole field more rigorous and scientific.
The FDA used a variety of carrots in addition to the “stick” of gatekeeper:
From the beginnings of the Eisenhower administration and probably earlier, FDA officials acted intentionally, strategically, and with foresight to establish numerous committees of liaison to the professions. Agency officials established not just medically specialized “advisory committees” of the sort that became institutionalized in the late twentieth and twenty-first centuries, but also more temporary committees that helped the FDA recruit and retain allies and consultants.
The Administration cultivated relationships with academic luminaries in pharmacology, and many of their promising students became part of it. Dr. Frances Kelsey, a Professor of Pharmacology at South Dakota State University who had done important research on the teratogenic effects of drugs on animal fetuses, was an archetypical example. She had come highly recommended to the agency, and though she developed a reputation as being a more exacting drug reviewer than most, the agency as a whole had become more cautious over the decades.
Thalidomide, marketed as Contergan in Europe, was being widely used there as a sedative, and the company (Merrell) submitted a drug application to the FDA. Kelsey held up the application due to safety concerns, even in the face of vigorous company complaint, and was vindicated when it was later tied to an outbreak of birth defects in Europe.
This might have remained the stuff of obscure industry history if the antitrust subcommittee led by Senator Estes Kefauver had not leaked the details of the story to the reporter Morton Mintz. Kefauver, who had been leading high-profile hearings on the “drug industry” and had been trying to shorten their drug patent periods as well as incentivize generic drug prescription, gave Morton Mintz key data about the Thalidomide saga as well as Frances Kelsey’s role in it.
1962 Amendments and After…
The Drug Amendments of 1962 were opposed by the Pharmaceutical Manufacturers Association, but the FDA’s star was ascendant with the Thalidomide crisis having shown its worth.
At their core, the Amendments contained three provisions governing pharmaceutical regulation (table 4.1). They first required affirmative evidence of “effectiveness” and “safety,” evidence in the form of “adequate and well-controlled investigations,” before any “new drug” could enter into interstate commerce. Second, they required designation of a medicine as an Investigational New Drug during its period of experimentation (and submission of the IND to the agency), and empowered the Administration to nullify this status (and hence development of the drug) if research protections for patients were not being observed, if the clinical trial protocol was not sufficiently rigorous, if pregnant women were being exposed to teratogens, or if any evidence of research as commercialization emerged. Third, they required the Administration to lay out and enforce new procedures to protect the interests and rights of patients in medical research.
The impact of the law was significant: Before 1960, there are no references to phased trials in the American and European medical literature, and there is no reference to a “Phase 3” study in Western medical literature before 1964. In the early 1960s, reports of “Phase 1” and “Phase 2” experiments appear haltingly, then rapidly near the end of the decade (table 4.2). What is more, American researchers and doctors began to reflect systematically on the relationship between earlier phases and later phases.
In the 1960’s, as the FDA continued to gain in power, it met with some moderate resistance from organized medicine. These incidents illustrate the reputational politics that the FDA is sensitive to: when comments by Frances Kelsey at a medical conference were taken to indicate that patients always had to be informed that they might receive a placebo, a leading clinical trialist at Harvard, Henry Beecher, wrote to the FDA Commissioner. In another incident, the FDA’s General Counsel William Goodrich implied that medical journals might be liable for misleading advertisements, which prompted a prominent Cornell pharmacologist Walter Modell, who had previously been an ally of the FDA, to publicly rebuke them.
In both cases, to varying degrees, those statements were publicly walked back by the FDA.
Sometimes public dissent against the FDA could damage one’s career, even for the most credentialed academic, as Louis Lasagna’s advocacy for combination antibiotics demonstrated:
Lasagna’s advocacy for Panalba was risky and vocal, and it marked the beginning of a steady decline in his status among medical academicians. Lasagna’s name was golden in the 1950s, when he had authored pathbreaking papers on the placebo response and clinical trial design, when he had founded the nation’s first clinical pharmacology department at Johns Hopkins, and when he had testified in support of efficacy standards at the Kefauver hearings in 1960.
…The diverging paths of Louis Goodman and Louis Lasagna marked the splintering audiences of the Food and Drug Administration as well as the agency’s enduring scientific legitimacy. In the status-conscious world of academic medicine, Louis Lasagna never fully recovered from the Panalba battle.
An important feature of FDA history in the 60’s and 70’s was the congressional hearing. Because of changes in how congressional committee chairs were chosen, congressional hearings became more important in this period. The obligation of FDA officials to appear before Congress when requested and to testify was an important check on its power and a venue where its public reputation was maintained.
Criticism from an industry-friendly senator could strengthen the FDA’s image as pharma policeman while an FDA whistleblower like John Nestor testifying to its regulatory inadequacy could force less accommodation with the drug industry by effectively shaming the FDA into more stringency.
