Jan 11 Here in India, we are readying for the "rollout" of two corona vaccines, Covishield and Covaxin. While that's good news of course, there are some troubling aspects to this rollout, especially about their clinical trials. I've written before about trials and their mathematical nature, and it's in that spirit that I wanted to explore my concerns about these vaccines.
This column appeared last Friday, Jan 8. Take a look: https://www.livemint.com/opinion/columns/what-numbers-say-or-don-t-about-a-vaccine-11610041019752.html Reactions welcome, as always. yours, dilip ---- What the numbers say, or don't, about a vaccine Here's something worth forgetting about any vaccine for the Corona virus - though really about any drug. I'm talking about the notion that the vaccine will necessarily have no side-effects; that it will therefore be "100% safe". It's worth forgetting, because in this context, that is a meaningless number. For every drug known to mankind has some side-effects. They may not be serious, they may not affect you in particular, and even if they do, you may not notice them - but they're there, and some who use the drug will experience those side-effects. And since that's the case, the challenge for every company that produces a new drug is not to attain a mythical "100% safe" mark. Instead, it is to evaluate the risks and side-effects of the drug and weigh those against the benefits. It is to then make this knowledge available to customers who buy and use the drug. For just one example, a simple web search will tell you that taking one aspirin daily has at least these two possible side-effects: a stroke caused by a burst blood vessel, and gastro-intestinal bleeding. If those sound serious to you, you will wonder: Why is aspirin on the market at all, and prescribed regularly by doctors? Simple. Because it acts to reduce blood's tendency to clot. That's why taking an aspirin a day can prevent a heart attack in people already at risk of one, or who have already had one. We learned this when aspirin went through its clinical trials. The scientists conducting the trials concluded that the benefits generally outweigh the risks, and that's why aspirin is widely available. Though to be sure, there are still some experts who don't believe this; and in any case, you as a potential consumer of aspirin should weigh the risks and benefits yourself, before making a decision. Much the same analysis and reasoning apply to the vaccines against Corona that are now appearing. And that's how we should examine the claims about the vaccines against the Corona virus that are now being administered in India: Covaxin and Covashield. As we now know, these two vaccines have been approved for public use in India. One, Covaxin, was approved without any public disclosure of data from its trials. In fact, the other, Covashield's, claimed Phase-3 trial doesn't look like one either: as the health expert Dr Gagandeep Kang said recently, it is "what would be called a Phase-2 study in other parts of the world, i.e. for safety and immunogenecity and not for efficacy." Given all this, how should we react to the claims being made about these vaccines? Remember that these various trials are essentially statistical and mathematical exercises. Thus we should examine them in those terms and no other. "EFficacy", for example, is a measure of the ability of the vaccine to generate what we are all in search of, an immunity to the virus. We determine that statistically, after a large Phase-3 trial, often on tens of thousands of people. If two-thirds of them develop immunity, for example, we say the vaccine has a 67% efficacy. Only, we have no Phase-3 data for Covaxin. So we have no way of knowing what its efficacy really is. What we have instead are claims. The Drugs Controller General of India, VG Somani, was quoted in the Indian Express on January 6: "The Phase 3 efficacy trial [for Covaxin] was initiated in India on 25,800 volunteers and till date, approximately 22,500 participants have been vaccinated across the country and the vaccine has been found to be safe." What do we make of this statement? To start, note that it does not address the issue of efficacy at all, even though Somani calls it an "efficacy trial". After an "efficacy trial", we should see language something like this: "15,000 of the 22,500 vaccinated participants - 67% - have developed immunity to the virus." Instead, we get the claim that "the vaccine has been found to be safe." No measure of efficacy there. Though even "found to be safe" is merely a claim. It should have been supported by data from Covaxin's Phase-1 and Phase-2 trials, which were explicitly meant to test safety. We know this because of the mandatory submissions about those trials by Bharat Biotech - the creators of Covaxin - to the Government of India's "Clinical Trial Registry - India" (CTRI, at ctri.nic.in). According to those submissions, Covaxin's Phase-1 trial was registered on July 1 2020. The drug was to be administered to 1125 volunteers and the trial had an "estimated duration" of 15 months; that is, it would run until October 1, 2021. But just over two months later, on September 8 2020, its Phase-2 trial was registered, to run on 124 volunteers for 8 months, or till May 8 2021. The "primary outcome" for both these trials, again according to those CTRI submissions, was to check for "adverse events" and to evaluate immunogenecity; in other words, the drug's safety and its ability to produce an immune response in volunteers. Make what you will of these declared trial durations; that we are still months away from even one of the two trials being completed; that the second trial began while the first was still in progress. But note that these tests for safety ran on a sum total of 1249 people. We have no public data on how these people reacted to the prospective vaccine, but Somani tells us "the vaccine has been found to be safe." In fact, he even used a number in the same news report: the vaccine is "110% safe". What did he mean, you might wonder: that of 1249 volunteers on whom Covaxin is being tested for safety, 1375 showed no side-effects? The MD of Bharat Biotech, Krishna Ella, was still more emphatic a few days earlier. ANI quoted him saying "our vaccine is 200% safe." With all this safety apparently in the bag, Covaxin's Phase-3 trial was registered at CTRI on November 9 2020. Phase-3 was intended primarily to "evaluate the efficacy" of the vaccine, while secondarily evaluating its safety and immunogenecity as well. This one was indeed for 25,800 volunteers and was to run for a duration of 1 year - till November 9 2021. Make what you will, again, of this declared duration; that the Phase-3 trial began long before the Phase-1 and Phase-2 trials are scheduled to end; that we are again months away from the scheduled completion of Phase-3. But less than two months later - months before any of its three trials are concluded, without any data about those who volunteered for the trials - Covaxin has been approved for public use. Our Health Minister tells us this is "in clinical trial mode". In theory, all 1.4 billion of us Indians can now have it injected into us. Numbers, numbers. From 110% to 200%; from 124 to 1125 to 25,800 to 1.4 billion; from 8 months to 12 months to 15 months. After all, remember again that these trials are essentially statistical and mathematical exercises. So we should expect plenty of numbers. Except ... especially for a vaccine that has been approved, these are hardly the numbers we should expect after these exercises. What fraction of those 124 developed adverse side-effects? What fraction of the 22,500 developed immunity to the virus? How did that compare to groups who got placebos as a necessary part of the trials? (The trials did use placebos, I presume.) Numbers like that. Think of them, yearn for them, over the next weeks and months, as you prepare to be vaccinated. -- You received this message because you are subscribed to the Google Groups "Dilip's essays" group. To unsubscribe from this group and stop receiving emails from it, send an email to [email protected]. To view this discussion on the web, visit https://groups.google.com/d/msgid/dilips-essays/CAEiMe8r47zyhK%2BHbOEH9V8X%2Bp4MXXCKcJNd0A0PN%3Dqu3%2B7zHXg%40mail.gmail.com.
