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“The FDA Almost Killed Me” – A True Story

“The FDA Almost Killed Me” – A True Story

Daniel C. Elton, Ph.D.


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.

 

John at a February 14th protest outside the FDA, organized in conjunction with the DC Transhumanist Party, where we protested the FDA’s failure to approve the AstraZeneca vaccine while millions of doses languished in a factory in Baltimore and thousands died daily from COVID-19.

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.

To the FDA: Approve Leronlimab Now for Critically Ill COVID-19 Patients – Article by Dan Elton

To the FDA: Approve Leronlimab Now for Critically Ill COVID-19 Patients – Article by Dan Elton

Daniel C. Elton, Ph.D.


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.

CytoDyn initiated two Phase IIb/Phase III clinical trials in mid-April 2020 to study mild-to-moderate COVID-19 and severe or critical COVID-19. To their credit in 2020 the FDA did provide about 60 emergency IND (eIND) authorizations that allowed patients to receive Leronlimab. However the company had to defer seeking eIND authorizations to accelerate the pace of enrollment in their clinical trials.

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.

Medical educator Dr. Mobeen Syed has said this:

“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. 

A Summary of the USTP’s FDA Reform Panel – Article by Dan Elton

A Summary of the USTP’s FDA Reform Panel – Article by Dan Elton

Daniel C. Elton, Ph.D.


The U.S. Transhumanist Party livestreams special Enlightenment Salon events every Sunday at 4 p.m. on YouTube. Two weeks ago, on April 4. 2021, the USTP organized a special Enlightenment Salon panel event on FDA reform. In addition to myself, the following people participated on the panel, which was moderated by USTP Chairman Gennady Stolyarov II:

  • Prof. Alex Tabarrok, Bartley J. Madden Chair in Economics, George Mason University
  • Dr. Max More, President Emeritus, Alcor Life Extension Foundation
  • Jim O’Neill, CEO, SENS Research Foundation
  • Dr. Edward Hudgins, Founder, Human Achievement Alliance
  • Prof. Garett Jones, Mercatus Center, George Mason University
  • Willy Chertman, Medical Student and Blogger

The entire panel was probably the most information-dense event the USTP has done. I kicked things off by giving a short presentation, which I managed to blaze through in 15 minutes. (The slides can be viewed here.) The presentation set the stage for a very informative and productive discussion.

My only regret was that we didn’t have any women on the panel. However, during the course of researching my presentation, I found out about the work of Dr. Mary J. Ruwart. Dr. Ruwart estimated the number of people who die every year from FDA delays to be around 150,000 per year in her book Death by RegulationSo, I am happy to announce that Sunday, April 25th, from 4 – 6 p.m. Eastern Time, 1-3 p.m. Pacific Time, the USTP will be doing a special Virtual Enlightenment Salon with her.

Here is the recording of the FDA reform event. At 00:05:00 my presentation kicks off:

I’ve written a summary of the major points each of the panelists (and two others) made during approximately the first hour of the session. These are heavily paraphrased. (Instead of providing direct quotes, I shortened what was said in most cases while maintaining the core meaning of what was communicated.) I have put my own comments in italics.

Prof. Alex Tabarrok:

  • The FDA can approve a bad drug (Type I) or fail to approve a good drug (Type II). If they approve a bad drug, people who were affected will go on Oprah, and there will be huge backlash. If they don’t approve a good drug, there is no backlash. The invisible graveyard is a statistical reality, but it’s hard to see. This can be seen easily by asking people to name a time when the FDA approved a bad drug (or a drug with unexpected side effects). Lots of people can think of something. Many point to Thalidomide, which is actually a drug that was approved in Europe and caused birth defects. Thalidomide, incidentally, has many important applications but was not approved by the FDA until 1998.
  • When you have a Type I error, you learn something — we learn about the harms of a drug, and we change our behavior. With a Type II error we never learn anything. We can’t see the consequences of a failure to approve, and even worse, we can’t see the many drugs that never even made it to FDA-mandated trials in the first place because they were deemed too risky to justify the cost.
  • Reciprocity is a sensible reform that is one of the most feasible.
  • The FDA likes to think they are the “gold standard” for drug approval. Yet, people in other countries don’t worry about whether drugs are FDA-approved. For food safety we already have reciprocity with Canada.
  • The FDA has been working for 40 years on new standards for approving sunscreens. So Europeans have much more advanced sunscreen than the US.
  • If aspirin were invented today, it probably wouldn’t be approved.
  • One thing U.S. policymakers have done already, which is probably the smartest thing they have done in a while, is PEDUFA (Prescription Drug User Fee Act). The drug developers pay an extra tax as long as approvals are sped up. The FDA was happy because they got to expand their bureaucracy, and drug companies were happy because they could get to market faster.
  • In the EU the EMA “farms out” reviews to private companies. (So the EMA is more like “an approver of approvers”). Private companies can do a good job – for instance, look at Underwriters Laboratories in the realm of electrical devices. (If you look at many electrical devices, you may see a “UL” seal.) Many major companies like Amazon won’t carry devices unless they are UL-approved.
  • There is no formal process whereby where if a disease is more deadly, then the standards should be lowered to speed approvals. For instance, for pancreatic cancer, which often kills within 6 months, the standards should be lower (and more risk should be tolerated), since patients have less to lose. For something like acne treatment, the standards can be much higher. The FDA recognizes this to some extent in practice, but it’s totally informal – technically it’s not supposed to happen. However they could do this formally and adjust the required statistical significance levels. They could use Bayesian statistical techniques as well.
  • There’s no route to approve a drug for anti-aging. If a company wants to do R&D on anti-aging therapeutics, there is not a clear route for approval.

Dr. Max More:

  • We should keep in mind full abolition of the agency as a long-term goal. [My response: I am against full abolition, but I agree with this. Everyone should at least consider abolition, and if they are against it, explain in some detail why the government needs to be involved versus using private-sector companies and tort law. Going back to first principles regarding the role of government is healthy, especially in places like Washington, D.C., where government institutions are taken for granted and not questioned as much as they could be.]
  • We should keep in mind Milton Friedman’s statement that expecting the FDA to behave differently than it does is like expecting a cat to bark (Note: He said this in a 1973 Newsweek column.) We can’t just say, “We want the FDA to do X”; we have to make sure incentives are in place so people actually do the things we want. Legal mandates can help, but it’s easy for people to skirt around them if the proper incentives don’t exist.
  • We are facing an enormous cultural barrier when it comes to reforming the FDA and CDC. We don’t have a proactionary culture anymore; we have a very fear-based culture, and a simple solution to it does not exist. However, we have a good opportunity right now just like the AIDS activists had a good opportunity in the 1980s.
  • The proactionary principle is a “grab-bag” of tools based on a certain value perspective which basically says that progress is fundamentally good. We aren’t omniscient, so we have to learn by doing. As Alex Tabarrok said, you can’t really learn things without making mistakes. It’s impossible to make progress, like some rationalists believed, by just sitting in chairs and thinking carefully. We have to become empirical. You can “look before leaping”, but you also have “look while leaping” and adjust how you land, to use a crude metaphor.
  • Cost-benefit analysis is a basic approach that is used in many organizations but doesn’t seem to be used as much in government agencies. It shouldn’t be controversial. Mandating cost-benefit analyses would be a step towards using ideas from the proactionary principle.
  • We should institutionalize the Devil’s Advocate procedure and institutionalize respectful disagreement. Instead of having the most powerful person in the room getting what they want railroaded through, we should require debate and motivate decision makers to ponder both sides. Other approaches could help, such as reference class forecasting, structured argumentation techniques, auditing procedures, and auditing review panels.
  • Reciprocity seems like a no-brainer that is relatively easy to achieve, and would greatly reduce costs.
  • Besides getting out these great ideas, we need to figure out how to get people to follow those ideas. Laws can help, but people can choose to not follow them. How do we put “bite” into laws? I think an annual audit on the FDA’s decision making would be a good idea. Importantly, the auditor’s report should be made public. The auditors should come from a variety of institutions, for instance a variety of think tanks from different sides of the political spectrum.