Congressional hearings seemed, at least in the 1970s, to be the strongest check on FDA behavior. When Senator Gaylord Nelson read The Doctor’s Case Against the Pill, and started hearings into the FDA’s approval of it, and its widespread use, the end result was, after much criticism from prestigious physicians, scientists, and consumer safety advocates, the creation of the patient-package-insert. (see chapter 9)
An illustration of how the FDA sought to collaborate with other scientific institutions can be seen in how it dealt with medications that had been approved before 1962 and the formal recognition of an efficacy standard. Thousands of drugs had been approved in the 1940s and 1950s on the basis of evidence that were wholly inadequate by 1962 FDA standards. These drugs had now been incorporated into clinical practice for many years, and so any FDA action on them would be seen as doubly intrusive by physicians. To strengthen their position and reduce their workload, the FDA collaborated with the National Academy of Sciences to evaluate these old drugs.
The 1970s probably marks the peak of the FDA’s power, as a series of court decisions endowed the Administration with the authority to issue rules with “the force of law” and creating “a presumption in favor of agencies that claimed legislative rulemaking authority”. When the FDA does not want to create formal rules, which require an elaborate process, it also uses “nonbinding” guidance documents which are, in reality, quite binding:
Because the Administration has the ultimate say over whether and when a new drug will be marketed, its mere suggestions and intimations induce compliance even where they are not backed by legal authority. The agency’s use of Federal Register policy statements and “guidance documents” (nonbinding statements of policy that are not customarily published in the Federal Register but are published under the auspices of the FDA itself) permits its officials to avoid the more costly and elaborate process of formal rulemaking, while still gaining acquiescence with its regulatory wishes.
With its arsenal of new authorities and the powers that flowed from them, the Administration began in the 1960s and 1970s to exercise vast sway over the medical marketplace. Familiar over-the-counter remedies and doctor-prescribed pills vanished. The place of the general practitioner in drug development waned to the point of disappearance, as companies could no longer rely upon doctors’ casual observations or observations of patient histories to buttress claims of safety and effectiveness.
Though there were occasional media critiques of the FDA in the late 1960s, the 1970s and 1980s were really the beginning of a sustained critique of the FDA from the right. This came from many quarters: business-friendly publications like the Wall Street Journal, prominent economists like Sam Peltzman who were quantitatively assessing regulatory impact on innovation in various industries, and industry organizations. In 1974, the American Enterprise Institute played a key role by launching the AEI Center for Health Policy Research, which brought together pharmacologists, industry officials, and economists. The “drug lag”, coined in 1972, was the time between a drug being introduced in Europe vs the US, and along with the cost-benefit analysis of regulation, was a key critique of the administration. A sign of the success of these critiques was that while top FDA officials publicly rejected the premise of the drug lag, inside the administration, increased attention was paid to the drugs that had already been approved in peer countries.
Even as libertarian-aligned think tanks, academics, and newspapers criticized the FDA for being too cautious, the opposite critique was sustained by consumer-protection groups throughout this period.
No voice more cogently or passionately articulated the case for rigorous drug safety standards than that of physician-activist Sidney Wolfe, and no arrangement better amplified the concerns of Wolfe and his allies than the committee systems of the U.S. House and Senate. Wolfe helped to found the Health Research Group, a subsidiary of Ralph Nader’s Public Citizen, in 1971.
Wolfe had no formal role in the Administration, but by careful use of administrative procedures like FOIA requests and citizen petitions, combined with journalist connections, he could push the FDA into action when it was reluctant. The whole section on him is worth excerpting:
Wolfe’s principal weapon was his threat to the Administration’s consumer protection image. The credibility of this threat depended on a set of strategies by which Wolfe and his organization could embarrass the agency, extract data from it, influence the FDA’s decision agenda, or (less commonly) induce courts to force the agency to take a given action.
First, he was adept at using administrative procedures refined in the 1970s, including Freedom of Information Act (FOIA) requests and citizens’ petitions, to pry important drug safety and procedural information out of the agency, or to place contentious and uncomfortable items on the Administration’s agenda. Second, Wolfe exploited the public comment period of the FDA’s advisory committee meetings on drugs, an opportunity that offered a public venue albeit with brief appearances. Third, Wolfe appeared regularly at congressional committee hearings as an invited guest, and his ties to committee chairs and their staff gave him indirect access to committee powers (replete with tools for discovery). In the 1970s and 1980s, Wolfe worked partially in tandem with subcommittee chairmen ranging from Lawrence Fountain, Henry Waxman, and Ted Weiss in the House to Senators Edward Kennedy and Abraham Ribicoff.
Fourth, Wolfe maintained ties to journalists over a period of several decades (Morton Mintz, Christine Russell, Philip Hilts, and others). He used these journalists to publicize actions (such as the taking of surveys of FDA medical officers) that would otherwise not have received much public attention. Finally, Wolfe and his organization shrewdly used lawsuits and the threat of legal action to induce rulemaking and jar the agency into action. The strategies of administrative maneuvering, advisory committee testimony, appearances at congressional hearings, and media access became much more pivotal to Wolfe’s leverage over the FDA after 1979, when a federal judge limited the right of Nader’s group to sue agencies on behalf of the general public.
A clear demonstration of the conservative sentiment of the times was the backlash against the FDA when it attempted to regulate supplements more stringently:
In August 1973, the Administration published fourteen final regulations and five proposed rules that governed the labeling of foods and food supplements.
