The FDA needs to approve the COVID-19 vaccines. Right now.

I’ve spent untold hours fighting bureaucracy during the course of my life. Sometimes the issues are big, sometimes small, but I often get incredibly frustrated when I see organizations–and the people who work for them–enforcing rules without thinking, often to the detriment of everyone involved.

Usually, though, bureaucratic rules are little more than annoying time-wasters. They don’t usually cause actual harm to people. Right now, though, the FDA’s failure to fully approve the Covid-19 vaccines, and its rigid adherence to its own rules, is not just wasting time. It’s killing people, albeit indirectly.

The FDA needs to approve the Covid-19 vaccines, and they need to do it now. They claim to be working hard on doing just that. The vaccines have already been administered to hundreds of millions of people, and the ones used in the U.S. and Europe have proven to be remarkably safe and amazingly effective. So what is the FDA waiting for? Well, according to them, they have to wade through the paperwork.

As nearly everyone knows, here in the U.S. we have three approved vaccines against SARS-CoV-2, from Pfizer-BioNTech, Moderna, and Johnson & Johnson. The first two are messenger RNA (mRNA) vaccines, an innovative design that is strikingly effective, reducing the chance of infection by over 90%.

The U.S. now has an ample supply of vaccines, but we are struggling to get everyone vaccinated, in large part because so many people are either hesitant to get the vaccine or downright opposed. Let’s leave aside the blatant anti-vaxxers for today, many of whom are so deeply misinformed that changing their minds is probably impossible.

A much bigger problem, and one that we can fix, is the far larger number of people who are waiting for the vaccines to get full FDA approval. Not only are many individuals waiting, but many large institutions, including the U.S. Defense Department, have announced that they will mandate vaccines for their personnel once the FDA formally approves them.

Right now, the 3 vaccines in the U.S. are only conditionally approved, under the FDA’s Emergency Use Authorization (EUA). The fact sheet that the FDA provides with these vaccines includes a number of caveats, and states that “there is no FDA approved vaccine to prevent Covid-19.” That statement is not, to put it mildly, very convincing.

Full approval requires the FDA to review “hundreds of thousands of pages of documents,” a process that usually takes 10 months, or maybe six months for a “priority” application. Pfizer only submitted its paperwork on May 7, and Moderna on June 1, so even the FDA’s priority process would leave us without an approved vaccine until the end of 2021. That’s just too long.

I’ve heard the FDA’s excuses. The FDA’s Director of Biologics, Peter Marks, explained in a letter to the NY Times that

“any vaccine approval without completion of the high-quality review and evaluation that Americans expect the agency to perform would undermine the F.D.A.’s statutory responsibilities, affect public trust in the agency and do little to help combat vaccine hesitancy.”

Sorry, Dr. Marks, but these excuses are nonsense. The Covid-19 vaccines have been rolled out with unprecedented speed, it’s true, but we’re now seeing the results of a real-time, real-world experiment on hundreds of millions of people, and–luckily–the results are great! Have you and your colleagues at the FDA not noticed this?

Furthermore, everyone knows that the vaccines will be fully approved in the next few months, and multiple government officials, including the President, have said so quite openly. So why not approve them today? Because you have to follow a set of bureaucratic rules that were not designed for a pandemic?

The virus doesn’t care about the rules. Infections in the U.S. are skyrocketing again, because of the Delta variant, and the only way to end this pandemic is to get nearly everyone vaccinated. Until we have full approval of the vaccines, we’re simply not going to get there. By relying exclusively on the paperwork provided by the vaccine manufacturers, and ignoring the enormous amount of real-world data that everyone can see, the FDA is prioritizing process over results.

The FDA says that it’s now in a “sprint” to approve the vaccines, but with every day that passes, more people get sick, and the virus has more time to mutate and become more deadly.

Listen, FDA: rules are created for a reason. In case you haven’t noticed, the pandemic is a worldwide emergency that cries out for you to bend or break the rules if doing so will save lives. We all want a safe and effective vaccine, but there’s an overwhelming amount of evidence that we already have at least 3 of them (and probably 6 or 7). You can approve the Pfizer-BioNTech and Moderna vaccines today, and if new data emerges, or if you discover something startling and unexpected in those millions of pages of paperwork, you can withdraw approval. There’s nothing preventing this except bureaucracy.

So don’t tell us that you (FDA) have to “complet[e] the high-quality review” or you’ll somehow be shirking your responsibility. That response is equivalent to saying “we can’t look at the overwhelming evidence from the real world, we can only look at the paperwork that the vaccine companies provided to us.” In other words, “nanner nanner we can’t hear you” rather than considering the fact that hundreds of millions of people have taken the vaccine and that it’s working.