Gennady Stolyarov II:

  • The USTP agrees that abolishing the FDA should not be out of the question. In our Platform, Section CXVIII states:

Section CXVIII [Adopted by a vote of the members during March 25-28, 2020]: Given the extreme delays, bottlenecks, and expenses created by the mandatory approval processes on the Food and Drug Administration (FDA), the United States Transhumanist Party supports abolishing the FDA and replacing it with a Radical Life Extension Administration (RLEA), whose mandate would be to prioritize the rapid development of potential disease cures, treatments, and vaccines – including any possible cures or vaccines for COVID-19, as well as treatments to mitigate and reverse the disease of biological aging, the major risk factor for COVID-19. The RLEA would allow the marketing and collection of patient data on any potential cure, treatment, or vaccine which has passed affordable safety testing at a reasonably acceptable threshold.

Jim O’Neil:

  • I’ve had the pleasure of working with the FDA quite a bit, and in my experience most of the people there are very smart, and they actually believe in approving things, contrary to what it may look like from the outside.
  • The problem is that incentives matter, and the FDA is a central point of failure.
  • When someone has a severe side effect from a drug, the FDA Commissioner gets hauled in front of several Congressional Committees and is interrogated. When someone dies because something wasn’t approved, there’s total silence in Washington. We should blame Congress, not the FDA, for that incentive being in place.
  • Individuals respond to the institutional incentives, but they also have personal incentives. A lot of people want to be the next whistle-blower who finds the next thalidomide and calls a halt to it. Both of these are pretty severe and would affect even the most principled person in ways they couldn’t even detect.
  • I disagree with Alex that “FDA not recognizing aging as a disease is a major problem.” In order for the FDA to reasonably measure success of any therapy, there must be metrics and biomarkers. It’s not the FDA’s job to do all the scientific work to develop biomarkers for aging. That’s the job of the science community and the NIH to some extent. There are epigenetic clocks, but we need a lot more work on those. Those clocks can then be run through the FDA’s biomarker approval program.
  • The second thing I disagree with is Dan’s idea of making the FDA independent from HHS. I think that would make things worse.
  • My favorite approval ideas fall under the category of “progressive approval” or what Dan calls “tiered approval”. Contrary to what the FDA often thinks, doctors and patients are capable of processing information and making risk-benefit calculations using their knowledge about the specific situation they are in. The more information provided and the more transparency, the better. The FDA should focus back on their original mission of safety and purity. I absolutely support repealing the 1962 Kefauver-Harris Amendments.

Prof. Garett Jones:

  • I come at this as an macroeconomist. I think we can learn from what economists have learned about central banks around the world. The FDA should be as independent of congress and the president as central banks are or as judges are.
  • The Federal Reserve is a panel. That’s how we run the SEC, the FEC, the Federal Reserve, and the Supreme Court. There seems to be some magic to having a panel — it’s probably giving us a bit of the Law of Large Numbers in decision-making.
  • Another aspect of these panels is they have long terms. They are probably going to be serving under a few different Presidents. As I say in my book 10% Less Democracy, “short terms make short-term thinking”. Political independence can lead to decision-making independence, and we have evidence that’s a good thing.
  • Discussions in institutional reform have “high marginal product” right now, as an economist would say. Congress moves slowly, but Congresspersons tend to look for big opportunities for reform a couple years after a crisis. The Federal Reserve was established in 1913 but was born out of the Panic of 1907. Six years was how long it took between a huge financial crisis and Congress getting around to making some reforms. We saw something similar after the global financial crisis – it took about 2-3 years. The ideas that people are discussing now will be part of the information ecology of the next few years in Washington, D.C.
  • These ideas of long terms, independence, and panels are a good path for decision making. I am an unreformed Tabarrokian, so I agree with everything Alex Tabarrok has written about FDA reform (chuckle). What I want to push here is institutional reforms that seem to work in a wide variety of settings. A little more financial and legal independence will lead to a situation where Congress is less of a source of fear for FDA officials.
  • A lot of people on social media have told me that the President is in charge of the FDA. These people have never actually talked to anyone who worked on Capitol Hill — agencies live in fear of their Congressional overlords. They live in fear of the Senate Majority Leader and the Speaker of the House, who have power over their budgets. They also know that if they make a mistake, they can be hauled up before Congress and fired ignominiously.
  • There is a risk that a more independent agency may misuse its freedom. However, in practice, if we look at the data, independent agencies with long terms have high benefits and low costs.
  • It’s fun to complain about the FDA, but it’s wise to complain about Congress.

Dr. Ed Hudgins

  • We’ve been talking about how FDA regulators are always in fear of Congress. What I want to see are FDA regulators in fear of patients who want to get access to medications at less cost and quicker.
  • One of the most egregious examples of defining efficacy was when the FDA decided that 23andme could not offer advice on whether someone was prone to breast cancer. Essentially they thought that women were too stupid to understand the information and would rush out to get a double mastectomy without getting a second opinion.
  • Another example is in 1989-1990 when they wanted to classify a urine sample cup as a “class A medical device”, in the same category as a heart valve.
  • In April 2019, the FDA stated that it wants to regulate artificial intelligence as a medical device.
  • There are many consultants now, whose entire job is to help companies get through the FDA bureaucracy. So there’s a whole industry now just to help people get through the FDA — and that’s part of the problem now, too.
  • The “Free to Choose Medicine” idea should be at the top. Something like this was created around 1992 during AIDS crisis. Congress stepped in and put pressure on the FDA to do something. What they did was create a parallel track where sufferers could access a particular medication for AIDS during the three years it was being tested. 12,000 people took advantage of that, so there are 12,000 people who are not in the invisible graveyard as a result.
  • The idea of a parallel track has been put forward by Bart Madden. Data from people on that track would be put into a public real-world database.
  • There are alternatives to randomized controlled trials (RCTs). If observational data is put into a public database, then doctors can look at that data and make informed recommendations. Drugs would be able to fail quicker, too.
  • In the case of AIDS, it was patient groups that besieged the FDA’s buildings. In light of COVID-19, and people seeing that the system isn’t working for them, we have an opportunity now to push for change.
  • There’s momentum for FDA reform building off of the right-to-try legislation that has been passed in many states. In Texas and North Carolina there are strong pushes to broaden right-to-try to people like patients with Alzheimer’s Disease.