Led by Wisconsin Senator William Proxmire, Congress in 1976 passed an amendment to the 1938 Act which extended the “generally recognized as safe” (GRAS) exemption for vitamins and minerals to dietary supplements. The “Proxmire Amendment” prevents the Administration from restricting the potency of a vitamin or mineral supplement based on either of two criteria: (1) food misbranding charges or (2) on the premise that the supplement would qualify as a drug if it surpassed the agency’s desired level of potency. For almost two decades, FDA officials largely backed off from rule-making on supplements.
In the late 1990s, the FDA again attempted to regulate supplements and faced a similar legislative rebuke.
Overall, though the FDA faced some setbacks when it attempted to regulate supplements, it survived the conservative turn in the 1980s with its power and reputation mostly intact, an impressive achievement for such a powerful regulatory agency. In some ways, the criticism from the libertarian perspective may have strengthened the FDA’s reputational position:
[I]t would be wrong to conclude that the persistence of criticism and scrutiny has undermined the agency’s reputation and power. It is certainly plausible that criticism has depleted morale, and on occasion publicity and hearings have weakened its leadership.
For those who have paid attention to the increasing polarization of US politics over the last 20 years, this may sound familiar – criticism from your enemies can be a reliable signal to your allies that you’re on their side. In a similar way, pharma and libertarian criticism of the FDA may strengthen its reputational position in the views of consumer-protection groups and allied groups.
AIDS and Cancer
The “drug lag” criticism was a long-lasting and effective critique of the FDA, but Carpenter seems to argue that the most significant reforms of the FDA were really brought about by inter-agency squabbles over cancer drugs and the moral outcry of the HIV epidemic. The interactions of AIDS activists and the FDA are probably more well-known than the turf battle between the National Cancer Institute (NCI) and the FDA, but it appears that the latter may have been more influential.
NCI-supported investigators were developing combination chemotherapies that were very promising, modeled after the lucky discovery of platinum’s anticancer potential by physicist Barnett Rosenberg. From 1975 to 1977 Robert S. K. Young, an FDA medical reviewer, repeatedly took issue with the study protocols of combination chemotherapy trials and halted several trials. A prominent MD Anderson oncologist, Emil Freireich, retaliated by reading out a list of complaints about FDA interference into NCI-funded trials at an important meeting of President Ford’s Cancer panel. Benno Schmidt, the chairman of the panel and a prominent official in Ford’s Administration, agreed with him. Young’s supervisor William Gyarfas stuck by his subordinate.
Young overreached when in a 1977 Advisory Committee he attempted to more aggressively regulate the clinical trials of combination chemotherapy and effectively eliminate dosage variation in chemotherapy without preclinical studies. The Committee voted against his proposal, and this caught the attention of Richard Crout, then-head of the Bureau of Drugs. Crout met with the head of NCI and basically admitted his subordinate had overreached, and they worked on a series of protocols to relax FDA restrictions for terminally ill patients.
While this might have been the end of the bureaucratic conflict, the NCI had decided to escalate:
House Health Subcommittee chairman Paul Grant Rogers (D-FL) released a December 3, 1976 letter from the American Cancer Society calling for full “NCI control over the testing of new anticancer drugs, instead of FDA control” for nonprofit research sponsors. This transfer of power would be accomplished, as ACS representative Nathaniel Polster hoped, by amendments to the National Cancer Act. While NCI officials were largely silent about the ACS proposal, M. D. Anderson’s Freireich was not. He openly called for deep “structural changes” so that the “FDA can never again shut [down cancer research].”
This would be a huge escalation. If the NCI succeeded in wresting control over regulation of a specific disease, it would set a precedent for continued piecemeal diminishment of FDA authority:
And to Administration officials concerned about the maintenance of their authority over clinical trials, the ACS-NCI proposal raised the specter of debilitation by precedent. Once an exception for one category of illness was carved out of the FDA’s power over clinical research, it was feared, demands from representatives of other diseases would soon follow. As if to confirm the FDA’s premonitions, Solomon Garb of the Citizens’ Committee for the Conquest of Cancer seized upon the NCI-FDA dispute and called for ending FDA power over any clinical trial in which patients have “poor prognoses.” Garb’s remarks introduced a different and more formidable voice to the growing chorus of criticism, in part because the Citizens’ Committee was an amalgam of union, scientific, corporate, scientific, and civic leaders…
This proposal didn’t come from a fringe libertarian or anti-government organization but from respected sources. The NCI and the FDA eventually came to agreement:
DeVita and Crout settled on a new procedure whereby “stop orders” for NCI-sponsored trials for terminally ill patients could be issued only by the Bureau of Drugs chief (Crout himself at the time) or the deputy chief (Marion Finkel, at the time). The two groups later agreed to use the nation’s forty comprehensive cancer centers to mediate the surveillance of research protocols. The new arrangement embedded meaningful victories for both sides. For the Institute, the new procedures effectively bypassed Robert Young and, more notably, William Gyarfas, Director of the Oncology Drugs Division. NCI officials and their grantees would now deal more directly with Crout and Finkel, who were more trusted within oncology networks. And the Institute’s détente with the FDA helped it to buttress claims that it was being “dominated”…
The Administration would retain full control over cancer trials. The NCI would now officially acknowledge and defer to the IND regulations, and in so doing it would develop a “Master Plan” of drug development…
By January 1979, the dispute had issued in a document with odd legal status but firm organizational commitments (figure 6.1). An informal procedure for resolving FDA-NCI disputes appears to have been worked out in April 1979. The procedure entailed four steps: (1) first devolving disputes to the lowest managerial level deemed suitable for negotiation—the Associate Director of the Bureau of Drugs (at that time, Finkel) and the Director of the NCI’s Cancer Treatment Division (DeVita), then (2) to negotiations between the Bureau of Drugs head (Crout) and the NCI Director, then (3) to negotiations between the FDA Commissioner and NIH head, and (4) finally, determination by FDA Commissioner himself if none of these previous options produced a resolution. The memorandum bound neither agency legally. It was rather an informal institution founded in a political equilibrium, a mutual wish to avoid the spectacle of open, public conflict among two agencies whose reputations generally benefited from being out of the public eye.
