Yves here. Note that this “full speed ahead on a vaccine” follows the FDA fiascoes on masks, testing, ramping Gilead stock, and emergency use authorizations for hydroxychloroquinine and plasma. This sort of thing may cheer Wall Street, but it’s the last thing cautious individuals want to see. And if you read the article, admittedly well into it, the authors give reasons to be concerned about this rush, the big one being that the FDA’s notion of “overwhelming” is anything but.
By Liz Szabo, an award-winning senior correspondent for KHN who previously covered medicine for USA Today and The Virginian-Pilot. Originally published at Kaiser Health News
A COVID-19 vaccine could be available earlier than expected if ongoing clinical trials produce overwhelmingly positive results, said Dr. Anthony Fauci, the nation’s top infectious disease official, in an interview Tuesday with KHN.
Although two ongoing clinical trials of 30,000 volunteers are expected to conclude by the end of the year, Fauci said an independent board has the authority to end the trials weeks early if interim results are overwhelmingly positive or negative.
The Data and Safety Monitoring Board could say, “‘The data is so good right now that you can say it’s safe and effective,’” Fauci said. In that case, researchers would have “a moral obligation” to end the trial early and make the active vaccine available to everyone in the study, including those who had been given placebos — and accelerate the process to give the vaccine to millions.
Fauci’s comments come at a time of growing concern about whether political pressure from the Trump administration could influence federal regulators and scientists overseeing the nation’s response to the novel coronavirus pandemic, and erode shaky public confidence in vaccines. Prominent vaccine experts have said they fear Trump is pushing for an early vaccine approval to help win reelection.
Fauci, director of the National Institute of Allergy and Infectious Diseases, said he trusts the independent members of the DSMB — who are not government employees — to hold vaccines to high standards without being politically influenced. Members of the board are typically experts in vaccine science and biostatistics who teach at major medical schools.
“If you are making a decision about the vaccine, you’d better be sure you have very good evidence that it is both safe and effective,” Fauci said. “I’m not concerned about political pressure.”
The safety board periodically looks at data from a clinical trial to determine if it’s ethical to continue enrolling volunteers, who are randomly assigned to receive either an experimental vaccine or a placebo shot. Neither the volunteers nor the health workers who vaccinate them know which shot they’re receiving.
Manufacturers are now testing three COVID vaccines in large-scale U.S. trials. The first two studies — one led by Moderna and the National Institutes of Health and the other led by Pfizer and BioNTech — began in late July. Each study was designed to enroll 30,000 participants. Company officials have said both trials have enrolled about half that total. AstraZeneca, which has been running large-scale clinical trials in Great Britain, Brazil and South Africa, launched another large-scale vaccine study this week in the U.S., involving 30,000 volunteers. Additional vaccine trials are expected to begin this month.
In trials of this size, researchers will know if a vaccine is effective after as few as 150 to 175 infections, said Dr. Robert Redfield, director of the Centers for Disease Control and Prevention, in a call with reporters Friday.
“It may be surprising, but the number of events that need to occur is relatively small,” Redfield said.
Right now, only the safety board has access to the trial data, said Paul Mango, deputy chief of staff for policy at the Department of Health and Human Services. As for when trial results will be available, “we cannot determine if it will be the middle of October or December.”
Safety boards set “stopping rules” at the beginning of a study, making their criteria for ending a trial very clear, said Dr. Eric Topol, executive vice president for research at Scripps Research in San Diego and an expert on the use of data in medical research.
Although the safety board can recommend stopping a trial, the ultimate decision to halt a study is made by the scientists running the trial, Topol said.
A vaccine manufacturer could then apply to the Food and Drug Administration for an emergency use authorization, which can be granted quickly, or continue through the regular drug approval process, which requires more time and evidence.
Safety monitors also can stop a trial because of safety concerns, “if it looks like it’s actually harming people in the vaccine arm, due to a lot of adverse events,” Fauci said.