Willy Chertman

  • The AIDS-FDA story is a little more nuanced than was described by Ed Hudgins and Max More. We all know about the militant groups like ACT-UP which pressured the FDA in the 1980s. However in the mid-1990s there developed a few counter-movements against that. One group was called Treatment Action Group, and they pressured the FDA to move slower because they felt the FDA was approving HIV/AIDS treatments that didn’t actually have much benefit.
  • A good book is Malignant by Vinay Prasad. It documents how, over the last twenty years or so, the FDA has lowered the standards for many cancer drugs. They often are approving drugs based on surrogate endpoints and biomarkers, and then the drugs don’t go through follow-up studies to show if they have actual clinical benefit. So there has been a natural experiment where we tried to lower the standards for cancer drugs, and it doesn’t seem to have worked very well. Of course, I’m not an economist, so there might be a way of adding up the costs and benefits where the marginal benefits have outweighed the costs.
  • The FDA had many failures during COVID-19. The first big one was with testing, both with the FDA and the CDC. Others were the decision to delay the approval of Pfizer and Moderna vaccines (by about 4-6 weeks), and the decision not to approve the AstraZeneca vaccine, which hasn’t had any transparency. Finally, there was a complete lack of experimentation with human challenge trials. What all of these share is there has been very little transparency and not much good reporting on these issues. There have not been any thorough investigations from journalists, and we don’t really know what’s going on. Before attempting reform we need to first go and find out what went wrong during COVID-19. We need a non-partisan investigation of all of these issues. We need to utilize Freedom of Information Act requests. We need to find out how Trump was involved, why approvals took the amount of time they did, etc.

Dr. Natasha Vita-More

  • Cosmetics does not need FDA approval pre-marketing. It only needs post-market approval if the company says something in their marketing materials that could be misleading. There are many doctors pushing crack cosmetic treatments and behaving in a very “loosey goose-y”. I have a hard time understanding how they get away with these things, unless there are big-monied interests behind them.
  • We all know about Theranos. In 2015 they got FDA approval for one of their tests. There’s clearly an imbalance here – many life-saving treatments struggle to get approval, but a company which is completely fraudulent like Theranos was able to get approval. [My response: This is a great point! Theranos did receive approval, but only for their Herpes test. If I recall correctly, this test was done with conventional laboratory equipment rather then their special “minilab” device, a fact which Theranos hid from investors. Theranos also utilized a loophole to sell tests without FDA approval.]

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. 

A Summary of Daniel P. Carpenter’s “Reputation and Power” – A Titanic Book on the History of the FDA

A Summary of Daniel P. Carpenter’s “Reputation and Power” – A Titanic Book on the History of the FDA

Willy Chertman
Edited by Dan Elton


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 book cover


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.

Origins

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

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.

1970s

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.

AIDS

Part of the 1988 ACT-UP protest for greater access to HIV-AIDS drugs that was held outside the FDA. Source: FDA/ Creative Commons.

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. 

1992

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. 

Lessons Learned

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

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.

To Maryland Governor Larry Hogan: Liberate Vaccine Doses from the FDA! – Article by Dan Elton and Edward Hudgins

To Maryland Governor Larry Hogan: Liberate Vaccine Doses from the FDA! – Article by Dan Elton and Edward Hudgins

Daniel C. Elton, Ph.D.
Edward Hudgins, Ph.D.


Note from the Authors: This was an op-ed we wrote in the first week of February 2021. Unfortunately, no newspaper wanted to publish it. We first submitted it to the Baltimore Sun, which promptly turned it down. We then submitted it to the Capitol Gazette, The Washington Times, and The Washington Examiner but never heard back from any of them. Sadly, this op-ed is just as relevant today as when we first wrote it almost two months ago. Since it was written, the evidence for the safety and efficacy of the AstraZeneca vaccine has only gotten stronger. An observational study of millions of people in Scotland published in early March found that a single dose of the AstraZeneca vaccine offers ~94% protection against hospitalization, outperforming Pfizer’s vaccine, which offered ~85% protection. Last week AstraZeneca reached an endpoint in the Phase III trial in the United States that the FDA requested, finding an efficacy of 76%, very similar to the previous Phase III trial result (70%). Despite all this, there has been no action from the FDA,and millions of AstraZeneca doses remain languishing in factories in Baltimore, Maryland and West Chester, Ohio as thousands of American taxpayers that are desperate for them die every day.

~ Daniel C. Elton and Edward Hudgins, March 31, 2021


If Maryland Governor Larry Hogan acts immediately and decisively, he can save thousands of Marylanders from suffering and death from COVID-19. A facility in Baltimore produces the very effective AstraZeneca vaccine and has stockpiled millions of doses. But the U.S. Food and Drug Administration, headquartered in suburban Maryland, which must certify all vaccines and medical treatments before patients can reap their benefits, is holding those doses hostage to its antiquated, bureaucratic red tape. Hogan should act now to liberate the vaccine to save the lives of Marylanders.

Over a year into the pandemic, over 8,200 Marylanders have died, and some 410,000 have suffered from COVID-19. Marylanders have suffered from a chronic shortage of the FDA-approved Pfizer and Moderna vaccines. AstraZeneca is approved in the E.U. and 19 other countries. So as our morgues fill up, what’s the FDA’s excuse for delay?

The AstraZeneca vaccine has passed Phase I and Phase II efficacy trials, which were published in the medical journal The Lancet in July and November 2020. A Phase III peer-reviewed study that was conducted in three other countries indicates the vaccine has an efficacy of 70 percent, ranging from 62 percent to 90 percent with different dosages. Most importantly, the vaccine showed a 100-percent efficacy at preventing COVID-19 hospitalizations and deaths. The AstraZeneca vaccine was also the first shown in a scientific study to reduce transmission. And unlike the two already-approved vaccines, it requires only regular rather than ultra-cold refrigeration. It has been given to over one million people in the U.K. without safety issues detected, yet FDA has requested that AstraZeneca redo most of their Phase III trials using patients from the U.S.

Some media outlets have reported that AstraZeneca’s vaccine “may not work” in the elderly. Unfortunately, AstraZeneca’s Phase III data published so far does not allow for efficacy to be determined for those older than 65. However, Phase I & II trials showed a similar immune response after the second dose across all age groups, including those over 65, so there are good reasons to believe the efficacy should be similar for the elderly. Even if the efficacy is much lower, because the elderly are at such high risk it still makes sense to give them the vaccine in order to save lives. This was shown clearly by Oxford bioethicists Jonathan Pugh and Julian Savulescu, who ran some numbers to show the grave consequences of denying the vaccine to the elderly. It is also true that recent results show the AstraZeneca vaccine is not very effective against the South African variant at preventing mild forms of COVID-19. However, the current study only addressed mild illness and AstraZeneca’s vaccine gives a similar immune response to Pfizer’s vaccine, which has been shown to protect strongly against hospitalization from the South African variant. The World Health Organization recently released guidance recommending the rollout of the vaccine not be halted due to this finding and that the vaccine be given to all age groups. 

The U.S. government has already contracted for 300 million doses of the vaccine, costing taxpayers over $1 billion. Yet with thousands dying daily and many more suffering from COVID-19 across the county, the FDA projects they won’t approve the vaccine until late April.  

Since FDA won’t certify the AstraZeneca vaccine immediately, Governor Hogan should act. He might invoke emergency authority to simply take possession of enough of the AstraZeneca vaccine supply in the Baltimore factory producing it to meet Maryland’s needs. But this would likely be unnecessary. He should request that the facility release the vaccine and inform them that the state will likely be able to guarantee no adverse repercussions from the FDA. After all, during the past decade over 40 states passed “Right To Try” laws that allowed terminally ill patients to access safe treatments not certified by FDA for efficacy. The only “repercussion”: in 2018 Congress passed bipartisan legislation, signed by President Trump, recognizing the state’s authority to do so. 

But in parallel, Hogan should call on President Biden to issue an executive order suspending the need for final FDA certification in this exceptional case.