And about that comment from the FDA about maintaining public trust? As Dr. Eric Topol pointed out in a recent op-ed, somehow the FDA managed to approve, in the midst of the pandemic, an incredibly expensive new Alzheimer’s drug (aducanumab) for which the evidence of effectiveness is very thin, and the risks of harm are very real. The FDA’s own advisors resigned in protest, and now the FDA’s inspector general is going to take another look at how this happened. And yet the FDA is worried about “public trust in the agency”? Give me a break. Meanwhile, the FDA can’t seem to find the time to approve the mRNA vaccines “despite massive evidence of their benefits.”

The FDA needs to stop hiding behind the mountain of paperwork. Millions of people will remain unvaccinated while the FDA reviews documents that merely tell us what we already know: the vaccines work, and they are safe. Give them full approval, today, and continue to monitor their safety carefully, and many lives will be saved.

Why do the Covid-19 vaccine trials take so long?

The whole world is waiting for a Covid-19 vaccine. More than 100 different vaccines are being investigated, and 42 of them are already being tested in humans, which is lightning-fast progress in the world of vaccine development.

11 vaccines are already in Phase 3 trials, which use thousands of volunteer subjects to test whether a vaccine really works. If any of these 11 trials are successful, as many scientists expect them to be, then the world might finally begin the process of opening back up.

By all accounts, though, we’re still a few months away from having an approved vaccine. Why does this take so long? Today I’ll try to answer this question. A little math is involved, but we don’t need much to get the basic idea across.

In a Phase 3 trial, we give the vaccine to large numbers of people to see if it works. Some of the 11 current trials use as many as 40,000 volunteers, so let’s use that number for the sake of discussion. In the trial, we might give the real vaccine to half the volunteers–20,000 people–and give a placebo to the other 20,000. A placebo is a harmless shot, typically just saline solution, that won’t have any effect. The volunteers don’t know if they’re getting the real thing; this is called “blinding.”

Then we wait. Here’s the problem: we don’t infect anyone intentionally, so we have to wait for naturally-occurring infections, and it might take a long time to see those. Subjects just go about their lives, and if they get sick, the study records that fact.

So the question is, how many people in each group of 20,000 will be infected in the first week? The first month? Two months? The answer is that we simply don’t know. To speed things along, scientists running the trials try to select volunteers who are more likely than most people to get infected, but we can’t really control the number of people who get sick.

Let’s suppose that after just one week of a trial, 3 people in the placebo group come down with Covid-19, and no one in the vaccine group gets sick. So far so good, right? But we can’t possibly conclude that a vaccine works based on just 3 cases. Statistics tells us that those 3 cases might have just happened by chance. (More precisely, if 3 cases occur in the 40,000 subjects, and if the vaccine doesn’t work at all, then there’s still a 12.5% chance that all 3 cases will occur in the placebo group.)

Suppose that 2 months roll by, and now we have 100 people in the placebo group who got sick, and only 10 infections in the vaccine arm. This is much, much better: without going into the math, a difference of 100 versus 10 would be highly significant, suggesting that the vaccine reduced cases by 90%.

But what if 2 months roll by and the placebo group only has 10 cases? Even if the vaccine group has zero cases, such a small number is not going to be enough to give us confidence that we have an effective vaccine. We want to see as many cases as possible–but we can’t force the issue. We have to wait.

In the US, the FDA has announced that a vaccine has to protect at least 50% of people in order to be declared effective. This means we need to see enough cases in to be confident that a vaccine confers that degree of protection. 50% is a pretty low bar, but so far none of the trials have announced even preliminary results showing that they’ve met that standard.

(Aside: “blinding” is really important in these trials. If subjects know they’re getting a placebo, they might be extra-careful to avoid exposure to the virus. This would artificially depress the number of cases in the placebo group. Conversely, if they know they’re getting the vaccine, they might be more reckless, increasing the exposures and cases in that group. In order for the results to be valid, we need all the subjects to behave the same.)

A faster option? There is a way to speed up this process: a “challenge” trial, where subjects are intentionally infected with the virus. The UK is preparing to start such a trial in January, first administering vaccines to healthy volunteers, and then exposing them to the SARS-CoV-2 virus about a month later. This is a far faster way to determine if a vaccine is working, but it creates serious ethical quandaries, because we don’t have a cure for the virus. If the world has an effective vaccine in January, I expect that the challenge trial will be cancelled. That wouldn’t be a bad outcome.

Got cold. Try zinc?

Having a cold is no fun.  Sore throat, runny nose, general feeling of all-around blechiness.  About the only good thing I can say about colds is that they don't last long, usually about a week.