While the NCI and FDA struggle would lead to a durable compromise between the two agencies, the Laetrile saga would come closest to threatening FDA power, and yet ultimately affirm it. From a libertarian perspective it is darkly amusing that the drug that came closest to breaking the FDA’s stranglehold was the charismatic but ultimately useless drug Laetrile.
Laetrile had been developed by an Ernst Krebs (of no relation to the Krebs cycle) who had failed out of medical school and whose father, incidentally, was also a conman physician. At various times its supporters described it as vitamin B17, as a relative of cyanide, and as amygdalin. NCI scientist Dean Burk had developed a molecular model that was supposed to demonstrate Laetrile’s anti-tumor activity and a San Francisco foundation applied to the FDA for an IND for experimentation.
Their IND was ultimately rejected by the FDA, which cited problems with the sponsors and monitors of the trial and its design. The key difference between the FDA’s rejection of Laetrile and its previous policing of quack medicines was the FDA exerting its power on the IND stage. This was a rhetorically powerful difference.
What most bothered many Laetrile supporters and their distant sympathizers was not the absence of Laetrile from the drug marketplace, but the absence of a permit for testing. Appropriating the juridical metaphor of a “fair trial,” they linked a populist ethic of self-medication to issues of justice and to more progressive norms of academic and intellectual freedom, the liberty of research and exploration of ideas. … By pressing the case for a total ban, by publicizing its seizures, and by assisting with state and federal prosecutions of Laetrile distributors, the Administration had resurrected a face that had been nearly invisible since the 1950s: the FDA as police.
Newspapers ran headlines criticizing the FDA for overreach. Organizations for therapeutic freedom sprung up across the country and a bill sponsored by Representative Steve Symms that would repeal the efficacy provisions of the 1962 amendments attracted over 100 sponsors. Several states passed laws legalizing Laetrile. The anti-FDA sentiment was nearly mainstream: Time Magazine, The Wall Street Journal, and the New York Times all ran editorials with some support for Laetrile proponents, or at least criticized the FDA’s overreach.
From the FDA’s perspective, several court cases were going in an unwelcome direction. Lower courts had issued an injunction against seizure of Laetrile, had decided that the FDA had the duty of showing lack of safety, not the sponsor affirmative proof of safety, and that the FDA had not exercised due process in its Laetrile ban. Since the regulatory power of the FDA was inextricably bound up with its flexible ability to issue rules and the affirmative requirement of drug sponsors to show safety and efficacy, these rulings were a threat to the FDA. In recognition of this enormous pressure, the FDA Commissioner did two contradictory things: one, he affirmed his agency’s judgement that Laetrile was ineffective and dangerous; two, he granted an IND to the NCI for Laetrile. In a PR coup for the Laetrile camp, they also testified before Congress to the Health and Scientific Research Subcommittee. The ability of the agency to offer different faces to different audiences is a recurring theme of Carpenter’s, who views it as key to the FDA’s long-term success.
In June 1979, in Rutherford vs United States, The Supreme Court reversed the Tenth Circuit, which had previously ruled that the FDA could not regulate drugs given to terminally ill patients. It was a powerful affirmation of the FDA’s regulatory authority. Though at this point the FDA could have likely dropped the Laetrile IND for any number of reasons, the FDA issued a conditional approval for Laetrile’s IND, which was set to be tested at rigorous NCI-affiliated institutions that the FDA trusted.
The Supreme Court decision, followed by the very public death of actor Steve McQueen, who had pursued a number of alternative medicine therapies including Laetrile after a mesothelioma diagnosis, led to the gradual decline of Laetrile’s political power. The FDA post-Laetrile had its legal power affirmed over every part of medicine: terminally ill patients, cancer patients, whether a given drug was even a legitimate experimental drug, etc.
Like the NCI and FDA power struggle, the AIDS crisis resulted in substantial concessions by the FDA. Unlike the former, the AIDS crisis played out much more publicly, and instead of bureaucratic warfare, the battle was a reputational one. The primary strategy of AIDS activists was to attack the FDA’s good name– instead of a public health agency and “protector of the American consumer” they sought to cast it as a villain who was killing AIDS patients through its slow and inflexible procedures. Until the 1990s AIDS was a slow death sentence, and in the early 1980s it was still poorly understood, with an official announcement by HHS Secretary Margaret Heckler that AIDS was caused by HIV occurring only in 1984. Retroviruses had only been discovered in 1970, and there were no targeted therapies for them until the HIV antiretrovirals.