Or Biden, backed strongly by the Maryland Congressional delegation, could request Congress pass emergency legislation creating a Free To Choose Medicine track parallel to FDA’s normal, slow certification process, on which COVID vaccines, tested safe and promising in Phase II or III trials, could be accessed by individuals, with informed consent. Such a track was created in 1992 for AIDS treatments, saving the lives of thousands of sufferers.

Or Biden could request Congress pass a reciprocity law certifying for the use of Americans any COVID treatment approved  in other advanced countries. Rep. Chip Roy (TX-21) and Sen. Ted Cruz, (R-TX) have introduced legislation allowing for reciprocal approval of drugs approved in other trusted countries. This proposal could be focused to allow access to COVID vaccines.

Since AstraZeneca is produced in Maryland and the FDA headquarters is also in Maryland, Hogan is in an ideal position to be the hero, shake things up, and break the bureaucratic walls separating citizens from a lifesaving medication.

If you agree that Hogan should act now, please sign this petition on Change.org:
Larry Hogan : Liberate the AstraZeneca vaccine from the FDA!

Ed Hudgins is founder of the Human Achievement Alliance and a science policy researcher.  He can be reached at ehudgins@humanachievementalliance.org. Dan Elton is  Director of Scholarship at the US Transhumanist Party.  You can reach him via direct message on Twitter (@moreisdifferent).

A List of Possible FDA Reforms – Compilation by Dan Elton

A List of Possible FDA Reforms – Compilation by Dan Elton

Daniel C. Elton, Ph.D.


I have ranked these according to my own perception of which have the most support among DC bureaucrats and members of congress.

  • Improving transparency. During the COVID-19 pandemic the public has been kept in the dark regarding how key decisions were made, such as the decision to issue an EUA for hydroxychloroquine, the decisions that pushed Pfizer’s EUA from early November to late December, and the decision to require additional Phase III data from AstraZeneca which delayed their EUA by at least 3-4 months. Currently the FDA keeps much of the information relevant to decision making confidential. In theory Freedom of Information Act (FOIA) requests can be used to obtain some information, but in practice FOIAs are slow-walked, may require litigation, and take years to resolve. There are many possible ways to increase transparency at the FDA, some of which are outlined in this recent article in STAT News. 18 specific recommendations can be found in this journal article from 2018. One of people referenced as a top candidate for FDA Commissioner, Joshua M. Sharfstein, is a poor choice when it comes to implementing other reforms but has been a leading voice calling for more transparency.
  • Reciprocity. If a drug/medication is approved by a regulatory agency in a different country which has equivalent standards to the FDA (for instance agencies in the UK or Japan, the European Medicines Agency (EMA), or Health Canada), it should automatically be approved by the FDA (and vice versa). Reciprocity would save both taxpayers and companies a lot of time and money. Imagine if the AstraZeneca vaccine had been approved on January 1st, a few days after the UK approved it. It’s easy to see that tens of thousands of lives would have been saved, especially when you consider it would have been given to the most at-risk first!  In 2015 Senators Mike Lee and Ted Cruz introduced the RESULT Act, which is primarily focused on implementing reciprocity.
  • Making the agency independent from the executive branch. It’s hard to insulate the FDA from political concerns as long as Congress controls the FDA’s purse, but it could at least be removed from direct interference from the executive branch by making it an independent agency like the FCC or Federal Reserve. There seems to be wide support behind this idea right now and recently four former FDA commissioners all endorsed this idea in an interview.
  • Rolling reviews. It should not take 3-4 weeks from the submission of an EUA application until a decision is made, especially when thousands are dying every day while waiting for vaccines. According to Dr. Marty Makary, a professor of public health policy at the Johns Hopkins Bloomberg School of Public Health who has conducted over a hundred clinical studies, the FDA “could have done the approval in 24-48 hours without cutting any corners”. Likewise, the approval of drugs and therapies after Phase III trials have reached an endpoint should not take 6 – 18 months. While the FDA does engage in a back and forth with companies prior to when they submit their paperwork for an EUA or approval, they do not use rolling reviews. Due to their rolling review systems other countries like the UK were able issue EUAs for COVID-19 vaccines faster than the FDA. Rolling reviews should be the norm, and the submission and analysis of trial data should made as streamlined and as efficient as possible without compromising the integrity of the analysis.
  • Tiered approvals. Doctors who want to provide new drugs to at-risk patients currently have to wait 5-10 years for lengthy Phase III trials to conclude and then another 6 – 18 months for the FDA to carry out their review of the trial data. Tiered approvals would allow a lower level of approval after just Phases I and II, freeing up treatments to those who need them most. The centrist Niskanen center has a white paper which suggests four levels of approval (see also their op-ed in The Hill).
  • Expansion of Right-to-Try. Federal right-to-try legislation was passed in 2018. However, it is very restrictive, and patients need to have met a number of strict requirements before they can try new medications and treatments, greatly limiting its utility.
  • Treating aging as a disease. Currently it is illegal to market an FDA-approved product as a treatment for aging. Even though aging is a harmful biological process, it is not considered a legitimate “indication” for a drug or therapy by the FDA. In other words, the FDA doesn’t view aging as a “disease” and therefore anti-aging treatments fall outside their mandate. Some specific aspects of aging are also not considered as legitimate indications. The FDA is currently operating in an inconsistent way as some conditions which are due to the aging process can are considered legitimate targets, such as osteoporosis and menopause, but others, like sarcopenia (age-related muscle loss /frailty), are not.  Many experts, including David Sinclair, have spoken out about this issue. Some companies have found ways to get around the FDA’s restrictions, such as by using certain metabolic markers to track the degree of damage from aging. However, the impossibility of getting FDA approval for therapies that directly slow down or repair the damages from aging greatly dis-incentivizes industry R&D investment in this area.  Fortunately, with advanced gene and stem-cell therapies on the horizon, the Congress and the FDA have already taken a few steps towards being able to review and approve anti-aging drugs and therapies. The 21st-Century CURES Act, for instance, mandated the creation of the Regenerative Medicine Advanced Therapy designation at the FDA.
  • Challenge trials in emergency situations. Many people, including a group of legislators, lobbied the FDA to give companies the go-ahead to do challenge trials, but there was no action. Thousands of volunteers for COVID-19 challenge trials signed up with 1daysooner.org but were unable to participate as they had wished to. As a result, data on vaccine efficacy was obtained much slower than it could have been.
  • Use of the proactionary principle for all drug & therapy approvals. The FDA should publish a transparent, quantitative, scientifically informed, and structured cost-benefit analysis for each regulatory action performed, which estimates the expected quality-adjusted life years (QALYs) saved versus risk of QALYs lost for both the action and inaction. The analysis should be made public, ideally sometime before the decision goes into effect. Crucially, the analysis should enumerate the risks and benefits of granting an approval and the risks and benefits of not granting it. See Max More’s overview of the proactionary principle and his chapter in The Transhumanist Reader, where he presents not just a principle but an entire framework for rational decision making. The key reform here is to make it mandatory that decision making at the FDA be highly structured and quantitative so it under less sway from political concerns and cognitive biases. If such a framework for rational decision making was in place it’s unlikely the FDA would have decided to delay Pfizer’s Emergency Use Authorization (EUA) from early November to December 11th, a decision which cost tens of thousands of American lives.
  • Free to Choose Medicine with a Trade-off Evaluation Database.  In brief, Free to Choose Medicine would create an additional track after Phases I and II to allow doctors to prescribe new therapies to at-risk patients who are unable or unwilling to participate in a Phase III trial. Patients in the Free-to-Choose Track would be mandated to submit data to a trade-off evaluation database, creating a trove of valuable real-world data (this could be genetic, biomarker, and adverse events data, for instance).  See this excellent podcast interview with Bart Madden for more information. 