Fauci said people can trust the process, because all the data that outside monitors used to make their decisions would be made public.
“All of that has to be transparent,” Fauci said. “The only time you get concerned is if there is any pressure to terminate the trial before you have enough data on safety and efficacy.”
Topol and other scientists have sharply criticized the FDA in recent weeks, accusing Commissioner Stephen Hahn of bowing to political pressure from the Trump administration, which has pushed the agency to approve COVID treatments faster.
Stopping trials early poses a number of risks, such as making a vaccine look more effective than it really is, Topol said.
“If you stop something early, you can get an exaggerated benefit that isn’t real,” because less positive evidence only emerges later, Topol said.
Stopping the studies early also could prevent researchers from recruiting more minority volunteers. So far, only about 1 in 5 trial participants are Black or Hispanic. Given that Blacks and Hispanics have been hit harder than other groups by the pandemic, Topol said, it’s important that they make up a larger part of vaccine trials.
Ending vaccine trials early also carries safety risks, said Dr. Paul Offit, a vaccine developer who serves on an NIH advisory panel on COVID vaccines and treatments.
A smaller, shorter trial could fail to detect important vaccine side effects, which could become apparent only after millions of people have been immunized, said Offit, director of the Vaccine Education Center at Children’s Hospital of Philadelphia.
Researchers will continue to follow vaccinated volunteers for a full year to look for long-term side effects, Redfield said.
And Fauci acknowledged that cutting a trial short could undermine public confidence in COVID vaccines. One American in three is unwilling to get a COVID vaccine, according to a recent Gallup Poll.
This has all the makings of a very messy situation. I have no time for anti-vaxxers, but I’d be very reluctant to take any Covid vaccine that hasn’t had a rigorous long term test. There is simply too much external pressure, political and economic, on regulatory systems that haven’t proven themselves robust enough in the past to give me confidence in any rapid approval.
The problem of course is that people with legitimate concerns about a vaccine will inevitably be lumped in with anti-vaxxers, who in turn will be crowing ‘I told you so’. And of course it will be politicised – not just in the US and UK, but we’ve seen in Russia and China and elsewhere that there is a groundswell of national pride in ‘our’ vaccine and it’s become used as a geopolitical tool.
I think that even if there is a major breakthrough soon it will be a long time before we will be able to see community level vaccination. A more realistic scenario is one or more vaccines being released on a phased basis parallel with rigorous studies, starting with the most vulnerable and gradually being extended to the general population only when the full results of proper clinical studies have been completed. This could take several years.
I don’t understand how they’re event making plans yet to circumvent normal processes. Phase II trials are where the rubber hits the road. Phase III weeds out even more drugs.
And I can’t even trust that they’ve done the Phase II trial correctly. Especially when they have almost no liability for screw ups.
Plutonium Kun and cocomaan: I agree with both of you. Your observations are the best and most rational approach to creating a viable, effective vaccine that meets with least resistance.
My only reservation would be with PK’s plan to start with the vulnerable. It seems to me that the vulnerable require some assurances–which would mean a wider scope of participants (stratified by age, demographics, gender) and a vaccine backed by more than cursory study.
I am wondering if short cuts could lead to liabilities. What Fauci has supposedly said, terminating a trial soon would be equivalent to breaking the safety rules of vaccine development. Phase III trials are NOT only done to assess vaccine efficacy as this article suggests and the director of the CDC seems to believe. Trials aren’t terminated when you have an early estimate of efficacy. The reasons these trials involve dozens of thousands of volunteers is risk assessment which is the other important arm of the trial. Besides, the duration of protection has to be assessed for at least 6 months.
Fauci’s and Redfield’s words are indeed a sign of strong political pressure. This is very insane. I can understand, and have become accustomed to see, quoted idiotic tweets from Trump but these other guys should know better.