An important advantage that AIDS activists had was that decades of organizing had left the gay community with many highly effective and experienced community activists. Many of them went on to form important groups: the most prominent of them were Gay Men’s Health Crisis, AIDS Foundation, Project Inform, and ACT-UP. Gay men were also highly concentrated in urban centers and in some places, like San Francisco, had achieved some degree of political power. Nancy Pelosi, a rising star in the Democratic Party, was sympathetic to many gay activist groups and a Congresswoman. All of these resources would eventually be mobilized against the FDA.
A key event was the story of HPA-23 and Rock Hudson. Rock Hudson, a movie star who had been diagnosed with AIDS in 1984, died of AIDS in 1985. Newsweek reported that before his death he had traveled to Paris to receive an experimental HIV treatment, HPA-23, which was being given there, though under poorly controlled conditions and with little good evidence. The FDA had banned even its experimental use in the US because of severe liver toxicity concerns; it then reversed course and allowed testing in 1985, likely due to the Newsweek story. Well-done trials in 1986 in the US later demonstrated severe toxicity and no efficacy, vindicating the FDA’s earlier caution.
The first effective treatment for HIV was azidothymidine (AZT), which was being developed by Wellcome, a reputable drug company that had substantial experience with the FDA. To the FDA’s credit, the AZT path to approval was remarkably quick: the company first started investigating AZT in June 1984 for possible HIV activity in-vitro; notified the FDA in April 1985, submitted an IND in June 1985, the FDA approved it in a week, and the first clinical trial (Phase 1) began in July 1985.
Phase 2 trials which had begun in February 1986 were halted early in September 1986 due to clear signs of treatment success, and AZT was officially submitted to the FDA for approval in December 1986. Eileen Cooper, a rising young star at the FDA, was in charge of reviewing it, and had been reviewing the AZT data for months before the official submission date. Even before the most militant AIDS activists had begun pressuring the FDA, she had been discussing with others on ways to speed and streamline the approval process.
She took two important steps. First, in September 1986 she had released AZT for compassionate use to 4000+ AIDS patients, which likely saved many lives. Second, she sought the support of the FDA’s Advisory Committee on Ineffective Drug Products in a January 1987 meeting, which would symbolically back up the FDA’s decision to approve AZT on the basis of a single prematurely ended clinical trial. This would achieve two contradictory goals: the rapid release of a likely effective drug to suffering patients; and satisfy the consumer-protection and public-health voices that generally urged caution.
Thus, even before much of the publicized anti-FDA activism, the FDA had demonstrated flexibility and speed in approving AZT. However Larry Kramer, a prominent playwright and activist in the gay community, viewed this as grossly inadequate, and penned a 1987 essay in the NYTimes attacking the FDA. Carpenter is skeptical of Kramer’s specific claims:
Kramer’s essay is shot through with inaccuracy and hyperbole. Of the therapies he mentions, only ddC (zalcitabine) emerged as a recognizably and broadly effective treatment for HIV/AIDS in the ensuing two decades—and its development had been accelerated by the Administration at the very time that AIDS activists were expressing strong doubts about it. Furthermore, many who perceived organizational problems at the agency—including journalists at the New York Times but also the George H. W. Bush administration—saw less a malady of bureaucracy and more a deficiency of resources. Like other AIDS activists, moreover, Kramer was equating the FDA with the Reagan administration when in fact much of Reagan’s and his administration’s ignorance of or indifference to AIDS was unrelated to FDA policy or regulations… Yet for all of its shortcomings and simplifications, and indeed because of them, Kramer’s essay was politically effective because it projected a simple, accessible, and forceful threat to the FDA’s reputation. Like much of the portraiture emerging from AIDS activists, it recast the Administration in terms and symbols diametrically opposed to those fashioned by Young, Cooper, and Tabor in the review and approval of AZT. In some ways, the FDA was being cast as a generalized but faceless bureaucracy, as an inefficient, an “intransigent,” “callous,” and inaccessible organization. In other ways, it was the Administration’s very gatekeeping power—over drugs themselves (the NDA process) and over clinical trials (IND approvals)—that was under attack. By serving as a “bottleneck,” a public health agency dedicated to consumer protection was lengthening the “roll-call of death.” Instead of raising genuine and substantive issues regarding clinical trial design with AIDS drugs, the Administration was in Kramer’s depiction imposing classic “red-tape” constraints upon medical research, nitpicking research protocols, shuffling words and sentences.
Beyond criticizing the FDA, local activists and physicians also directly subverted the traditional placebo-controlled trials:
Doctors would lie about their patients’ previous disease status to secure patient enrollment in a trial. Activist physicians and health-care workers would examine a pill to expose its placebo content. Once a placebo was identified, activists and patients would substitute the genuine treatment for the research subject, using supplies procured underground.