Figure from Bart Madden, “Free to Choose Medicine“, The Heartland Institute

 

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. 

USTP Director of Scholarship Dan Elton’s Letter to the FDA’s Vaccine Committee Meeting on the Emergency Use Authorization of the Johnson & Johnson Vaccine

USTP Director of Scholarship Dan Elton’s Letter to the FDA’s Vaccine Committee Meeting on the Emergency Use Authorization of the Johnson & Johnson Vaccine

 

Daniel C. Elton, Ph.D.


The public can comment on the FDA’s committee meeting tomorrow (February 26th) to discuss the Emergency Use Authorization for the Johnson & Johnson / Janssen vaccine candidate. Members of the public can submit comments via an online system here or via the mail. Attached is my letter. The main theme is transparency.  

 

To the VRBP Advisory Committee:

I am writing to request the FDA exhibit full transparency and show their cost-benefit calculations which justified such a long delay in approving the J&J/Janssen vaccine. Taxpayers deserve decisions that are made on the basis of rational cost-benefit analysis informed by the best science and data available. There is an incredible fog around key decisions that have greatly affected Americans during the COVID-19 pandemic – such as the FDA’s decisions that made it hard for at-home tests to be approved, HHS & FDA decisions not to pursue or support human challenge trials, and the FDA’s deadly decision to delay approvals of life-saving vaccines, most shockingly the AstraZeneca vaccine. With 2,000 – 3,000 Americans dying every day and millions of Americans desperate for life-saving vaccines (as evidenced by long lines across the country) it is only fair that taxpayers know the reasons for the FDA’s delays.

In a relentless pursuit of safety the FDA has ironically ignored the greatest safety concern to the American people – the SARS-CoV2 virus, and many have died needlessly as a result. Beyond normal expected utility based utilitarian calculations, the proactionary principle(s), developed by philosopher Max More and extended by Steve Fuller and others provide a good blueprint for conducting rational cost benefit analysis. It is my belief that the procedures the FDA have used to decide if and when to approve this vaccine have not utilized even the most rudimentary cost-benefit analyses, and lives have been lost as a result. I am open to changing my mind, however, if the FDA can produce a cost-benefit calculation that informed their decision making.

The interim Phase III collection period for the Janssen vaccine ended January 22 and they submitted their EUA application on February 4th. The American people have had to wait 22+ days for the EUA to be granted. Between February 4th – 26th, around 52,500 Americans will have lost their lives to COVID-19 (extrapolating the death rate forward 2 days from February 24th). In that time, countless others will have suffered under the ravages of the disease and the numerous sequela of “long COVID”. Even among those who have been lucky enough not to have their bodies invaded by the virus, most have suffered brutal economic and psychological effects from the pandemic.

As economist Tyler Cowen points out, it is a fallacy to think that manufacturing is the main bottleneck to getting life-saving vaccines to American people. Millions of doses of both the Pfizer and Moderna vaccines were available when the FDA finally approved them, showing that FDA approval was a larger constraint than manufacturing. While J&J may not have as many vaccines produced by February 26th as Moderna & Pfizer did at their EUA, if an expectation of an earlier EUA had been set by the FDA the company would have had a stronger incentive to ramp up production. It is incorrect to view the manufacturing and approval as independent – both are linked, with the timeframe set for one affecting the timeframe for the other. In economic terms, the elasticity of manufacturing to demand is not zero. Production of J&J’s vaccine began long ago so they could provide vaccines for their Phase I/IIa trial which began on July 22, 2020. While the company has faced production setbacks, a GSA report (GAO-21-265) estimates they will have 2 million doses available on February 26th.

The government of South Africa announced on February 10th that they would start administering the J&J vaccine to frontline health care workers. Now imagine if the FDA had made the J&J vaccine available just two weeks prior and assume that 2 million doses could therefore be distributed two weeks earlier as a result. At the current monthly rate of deaths, the average american has a 1/9,410 chance of dying from COVID-19 every 2 weeks. The risk of dying from the J&J vaccine, by contrast, based on the Phase I/II data and our prior knowledge about similar vaccines, is at most 1/1,000,000 (likely an overestimate). Assuming the vaccine is 100% effective at preventing death from COVID-19 (a safe assumption based on the current science), delivery of 2 million J&J vaccines 2 weeks earlier could save 212 lives and reduce suffering in many more. However, this number is obviously an underestimate because the vaccines will be distributed to the elderly and those with pre-existing conditions first, who have a 10x – 100x higher chance of dying from COVID-19 than the average American. So, the true number of lives that would have been saved is in the ballpark range 2,120-20,120.

The FDA’s decision to delay approval of the AstraZeneca vaccine by demanding additional American Phase III trial participants represents an even more egregious decision which surely cost thousands of Americans their lives. To be respectful of the purpose of the meeting at hand, however, I have restricted my discussion here to the J&J vaccine alone.

I ask that the FDA produce a cost-benefit analysis and clearly explain the reasons for the following decisions:

  • The reason the FDA did not allow the J&J vaccine to be made available via the FDA’s Expanded Access Program after excellent Phase I/II safety & immunogenicity data was published The Lancet on January 13th, 2021. (side note: see this article in STAT)
  • The reason the FDA did not recommend and/or advocate that those with a high risk of dying from COVID-19 obtain the J&J vaccine via the Right-to-Try pathway prior to EUA.
  • The reason the FDA, in October, created a requirement for a median 2 month follow up period in Phase III trials.
  • The reason the FDA decided not to recommend J&J use challenge trials to demonstrate the efficacy of their vaccine in a faster manner.
  • The reason the FDA decided not to allow pre-distribution of the J&J vaccine prior to EUA to speed up distribution.
  • The reason the FDA did not implement rolling reviews for the J&J vaccine.
  • The reason the FDA decided it needed 22 days to review J&J’s EUA application.

For each point, a cost-benefit calculation should be provided including a list of costs and benefits to the action vs the opposite action, ideally expressed in terms of quality-adjusted life years (QALYs) saved or lost.

Finally, I ask that in their communications and messaging the FDA focus on the efficacy of the J&J vaccine against hospitalization and death, especially against the South African variant, so Americans are informed first and foremost about the most important benefits of this vaccine.

Respectfully,
Daniel C. Elton, Ph.D.

 

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.

A Polite List of Requests to the FDA – Article by Dan Elton

A Polite List of Requests to the FDA – Article by Dan Elton

Daniel C. Elton, Ph.D.


A List of Requests to President Joseph R. Biden, Jr.,
HHS, FDA, and Congress: 

Approve the following vaccines for emergency use immediately: 


Give people the right to try the following vaccines: 

Seriously study and consider these actions: 

  • Allow hospitals and pharmacies to start stockpiling unapproved vaccines so they can be rapidly disseminated upon approval. 
  • Allow Moderna to give fractional doses. Data from Moderna’s clinical trials have illustrated that people between ages of 18 and 55 who received two 50-microgram doses showed an identical immune response to the standard of two 100-microgram doses.
  • Allow all age groups to get the vaccine. Research published in the journal Science indicates that as of October 2020, “individuals aged 20-49 are the only age groups sustaining resurgent SARS-CoV-2 transmission with reproduction numbers well above one”. Thus, targeting vaccines at these groups may accelerate the end of the pandemic and save more lives than continuing to restrict the vaccines to the elderly and vulnerable.
  • Consider making “First Doses First” national policy.