My understanding of the phased “new treatment” assessment process is
Phase I: toxicity trials: what is the highest tolerable dose of the agent and what are its short-term side effects? Outcomes are tracked, but are not the primary concern.
Phase II: absolute efficacy trials: does the agent result in a measurable effect on disease, compared with placebo control?
Phase III: relative efficacy trials: does the agent perform better than the current standard of care? The control treatment is another medication which is currently regarded to be the best available.
Given that there are no approved/tested treatments for COVID-19, I don’t think that Phase III trials can take place. The process would terminate with Phase II and if the agent shows acceptable toxicity and therapeutic effect within the tolerable dose range, it would become the standard of care and would be the Phase III control of future agents.
This in incomplete. Phase III is not only for efficacy measurement but also to detect adverse effects in a large enough population. If so, classify them as common or rare depending on observed frequencies. Detecting those can be tricky. Some of the adverse effects would be noticed only after challenge of vaccinated individuals indicating that to assess those longer times are needed. Besides, Phase III might incorporate cohorts analysis (by age, race etc.)
Some of the adverse effects, such as Antibody-dependent Disease Enhancement can be seen only after vaccinated individuals become challenged by the disease so these are not detected during Phase I/II trials with so few vaccinated individuals.
“Each study was designed to enroll 30,000 participants. Company officials have said both trials have enrolled about half that total. AstraZeneca, which has been running large-scale clinical trials in Great Britain, Brazil and South Africa, launched another large-scale vaccine study this week in the U.S., involving 30,000 volunteers. Additional vaccine trials are expected to begin this month.”
I may have missed it but I am wondering how these “volunteers” are recruited. Are they paid? What are the criteria to be included? What does the contract that is signed state? How many healthcare professionals have volunteered? What is the socio demographic composition of the volunteers? Many other questions arise. I have seen very little in the MSM on this subject.
Then: “Researchers will continue to follow vaccinated volunteers for a full year to look for long-term side effects, Redfield said.”
So, the vaccine may be released for use before a year is up, yet “long-term side effects” may still occur. The sentence also seems to indicate that the side effects will only be studied for a year. My understanding is that side effects may take more than a year to develop.
The article does not indicate who is on the Safety Board nor how they are appointed, how they are paid, etc. For transparency, it would be necessary to know much more about the Safety Board.
(Having once been concerned about a trial of a treatment involving my own health, these studies are highly complex. One factor that for me is vital is: How do my medical characteristics match up with the selection factors for the trial? In this case, for example, if you are 65, have diabetes and obese, are people like you in the study? This is even more important if the Government decides to force vaccination upon you.)
On Reddit, of all places, there are frequent discussions about these trials, and semi-regularly people pipe up who are participating in them. You could try to find those posts, or ask your questions there:
Here you find what the NIH has to say about Data and Safety Monitoring Boards: https://www.nidcr.nih.gov/research/human-subjects-research/toolkit-and-education-materials/interventional-studies/data-and-safety-monitoring-board-guidelines From section II: “The Program Official (PO) holds primary responsibility for the formation of the DSMB unless the Clinical Terms of Award for a grant or the Roles and Responsibilities negotiated for a protocol specifically identify this as the responsibility of the grantee. The PO (or grantee as specified) is responsible for developing the roster of potential DSMB members. Recommendations for proposed members are solicited from many sources. Study investigators and the industry collaborators should have the opportunity to review the list of proposed members before the candidate’s interest and availability are confirmed by the PO (or grantee as specified). The proposed roster of members must be submitted to the Director, Office of Clinical Trials Operations and Management (OCTOM), NIDCR, and NIDCR Medical Monitor for review and approval before invitations are issued.”
I’ve always been Pro-Vaccine…the science is sound, and there were a few people in and around my family who had polio back in the day, so Salk was a sort of minor saint among my people.
Out of the four of us in this house, I alone have had the flu at all in 10 years…once…a Type B that the vaccine makers missed a few years ago….and didn’t hide that they’d missed it.