In California activist Martin Delaney ran an unofficial trial with “Compound Q”, distributing it to patients that had failed to respond to other drugs and bypassing the FDA entirely. Part of the project’s explicit aim was to push the FDA harder against its traditional approach to drug development.
Activists like Delaney and Kramer also personalized their criticism of the FDA by singling out Ellen Cooper, the medical reviewer for AZT (and the FDA’s unofficial point-person for HIV drugs), attacking her in the New York Times and in ACT-UP manuals. The peak of activist militancy was probably the October 1988 Rockville demonstration against the FDA. More than 1000 activists gathered in front of the FDA and displayed a banner that read, “Federal Death Administration”. Of note, these protests occurred after the AZT approval. Media coverage followed the protest, and the FDA responded by hosting a press release which effectively restated the new procedures that Ellen Cooper had developed for AZT. This announcement made newspaper headlines, though activists viewed it as a publicity stunt, not as a substantive change.
The most substantive change was probably the “Subpart E” regulation, which would allow for the possibility of a single expanded Phase 2 Trial sufficing to prove safety and efficacy for certain debilitating diseases. Again, this formalized the process that AZT had undergone, and this and other changes had actually been foreshadowed by the FDA’s behavior with cancer therapeutics. This is a recurring observation by Carpenter – phase shifts in FDA behavior are usually preceded by more subtle but similar behavior years or decades before. AZT had sped through the FDA approval process faster than any drug before – but it followed the template of cancer drugs before it. Continuity, not revolution, is the running theme of the FDA’s history.
ACT-UP was very strategic: some elements of conservative politics had long wished for a repeal of the 1962 Kefauver-Harris Amendments, but ACT-UP made sure to maintain “organizational and rhetorical distance” from those groups, which likely preserved their credibility with other forces. ACT-UP overplayed their hand in 1991. With the looming threat of another protest, ACT-UP demanded a 30-day review of DDI, which was undergoing the reformed approval process that incorporated surrogate endpoints (CD4 counts) and a historical controls of the patient’s previous history. Though they received a letter from the FDA Commissioner in response, the approval took more than 30 days, and so ACT-UP staged another protest. It was a dud in comparison to the 1988 protest, with many fewer protesters and little media attention.
This was likely because the FDA had neutralized much of the group’s criticisms by moving quite quickly with approvals and liberally allowing treatment INDs (which allow “compassionate use” of drugs outside of trial settings). The FDA had also begun reaching out to less militant AIDS groups and invited activists into Advisory Committee meetings. In a move reminiscent of how the FDA recruited prestigious academics in the 1950s and 1960s, the FDA waved the “carrot” of being a (partial) insider to neutralize opposition. Another factor may have been a changing media narrative that argued (apparently without evidence) that Reagan-era cuts were the reason for FDA slowness, which exonerated the FDA of blame.
The unofficial buyer’s clubs popularized in film were treated deferentially by the FDA in comparison to Laetrile sellers decades before. It tread lightly, likely in fear of invoking the “FDA as policeman” image.
Something inconvenient for the libertarian and AIDS activist critique of the FDA was the “medical reversal” on the DDC/DDI/AZT combination therapy. After DDC and DDI were approved in 1992 on the basis of surrogate endpoints showing boosted T-cell counts, follow-up studies failed to show benefit relative to AZT alone, and the combination was more toxic than AZT alone. This led to an internal debate in the AIDS-treatment-activist sphere. Here is one account, from Treatment Action Group, an organization that successfully pushed for stricter AIDS drug standards instead of continued loosening of regulatory standards. For a book-length treatment on the loosening of regulatory standards in the cancer world, and the consequences that followed, read “Malignant” by Vinay Prasad.
A less visible but likely more important event in FDA history was the Lasagna Committee, which was announced in 1988, and gathered many of the FDA’s critics.
Rhetorically, Administration personnel claimed from the late 1980s onward (with great plausibility) that drug review delays were primarily a matter of staffing. Internally, FDA leaders looked at the oncology drug division as an exemplar of what quick NDA review could look like, as many of its reviews were completed in less than a year. Oncology drug reviewers were quietly transferred to the anti-viral division, and new medical reviewers were hired. In the late 1980s and early 1990s, drug review times for new molecular entities – perhaps the single most important quantitative measure on which the Administration was judged in pharmaceutical politics – began to decline appreciably
In 1992 FDA Commissioner David Kessler, patient advocates, pharma industry representatives, congressional committee chairs, and President Bush’s staff agreed to the Prescription Drug User Fee Act, which informally bound the FDA to review time goals and effectively taxed drug companies per drug application. To the degree that FDA staffing was the rate-limiting step on drug approval, this would speed approval, but critics said it eroded the FDA’s willingness to push back against shoddy drugs. I am not sure how to evaluate that claim, but I don’t understand the mechanistic claim – the user fees tied the FDA to a review timeline, but it didn’t mandate approval or penalize rejection. Carpenter writes that it might have eroded FDA culture by tying it financially to pharma, but this seems somewhat implausible, because it did not tie funding to any drug in particular, or any particular target of “X% of drugs must be approved”.