The FDA has not moved fast enough given the gravity of the situation we face. Consider the following: 

  • Pfizer sent its paperwork to the FDA on November 22, 2020, but rather than immediately convening its panel of experts, the FDA scheduled a review meeting for December 10. During that three-week wait, 27,000 Americans died of COVID-19. According to Dr. Marty Makary, a professor of public health policy at the Johns Hopkins Bloomberg School of Public Health who has conducted over a hundred clinical studies during his career, the FDA “could have done the approval in 24-48 hours without cutting any corners”.  The slow rollout that followed after the FDA approved the vaccine on December 11 was not due to delays in production – Pfizer had millions of doses produced and sitting in cold storage at the time of the approval. 
  • While Americans were waiting for the Pfizer vaccine that millions of their taxpayer dollars had been invested in, the FDA went dark for 4 days during the Thanksgiving holiday, with almost all of its 17,000 employees taking that time off, including those working on critical COVID-19-related work. 
  • Moderna sent its paperwork to the FDA on November 30, 2020. As with the Pfizer vaccine, the FDA needlessly delayed the approval by scheduling the review meeting for December 17. 
  • The FDA’s equivalents in the EU, Canada, Switzerland, UK, Israel, and Singapore all use rolling reviews, evaluating data as it becomes available for the sake of efficiency. The FDA does not. 
  • The Sputnik V vaccine was approved September 4, 2020, over 150 days ago. In a paper in The Lancet, phase III results indicate it has an effectiveness of 91.6% and excellent safety profile. 
  • China began administering the CanSino Biologica vaccine to its military in June after Phase I and Phase II clinical trials established safety and immune response. (The phase II results were published in The Lancet on July 20th, 2020). China approved the vaccine for their public on December 24, 2020. 


Here’s what public-health experts are saying:
 


“The F.D.A. needs to catch up to the science… They are inadvertently killing people by not following the science.” – Michael Mina, Epidemiologist, Immunologist, Physician, Harvard Medical School.

“We’ve gone from ‘Operation Warp Speed’ to develop a vaccine to ‘Operation Turtle Speed’ to review it… The FDA needs to stop playing games and authorize the Oxford-AstraZeneca vaccine.  It’s safe, cheap ($2-$3 a dose), and is the easiest vaccine to distribute.”Marty Makary, M.D., a professor of health policy at the Johns Hopkins University School of Medicine. 

I do think we’ve been too conservative… companies that potentially make public health diagnostic tests did not feel that there was, for example, a pathway to get those approved at the F.D.A.”Vivek Murphy, President Biden’s nominee for Surgeon General.

“We’ve already bought 300 million doses of the AstraZeneca-Oxford vaccine. We’ve paid for it — over a billion dollars — so let’s use it… I know we have some of that vaccine stockpiled.”Dr. Peter Hotez, dean of the National School of Tropical Medicine at Baylor College of Medicine and the lead developer of a COVID-19 vaccine being produced in India.


More quotes from notable public figures: 

“For years the FDA was focused on, don’t repeat thalidomide. Drugs must be safe. AIDS forced a hard reckoning. The people who are dying while you wait matter. But this is a third, even harder conceptual change. Stopping the spread of the disease matters. And the FDA does not have the years it took to make the AIDS change of mindset.”John Cochrane, Senior Fellow at the Hoover Institution. 

The new strains spread quickly. The speed of our countermeasures will decide our fate. What feels like reasonable delays in our normal experience of time — a few weeks here for Congress to debate a bill, a few weeks there for the F.D.A. to hold meetings — could lead to the kind of explosive infections that overwhelm our hospitals and fill our morgues.”Ezra Klein, co-founder of Vox.

“The US failure to authorize the AstraZeneca vaccine in the midst of a pandemic when thousands are dying daily and a factory in Baltimore is warmed up and ready to run is a tragedy and dereliction of duty of epic proportions. The AZ vaccine should be given an EUA immediately and made available in pharmacies for anyone who wants it while continuing to prioritize Moderna and Pfizer for the elderly and essential workers.”Alex Tabarrok, Bartley J. Madden Chair in Economics, George Mason University. 

“It’s amazing that not only is this vaccine (AstraZeneca) not approved, there’s no political pressure to approve it.”Matthew Yglesias, author of One Billion Americans: The Case for Thinking Bigger.

“The UK has authorized #AstraZeneca vaccine for #CV19 but #FDA won’t “because of questions about its efficacy among older people.”
Then authorize its use for younger people!
Dear FDA: Get out of the way!
Over 7,000 Americans died of CV19 in the past two days!
You are murdering us!”
– @Robert Zubrin on Twitter, author of The Case for Mars and The Case for Space.

Further reading: 

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. 

How We Can Judge the Safety and Efficacy of New Vaccines Prior to Phase III Data and Why We Must – Article by Dan Elton

How We Can Judge the Safety and Efficacy of New Vaccines Prior to Phase III Data and Why We Must – Article by Dan Elton

Daniel C. Elton, Ph.D.


A common refrain we hear from public intellectuals about vaccines prior to Phase III data is “we don’t know anything about the safety or efficacy of vaccine X”. This attitude is both false and misleading to the public, instilling uncertainty and fear about vaccines. To see why it is false, consider if a normal vaccine safety study was done, but by coincidence all of the vaccines were given in hospital rooms that were painted blue. Could we conclude on the basis of such a study whether the vaccine would be safe if administered in rooms painted red? Yes, we can, and we should. We can utilize two forms of reasoning to conclude that the vaccine is safe if given in red rooms, even though we have no data on the matter.

The first form of reasoning roughly approximates the way an ideal Bayesian statistical reasoner would function to compute what is called a “prior probability distribution”. Under this form of reasoning, we consider the millions of doses of similar vaccines (called the “reference class”) that have been administered. For instance, we might consider the vaccines developed for very similar coronaviruses like SARS and MERS.  We note that if the color of paint did affect the safety of those vaccines, this would have likely been detected over the course of prior studies and over the course of millions of doses given previously. Of course, there is a chance the correlation might have been missed. To figure out how big that is, we can go a level deeper and consider a reference class of “things people might notice or fail to notice in medical studies”. We can conclude that for prior vaccines, if such correlations existed they would generally be picked up. On the basis of this and the fact that no such correlation was ever discovered in the reference class of prior vaccines we can conclude that the probability of vaccines like the COVID-19 vaccine being dependent on the color of paint is very small. 

The second type of reasoning, which happens to be much more straightforward in this situation, is what the physicist David Deutsch calls “reasoning from our best explanation of the world”. According to the philosopher of science Karl Popper, we should reason using our explanatory theories of the world which have survived the most rounds of attempted falsification, and which have the highest degree of falsifiability (this rules out non-testable explanations like “vaccines work via invisible ghosts”). In more prosaic terms, this simply means reasoning using the best scientific theories which make predictions in the domain under consideration. We note that our best theories of vaccine function do not anywhere depend on the color of paint in the room. Instead they depend on things like T-cells, binding affinities of molecules, the concentrations of certain molecules in the body, etc. So, we decide that the vaccine is safe regardless of the color of paint in the room where it is administered. 

Both of these forms of reasoning are valid and both are foundational to science, rationality, and human progress. Both of these types of reasoning can be used to say that vaccines under development are likely to be safe and effective before any data comes in. It’s why a reporter who interviewed numerous top scientists reported that they all told him that “they expected the vaccines were safe and effective all along.” Yet instead of proudly sharing this important knowledge with the public, we rarely hear scientists say publicly that they expect the vaccines are safe and efficacious. Instead, they hedge, saying “we have to wait until the data comes in”. This is unethical both on Kantian grounds (they are lying) and on consequentialist grounds, because it leads to undue caution and the public being afraid of vaccines. 