(we did all get the flu prior to that, once, when we got covered up with our doings and missed the vaccine(they ran out)…never again, lol)
But i won’t be in the front of the line for this.
Trust and Legitimacy…and “bite me once…”, with things like Vioxx, etc…and the long term hollowing out and capture of regulatory agencies, including the FDA…as well as all the surreal nonsense we’ve been treated to this year…well, no.
so well done, America.
Out here, there’s a lot of anti-vaxxers…has more to do with religion than with politics. And Facebook, of course…larded on to a general lack of understanding about Science. There’s even otherwise smart people I know who are in this camp…and they and their kids endure the flu every year,lol.
One of these otherwise smart ones is very forceful in her circles, as far as influence and “winning arguments”…I find that i can pretty easily eviscerate whatever argument she’s making, but i am thereby ruled a crazy person.
You can’t win against these folks.
and that was the situation BEFORE all this Covid insanity.
So I’ll be waiting for at least a month or two before i offer up my arm.
Let the Natural Experiment have time for any egregious adverse events to manifest.
It’s an uncomfortable position to be in, for sure.
so again, Well done, America.
Keep on shining on that hill.
an object lesson for the world of how not to do things.
I’m waiting a year or so before offering my arm. Way too much danger of an Outcome like:
“oops. Didn’t know it would kill old guys with pre existing conditions. Oh, well. Too bad. So sad.”
I have never liked introducing substances into my body which it cannot reject. As a result I have never had a flu vaccination — indeed, I avoid medical practice of any sort when possible. I have had flu-like illnesses three times in my 80 years, the first two when still within the shadow of imposed vaccination. I’ve avoided the plague (and previous flu epidemics) by masking, distancing, and avoiding closed, unventilated environments; if most other people had done so, the virus would have long since disappeared. I suppose many people cannot because they are forced or tricked into employments where self-protection is difficult or impossible. Vaccination is a sort of violent solution to that problem, as well as the deep urge of humans to congregate in bars and bark and howl at one another. We are a remarkable species.
In any case I am not at all uncomfortable about avoiding COVID-19 vaccination until the early adopter types have tried it out for awhile. It’s only common sense. The situation has been made much worse by the politics and accompanying propaganda, lies, and obfuscation. And the aforesaid barking and howling, of course.
I don’t think the US has a monopoly on the tendency to do things the hard way.
For the large donor class, the point of rapid vaccine development is to declare victory as soon as possible, just as it was with Reopening. They didn’t care about the dead that might result from Reopening, and they won’t care about the dead and suffering that result from a harmful or ineffective vaccine.
What I will be watching to see is the vaccine uptake among the concierge medicine class; they had early access to scarce tests, and they will have first shot at the vaccine.
Flu vaccine is often held up as an exemplar, but my experience has been pretty poor — maybe about 40% effective. I will still get it, because I have too few ski touring seasons ahead of me, and I cannot afford to lose more time to the Flu. I will get it again, but count me a skeptic.
Every year there are two types of media stories about the Flu immunization that happen, as if they are part of the turning of the seasons: in late Summer, the Get Your Flu Shot stories, and in late spring, the Gosh The Vaccine Didn’t Work Too Good stories. I won’t say they are making excuses for poor immunization performance (in 2014-15 the vaccine in the UK had a 3% effectiveness rate in most people!), but something is not right. You wonder if the whole Influenza effort as been “optimized” for something other than immunity.
While the mass media stories attribute the lack of effectiveness to the difficulty of identifying which strains of Flu active during the austral Winter will be active in the boreal Winter, plenty of medical commentary points to lack of resources devoted to identification of the strains, limitations of the vaccines themselves (the move this year from a three-strain trivalent vaccine to a four strain quadrivalent vaccine, and double-strength vaccines for people over 65 is acknowledgement of this), and a shortage of vaccine production facilities that require longer lead times for production (forcing the choice of virus strains to be identified early in the southern Summers). There also appears to be a lack of funding for evaluating effectiveness after the fact.
