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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
  • Will C. , 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.

Will C.

  • 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.