Unfortunately, there is little incentive for scientists to tell the truth about what the likely risks and benefits are with new vaccines before full Phase III data is published. If, for instance, one or two people suffer severe side effects in a Phase III trial (which is rare, but has happened) a scientist who said they suspected it was “very safe” might receive harsh criticism for making a premature assessment. On the other hand, the same scientist will get no pushback for saying “we need to wait for data to make a judgement”. Indeed, they are likely to even be praised for exhibiting the virtues of “caution, prudence, and scientific skepticism”. Moreover, under no scenario should someone be allowed to get a vaccine until the full data comes in, even though it’s fine to allow people to sign up for studies where they have a 50-50 chance of getting the vaccine. Not very consistent, eh?

As US Transhumanist Party Chairman Gennady Stolyarov II has described in detail in an an earlier publication on this site, all of this is the result of a deeply flawed and deadly ethical principle called the precautionary principle, which unfortunately many people have fallen under the sway of. The principle originates in the environmentalist movement but is widely applied in medicine, and was instrumental in decisions such as the Bush administration’s ban on stem-cell research and decisions to ban life-saving GMO technologies such as golden rice. It has been formulated to varying degrees in several different ways. The United Nations World Charter for Nature (1982) issued one version of the principle, stating: 

Activities which are likely to pose a significant risk to nature shall be preceded by an exhaustive examination; their proponents shall demonstrate that expected benefits outweigh potential damage to nature, and where potential adverse effects are not fully understood, the activities should not proceed. 

The principle starts off OK but dives into serious error in the last line. The issue is that the precautionary principle only focuses on the potential adverse effects of proceeding and ignores the potential adverse effects of not proceeding, i.e., the effects of delay. As should now be clear in the case of the COVID-19 vaccines, not proceeding can sometimes be much more deadly than proceeding! There is often a high but unclear risk to not proceeding, and a low but unclear risk to not proceeding. (Picture two probability distributions, both wide (unclear) but one with a mean that is distinctly higher than the other). That’s where the precautionary principle throws expected utility theory (cost-benefit analysis) out and says we cannot proceed. The Nobel Prize-winning physicist Freeman Dyson stated the issue as follows: 

The Precautionary Principle says that if some course of action carries even a remote chance of irreparable damage to the ecology, then you shouldn’t do it, no matter how great the possible advantages of the action may be. You are not allowed to balance costs against benefits when deciding what to do.” — Freeman Dyson, Report from the 2001 World Economic Forum

Imagine an alternative world in which our society and government was not under the sway of the precautionary principle. In this alternative world, scientists would give their truthful assessment of new vaccines to the public, stating that they are likely safe and effective, using one or both of the reasoning methods mentioned above. In such a world, given the clear potential harms of inaction, the public would be allowed to purchase new vaccines if they wanted, if the companies manufacturing them were comfortable doing so, and if they were fully informed prior to their decision that they were taking an unapproved product that carries potential risks but also potential benefits. Initially, only a few people would purchase the vaccines, perhaps on the basis of Phase I results. These would be folks like those who injected themselves with a DIY vaccine over the summer, and the tens of thousands who were willing to participate in clinical trials as early as last spring. Companies would be incentivized to survey those who took the vaccine and collect self-reported data on their outcomes, which is very cheap and easy to do. After a few months going by without any of those people keeling over and dying, and with very few (likely none) of those people getting hospitalized for COVID-19, more people would feel comfortable getting the vaccine. Things would quickly snowball, with more and more people becoming willing to get the vaccine. During this time the distribution system would have been stood up and become operational, with on-site stockpiles building up ahead of the FDA’s Emergency Use Authorization (currently, the FDA does not allow hospitals to stockpile unapproved vaccines ahead of their EUA). To present this case in its strongest form, in a future post I plan to estimate how many lives would have been saved, assuming many vaccines had become available to those who wanted them last March or August. However, I hope it’s easy to see that thousands of lives would have been saved in this alternative world.  

For more on the transhumanist alternative to the precautionary principle, the proactionary principle, see Max More’s excellent book chapter as well as the Wikipedia article and references therein.

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. 

Reject the Deadly Precautionary Principle: Approve All COVID-19 Vaccines Immediately! – Article by Gennady Stolyarov II

Reject the Deadly Precautionary Principle: Approve All COVID-19 Vaccines Immediately! – Article by Gennady Stolyarov II

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Gennady Stolyarov II


It should be a mild relief that vaccination efforts against COVID-19 are finally beginning in the United States, but they are beginning eleven months too late, while the pandemic surrounds us and most of us must wait months longer to receive vaccinations. Over 300,000 Americans have already died needlessly and preventably from COVID-19; hundreds of thousands more are likely to die in the coming months, even though the exact same vaccine from Moderna that is even today still undergoing Food and Drug Administration (FDA) review already existed in its current form by January 13, 2020. As David Wallace-Wells writes in New York Magzine, in an article entitled “We Had the Vaccine the Whole Time” (dated December 7, 2020):

You may be surprised to learn that of the trio of long-awaited coronavirus vaccines, the most promising, Moderna’s mRNA-1273, which reported a 94.5 percent efficacy rate on November 16, had been designed by January 13. This was just two days after the genetic sequence had been made public in an act of scientific and humanitarian generosity that resulted in China’s Yong-Zhen Zhang’s being temporarily forced out of his lab. In Massachusetts, the Moderna vaccine design took all of one weekend. It was completed before China had even acknowledged that the disease could be transmitted from human to human, more than a week before the first confirmed coronavirus case in the United States. By the time the first American death was announced a month later, the vaccine had already been manufactured and shipped to the National Institutes of Health for the beginning of its Phase I clinical trial. This is — as the country and the world are rightly celebrating — the fastest timeline of development in the history of vaccines. It also means that for the entire span of the pandemic in this country, which has already killed more than 250,000 Americans, we had the tools we needed to prevent it.

As has been demonstrated time and again during this pandemic, scientists and doctors have been the true heroes in their rapid and immensely creative responses, whereas institutions and their processes have failed massively, and our egregiously broken society and culture have precipitated abysmal mass-scale reactions and behaviors as well. But the major reason why now almost 300,000 Americans died who did not need to die at all, is the Precautionary Principle – a cornerstone of contemporary “bioethics” which is, in fact, deeply unethical. The Precautionary Principle is the fundamental reason why new medical treatments, including vaccines, are required in the United States to undergo extensive safety and efficacy testing before they are allowed to be provided to patients, even willing patients who may knowingly accept the risks of experimental medicines. Essentially, unless safety and efficacy can be rigorously demonstrated first, along with a sufficient lack of adverse consequences, adherents of the Precautionary Principle believe that no action should be taken to implement an innovation. Those who espouse the Precautionary Principle completely ignore, of course, the costs and risks of inaction – which, in the case of a global pandemic, can be measured in more than 1.62 million lives worldwide, but which have also resulted in far greater numbers of deaths from more “routine” otherwise terminal illnesses, whose victims might have been saved by new treatments whose approval the FDA delayed, sometimes for a decade or more while billions of dollars were spent on hyper-expensive efficacy testing.