FDA in the 2000s
Briefly, the FDA in the 2000s has been described as becoming increasingly lax on drug approval, particularly in cancer. This is covered in-depth in Malignant by Vinay Prasad. The Vioxx scandal, in which Merck was viewed as having concealed the fact that patients taking Vioxx were experiencing higher rates of cardiovascular complications, and in which the FDA seemed to take quite a long time to remove Vioxx from the market, also damaged the FDA’s reputation. In 2004 the FDA was widely viewed as having ignored science for political reasons when it kept Plan B (emergency contraception) prescription-only instead of making it OTC. Here is one perspective on that.
Scott Gottlieb, who had been a high-level FDA official before being Commissioner but also worked for the AEI (the leading think tank criticizing the FDA), had been anticipated to be a highly de-regulatory FDA Commissioner. I can’t find sources for this claim, but my impression is that Gottlieb has generally acquired a good bipartisan reputation and did not oversee a radical shift in FDA direction. He also won praise for moving somewhat aggressively against flavored vapes, which are widely viewed (rightly or wrongly) as a growing public health threat.
Approval is Final
Because approval of a drug is so symbolically powerful, and effectively stakes the FDA’s reputation to a given drug, the FDA only does so very deliberately. It is a social technology that reduces the immense complexity of an IND application (consisting of clinical trials, endless manufacturing and absorption data, etc.) into a binary YES/NO that physicians and nurses can rely upon. Reversing a decision is reputationally damaging, and the FDA has occasionally faced criticism from consumer-protection groups and even internal FDA employees that it is too unwilling to withdraw unsafe drugs from the market. This is problematic when drugs are approved based on surrogate endpoints instead of clinical endpoints, or when safety problems emerge after approval, as with Vioxx.
Carpenter comments on this:
It is interesting in light of these conflicts that, in the wake of the Vioxx tragedy of October 2004, higher FDA officials (including many long-term careerists) engaged in an organizationally motivated embrace of the status quo by defending randomized controlled trials and by disparaging pharmacoepidemiology. For different reasons, Deputy Commissioner Scott Gottlieb, CDER officials Sandra Kweder, Robert Temple, and others did not want to cede more control of the pharmaceutical market to David Graham and his colleagues at ODS. Yet it was also an extension of the familiar, an area where the agency had already developed capacity. Clinical trials have advantages when they are randomized and placebo-controlled. They also have drawbacks. Often tests are done on homogeneous patient populations, among patients who differ in many ways from the patients who will utilize the drugs in clinical situations. Clinical trials usually have an endpoint, and can often be too brief to allow analysts to detect whether the drug is inducing adverse events, particularly for toxicity, hepatotoxicity (or liver damage), and cardiovascular outcomes.
On Pressuring the FDA through Reputation
The FDA is responsive to both reputational and political pressure. The former is best thought of as arguing with the FDA on its own ground, which can be done from multiple perspectives. Patient advocacy groups can push the FDA to approve cancer drugs on less evidence; “thought-leader” physicians can sing the praises of an innovative drug and call the FDA slow; FDA whistleblowers can testify before Congress that the FDA is too deferential to pharma; consumer-protection groups can call the FDA’s approval based on a surrogate endpoint “reckless”. All these approaches seek to push the FDA in one direction or another, but fundamentally accept the legitimacy of the FDA and especially in the case of those pushing for more regulatory caution, hearken back to some idealized version of the FDA as a rhetorical device. In the early 2000’s, as the FDA was perceived to have relaxed its regulatory standards, especially on cancer, this occurs more often, with long-time FDA critics like Sydney Wolfe unfavorably compared the current FDA to the old FDA.
A recent example of reputational pressure was Eric Topol’s open letter to the FDA in October 2020 that criticized the emergency approvals of convalescent plasma, hydroxychloroquine, and remdemisvir, and pressured the FDA Commissioner to delay approval of a Covid-19 vaccine. Though many have criticized his actions, its method is illustrative: Topol, who has immense reputational power in academic medicine through decades of leading large clinical trials, publicly attacking Merck during the Vioxx scandal, and having critiqued the FDA in the past for its lack of action on Vioxx, was well-positioned to push the FDA to be more cautious. In addition, the emergency approvals Topol criticized (with the possible exception of Remdemisvir, and maybe Convalescent Plasma if you play with subgroup analysis….) seemed to have been regulatory bets that did not pan out, which left the FDA in a weak position. The politicization of hydroxychloroquine in particular made Topol’s arguments extremely appealing among the reputational audience (large medical journals, elite media, etc.) that the FDA caters to, which all dislike Trump. The combination of a weakened FDA and a strong attacker were the likely reasons for Topol’s success (and in the view of Alex Tabarrok and many others, the rest of the US’s disaster, since any delay in vaccine approvals likely cost many lives). Here an in-depth read on this.
The pro-regulatory counter to the previous paragraph is that vaccine approval was only an obviously good idea in retrospect and that vaccine hesitancy would rise with a rushed process. I think both of those claims are wrong, and I think Ezra Klein argues this well in a recent piece.
Political pressure takes the form of more direct action: Congressional committees can ask FDA officials to justify their actions and have public hearings that embarrass an agency that prefers less public attention. They can threaten FDA funding and if they’re playing hardball, threaten legislative action that directly alters FDA authority.