We still don't have a cure for the common cold, but it's not for lack of trying.  For decades, Nobel laureate Linus Pauling promoted mega-doses of vitamin C as a way to prevent colds, but he turned out to be wrong on that one.  Somewhere in the neighborhood of 200 different viruses cause us to get colds, and we don't seem to be able to get rid of any of them.

In recent years, the most popular new remedy is zinc, usually in the form of a lozenge.  The evidence for zinc's effectiveness is not entirely clear, but a review published just last month, which looked at 13 different studies, concluded that zinc seems to help, just a little bit.  All 13 studies were randomized controlled trials, the gold standard of research, and collectively they included 966 people.

That sounds encouraging, but the benefit was disappointingly small: zinc seemed to shorten the duration of a cold by about one day.  So instead of being sick for 7 days, you might be sick for 6 days.

Or maybe not: Dr. Terence Davidson from UC San Diego argues that if you look at just the more rigorous studies, the effect vanishes entirely.

Chunks of elemental zinc

Then there are the worrisome reports that Zicam, a zinc-based cold remedy, causes people to lose their sense of smell.  (This may not sound so terrible, but some people reported a permanent loss.  Imagine never being able to smell fresh-baked bread again.)  In 2009, these reports led the FDA to issue a warning advising consumers to stop using three particular Zicam products.  In addition to over 130 reports directly to the FDA, Zicam's manufacturer had over 800 additional complaints about loss of sense of smell.

In an ironic twist, Zicam markets its products as homeopathic remedies, which means that the FDA cannot regulate them. It also means that they shouldn't contain any active ingredients, because homeopathic preparations are diluted until they contain nothing at all.  But Zicam does contain zinc, quite a lot of it, and the FDA's warning letter demanded that Zicam stop marketing these products because they had never demonstrated that they were safe and effective.

Zicam markets a wide range of zinc-containing products, and the FDA's warning only affected three of them.  Zicam's website today states that "there is no valid, scientific evidence showing a link between Zicam and anosmia [loss of sense of smell]."  Strictly speaking, this is correct, but there have been published reports suggesting a link, such as this one from 2006 and this one from 2009.  These studies looked at nasal sprays, not lozenges, suggesting that the risk (if any) comes from spraying the zinc product directly up your nose.

Aside: Zicam also claims that their products cure allergies too, for which there is not a shred of evidence.  Their website makes the sweeping claim that "all Zicam products are both effective and safe when taken as directed." I see no reason to trust these guys.

Conclusion: I'm not taking zinc.  The side effects might be minimal, but the benefit is very small and possibly zero.  I'll stick with hot tea, which at least makes my throat feel better.  Or chicken soup.  That can cure almost anything.

An Alzheimer's disease breakthrough?

We all hope to get old one day.  But if we do, our chances of getting Alzheimer's disease increase dramatically as we move into our 80s.  As many as 50% of people over age 85 may be affected.  Much progress has been made in understanding the disease, which appears to be caused by "plaques" forming in the brain, but we have no treatment and no cure.

But maybe - just possibly - a dramatic new study offers the first real hope for a treatment.  In a paper published today in the journal Science, a team of researchers led by Gary Landreth at Case Western University and his graduate student Paige Cramer found that an orphan drug called bexarotene has a remarkable affect on mice afflicted with a condition similar to Alzheimer's in humans.  These mice have similar plaques in their brains, compose of beta-amyloid proteins, and they show behavioral and cognitive impairment similar to some of the problems experienced by Alzheimer's patients.

Within just hours of administering bexarotene to these mice, the plaques started to clear.  If that weren't amazing enough, within a few days the mice also recovered cognitive abilities that they had lost.  In particular, they regained the ability to make nests, a behavior that normal mice have and that the Alzheimer's mice had lost.  They also regained at least some of their sense of smell.

Bexarotene (Targretin^TM) is an orphan drug that is approved for use in humans to treat cutaneous T-cell lymphoma, a rare skin cancer.  It works by inhibiting a gene, RXR, that is involved in the production of beta-amyloid proteins.  Cramer, Landreth, and colleagues hypothesized that because bexarotene can cross the blood-brain barrier, it might just help to clear out the plaques associated with Alzheimer's.  It seems that they may be right.

A huge caveat here is that many promising drugs seem to work in mice but fail when used in humans.  This drug is different, at least in the sense that it is already approved for human use, but no one has tested it on Alzheimer's patients.  Studies are likely to begin very very soon, but it will take time - possibly years - before we know if it can slow the progress of Alzheimer's.  But for a disease that affects a huge percentage of the population, with no current treatment, this could be a huge breakthrough.