While laudable efforts were made in the United States to greatly accelerate the review timeframe for COVID-19 vaccines – hence the now well-known “Operation Warp Speed” – those efforts did not come in time for the hundreds of thousands who died and the hundreds of millions who now live in fear of death every day as the pandemic’s spread has become all-encompassing. Cutting the approval timeline from the typical unconscionable 4-5 years to 9 months is an improvement, but not nearly enough. Much more should have been done right away. Approval for the vaccines should have been granted as soon as they were developed, and instead of putting review roadblocks in the way, governments should have actively aided in vaccine production and distribution of all serious candidate vaccines from day one.

While New York Magazine’s David Wallace-Wells made the seemingly obligatory (during this tragically precautionary era) disclaimer that “To be clear, I don’t want to suggest that Moderna should have been allowed to roll out its vaccine in February or even in May, when interim results from its Phase I trial demonstrated its basic safety” (and Wallace-Wells still faced considerable vitriol for the quite modest observations he sought to make) – I do want to suggest exactly that. Indeed, I would go further and insist that it was a moral imperative to approve and facilitate the mass production and distribution of vaccines such as Moderna’s mRNA-1273 to willing members of the general population as soon as those vaccines were available.

Transhumanists reject the Precautionary Principle and instead follow the Proactionary Principle, which, per the description of Max More (Extropy Institute, 2004), “urges all parties to actively take into account all the consequences of an activity – good as well as bad – while apportioning precautionary measures to the real threats we face, in the context of an appreciation of the crucial role played by technological innovation and humanity’s evolving ability to adapt to and remedy any undesirable side-effects.” The Proactionary Principle does not ignore the potential for adverse consequences of an activity, but recognizes that there are situations when the benefits can greatly outweigh any potential adverse effects.

Imagine how, in an alternate history, a Transhumanist administration would have dealt with the COVID-19 crisis. Suppose, for instance, that Zoltan Istvan had been elected President in 2016 and thus was the President who faced the COVID-19 pandemic in 2020. Or suppose that Charlie Kam, the U.S. Transhumanist Party (USTP) Presidential nominee in 2020, had held the country’s highest executive office. The U.S. Transhumanist Party Platform contains 21 sections specifically addressing COVID-19 responses – proposals that were adopted by USTP members in late March 2020, and would have saved most of the lives of the COVID-19 victims had they been expeditiously implemented by governments. These proposals, indeed, are applications of the Proactionary Principle to the COVID-19 pandemic. Section CIII of the USTP Platform specifically states that “The United States Transhumanist Party supports the rapid research into effective cures and vaccines for COVID-19 and the harnessing of synergies from this research to also develop a cure for the common cold and more effective vaccination against influenza. Such research should proceed with no barriers, subject to the researchers’ expression of ethical intentions, and any regulations or processes that would delay the progress of such research should be immediately waived or repealed. In the effort to accelerate progress in this field, the United States Transhumanist Party advocates for an immediate $100 billion funding package for the rapid development of a COVID-19 vaccine, with all volunteers being accepted into human trials as soon as practicable.”

This is exactly what would have been done by a Transhumanist administration with the Moderna, Pfizer, AstraZeneca, and any other vaccines, including do-it-yourself experiments such as that undertaken by Josiah Zayner. The Transhumanist administration would have asked the vaccine developer one question: “Do you intend to apply this candidate vaccine in an ethical manner when offering it to the general public?” After giving an affirmative answer to that question, the vaccine developer would have the full legal right to test, give away, or sell its product to any volunteers capable of giving informed consent – provided that the recipients understood that the vaccine was experimental and had not passed the typical safety and/or efficacy tests. Receiving any vaccine would always remain entirely voluntary. Individuals who were uncertain or concerned about side effects – or even motivated by pseudoscientific, anti-scientific, or religious objections – would maintain the right not to get vaccinated. However, those who chose to get vaccinated would be shown clearly and quickly to have far lower incidence of COVID-19, and the statistical disparity in infection rates between the vaccinated and the un-vaccinated would grow too large in just a few months for reasonable people to ignore. Those who become vaccinated would be free to lead their everyday lives and participate in economic activities as usual, and massive disruptions to the economy and to people’s livelihoods would have been completely avoidable. The multifaceted advantages of vaccination under this approach would become abundantly clear in a relatively short time.

Testing would not be eliminated by the Transhumanist administration. Indeed, it would be accelerated and fully funded via the $100 billion emergency package (and likely via other resources as well), so that vaccine developers would need to pay absolutely nothing out of pocket for any compliance with testing protocols. However, testing would occur in parallel with mass distribution of the vaccines, and as much data as possible would be collected from vaccine recipients in the general population, to greatly augment the samples of tested patients. If any specific side effects manifested themselves in a statistically significant portion of the population, protocols for administering the vaccine would be adjusted in real time. For example, if a specific group of people were found to be particularly vulnerable to certain side effects, members of that group would quickly receive additional disclosures and warnings and would be able to make informed decisions in light of this information.

Could there conceivably be adverse side effects or even deaths of certain patients under this approach of mass distribution in parallel with testing? Of course, that is a possibility. However, the scale of such side effects and deaths would surely be orders of magnitude less than the all-encompassing devastation that the current sequential review-and-approval process has allowed to happen. So far nobody has died specifically from any COVID-19 vaccine. At least 1.62 million people in the world have died from COVID-19. Numerous others have died because of the fallout of the restrictive measures taken to contain the spread of COVID-19. Even if the vaccines had been far more dangerous than they actually are, it is absolutely impossible for them to have caused anywhere near the death toll inflicted by the disease itself and the societal havoc that it and responses to it have wreaked. This basic insight, whose evidence is all around us, is precisely what the Precautionary Principle misses. By placing all of the burden of proof on the innovation, the Precautionary Principle gives a free pass to the wantonly murderous status quo. Inaction is not safety. Inaction is quite frequently the greatest danger – and at no time is that truer than during a global pandemic. If we do nothing, any of a vast array of perils will befall us rather quickly.

The United States has already lost more people to COVID-19 than it had to all but one of its historical wars. The novel coronavirus is the enemy here to be sure, but the Precautionary Principle is an even more pernicious and insidious foe. The Precautionary Principle is responsible for the hundreds of thousands of American dead just as much as the novel coronavirus itself, since it prevented an implementation of an existing off-the-shelf solution that could have saved the vast majority of their lives. Every war in history has resulted in unacceptable death tolls because of fundamentally flawed premises – ideas and practices that brought about the war because people accepted them as commonplace and justified. Slavery, religious intolerance, jingoistic nationalism, and totalitarianism have all stemmed from deep moral errors that caused colossal loss of life – and fortunately most of humanity has recognized the great evil that these notions entail and has resoundingly rejected them. The Precautionary Principle, when implemented in institutions that have the power to make life-or-death decisions, is in that same league of moral errors; it will be remembered decades and centuries hence as the greatest destroyer of lives in our epoch.

How much senseless loss of life needs to occur before we recognize that our institutions, based on the Precautionary Principle, are wantonly negligent in allowing our fellow humans to die and are still withholding life-saving solutions from them? It is time to reject the Precautionary Principle once and for all and to institute the truly humane policy of allowing all rationally capable individuals to assess the risks and benefits of emerging medical treatments for themselves. This would not only save colossal numbers of lives in the immediate term, but also greatly accelerate medical discovery and technological progress – since innovators would be able to obtain data rapidly and iterate upon their approaches. The arrival of cures for cancer, dementia, diabetes, and biological aging itself will depend on how free medical innovators are to offer their treatments and how free patients are to accept them. Extensive and expensive pre-distribution review processes kill many more people than they save. End them now!

Gennady Stolyarov II is the Chairman of the United States Transhumanist Party.