The challenges to FDA practice which resulted in sustained reform are those that combine both approaches, along with policy solutions that can be proposed at the right political moment. Conservative think tanks had long wished to tie some FDA funding to drug approvals and hold the FDA to a deadline and when conservatives made sustained and substantial gains in the 1980s and 1990s, the FDA, first informally and then through legislative change, moved in that direction.
Sustained media attention also seems to be important for pushing the FDA, but is not essential. The NCI-FDA disputes were not as high-profile as the 1980s AIDS activism but effected reform that was just as important.
An important but vague “audience” that the FDA defers to is the medical community as a whole. This might be thought of as the “elite consensus” in medicine. By directly incorporating respected medical scientists and doctors onto Advisory Committees, the FDA accedes to this audience but also partially neutralizes it. Pharmaceutical companies seek to use this in their favor as well by recruiting big-name academic stars to head clinical trials or research divisions and thereby “borrow” some of their reputation. A sustained critique of the FDA from these directions would also likely be a powerful pressure. For instance, if Advisory Committees repeatedly disagreed with the FDA in one direction, they could likely shame it into changing course.
Theoretically this might be strengthened if a sitting Congressman/woman then called a hearing to directly ask FDA officials about controversial decisions or if sympathetic media ran pieces highlighting this discrepancy. This would be a direct reputational attack on the FDA and a veiled political threat because it would raise the specter of legislative reform of the FDA with enough political attention.
Regulatory Caution is Often Proven Right
As disappointing and non-contrarian as it is to agree with a large, slow-moving government bureaucracy, my impressionistic summary of Reputation and Power along with background knowledge from Ending Medical Reversal and Malignant is that the FDA has usually been proven right in its caution. Approvals based on surrogate endpoints sometimes work, but in Malignant Vinay Prasad makes a strong argument that this often doesn’t speed approvals and that a substantial number of drugs approved on surrogate endpoints are never properly followed up on. Low regulatory standards in cancer drugs have led to a proliferation of low-value treatments approved on the basis of surrogate endpoints that don’t predict clinical (a.k.a. useful) endpoints and that may not actually provide any benefit outside of carefully selected clinical-trial participants. (Editorial Note: For a counterargument, see this post and linked SSRN article on “Type II” errors at the FDA).
A full argument that strict regulation is required for medical innovation is too long for this paper, but Ending Medical Reversal is an excellent argument along these lines. Here is a summary of it. I fully agree with Cowen and Tabarrok that the FDA was far too slow during COVID-19, but I think the libertarian critique of the FDA (usually) goes too far.
The FDA is More Powerful Than You Think
– Apart from holding pre-market approval power over a drug, the FDA also intensely regulates drug experimentation in the first place. It also regulates drug labeling. By virtue of regulating a drug’s intended use (which has substantial effects on insurance coverage) it also informally regulates medical practice in general. And in a decentralized fashion, by being able to disqualify Institutional Review Boards (IRBs), it also regulates clinical research on a fine-grained level.
This IRB-mediated power means the FDA can effectively ban individual physicians or entire institutions from research.
To the degree that overly-cautious IRB’s (who are in turn fearful of FDA attention) constrained Human Challenge Trials, this seems like an under-appreciated cost of the FDA and one that has not previously faced any sustained challenge. The lack of a constituency that is visibly harmed by overly cautious IRBs makes developing political pressure on this more challenging, but this seems valuable.
The FDA and COVID-19 Vaccines
As a thought exercise, it is worth considering what a successful attack against Topol on the vaccine delay question might have entailed. Academic stars in medicine that argued for faster vaccine approval, in contradiction to Topol, would have been rhetorically effective. A less politically polarized COVID-19 response in general would have neutralized the specific anti-Trump claims that Topol made.
Not being in an election year and so proximal to November 2 would have removed the incentive for anti-Trump individuals and institutions to view an early vaccine approval as a Trump victory and likely alleviated some concerns that the vaccines were being “rushed through.” Elite media that favored faster approval and that continually raised vaccine approval salience would not have so favorably amplified Topol’s open letter.
There were some prestigious names contra Topol on vaccines like Walid Gellad but few or none with Topol’s star-power and connections. The prominent economists who pushed for faster approval were all, fairly or not, associated with a deregulatory perspective, which likely made their arguments less credible to the FDA. If the FDA had not burned their credibility on hydroxychloroquine early on, they would have been less vulnerable to Topol’s reputational attack. The somewhat Rationalist-aligned academics and institutions that consistently pushed for vaccine approval and human challenge trials have no cachet in the medical community, and so cannot effectively engage in this reputational battle as insiders.
Willy Chertman is a 4th-year medical student at University of Miami who studied biology and political science as an undergraduate at the University of Miami. When not in school, he reads and tweets about medical research and health policy at @willyintheworld and on substack at https://willyreads.substack.com.
Dan Elton, Ph. D., is Director of Scholarship for the U.S. Transhumanist Party. You can find him on Twitter at @moreisdifferent, where he accepts direct messages. If you like his content, check out his website and subscribe to his newsletter on Substack.