This year, I am making sure I will get a quadrivalent vaccine. After being sick with both Influenza A and B last year for most of the winter, I would love to get the double dose, but I am just a little too young for it.
I agree. I think the most important thing you point out is the lack of funding and resources to do the annual flu vaccine right…that says a lot, right there.
vaccines are generally money losers, and don’t fit well at all into the Profits Uber Alles Model of Modern Medicine.
we could, and should, do better as a species on this front.
That said, I have nothing but respect for the flu detectives at large in the chinese hinterlands right this moment, taking samples and attempting to figure out which strains will be the problem more than a year from now.
That they get it right as often as they do is a remarkable achievement, and those are the sorts of people who should have schools named after them.
adding: “What I will be watching to see is the vaccine uptake among the concierge medicine class; they had early access to scarce tests, and they will have first shot at the vaccine.”
yes…I’ll be monitoring them, too.
lots of healthcare people in my life to keep an eye on and periodically interrogate.
They’re the canaries.
….and to be clear…I want a safe and efficacious vaccine for covid, and i’d prefer that whatever percentage necessary for true herd immunity takes the shot…but the masters have screwed up the world far too much for me to just take their word for it.
(and I do, indeed, think about just that every october when we go for the flu shot…and it pisses me off how bad the bosses have allowed things to get)
Meanwhile, simple $1 paper test strips are in FDA limbo. Corruption or incompetence?
The fastest a vaccine has ever been developed was Ebola. In that case, because the fatality for the disease is so high, and because the number of people who would benefit from being vaccinated against Ebola was so low, the safety margin for error is actually quite a bit looser than you might think.
[It’s still worth having a vaccine, even if it kills say 0.1% of those administered with it, because the fatality for contracting Ebola is so high. You would only administer it to confirmed contacts of confirmed cases of Ebola, rather than blanket immunisation for everyone.]
That took five years.
I’m not an anti-vaxxer, of course, but only because I am aware how unbelievably rigorous and stringent the standards now are for getting vaccines to be approved. In this unbelievably politicised environment, with the enormous pressures on the scientists and regulatory authorities concerned, and given the speed at which this has been developed, I am very concerned about any “fast-tracked” vaccine.
All it will take is a handful of cases of GBS or some similar nasty – or even reports of the same, frankly, which seem inevitable – and your plan to achieve herd immunity through vaccine becomes very dicey.
halcyon: Thanks for putting this into perspective. I agree with your observations.
There is a national program for vaccine injury victims, established 1986. Anti-Covid vaccines are exempt:
Of course the FDA will greenlight it as quickly as possible. And even though the US gov’t (and other gov’ts around the world) are offering substantially funding to make sure these companies make profits, watch them gouge the US population, not once, but obviously with a booster vaccination as well, which will provide a profits’ bonanza.
Consider this nugget from the NY Times the other day: “If a COVID-19 vaccine yields a price of, say, $500 a course, vaccinating the entire population would bring a company over $150 billion, almost all of it profit…”
Every other developed country has evolved schemes to set or negotiate prices, while balancing cost, efficacy and social good. The United States instead has let business calculations drive drug price tags, forcing us to accept and absorb ever higher costs. That feels particularly galling for treatments and vaccines against COVID-19, whose development and production is being subsidized and incentivized with billions in federal investment.
When AZT, the first effective drug for combating the virus that causes AIDS, was introduced in 1992, it was priced at up to $10,000 a year or about $800 a month. It was the most expensive prescription drug in history, at that time. The price was widely denounced as “inhuman.” Today that price gets you some drugs for toenail fungus.
But investors already smell big money for a COVID-19 vaccine and it is their pressure, not Trump, that will ensure a quick roll out
The market cap of Moderna, a small Boston-area company that has partnered with the National Institutes of Health in the vaccine race, has tripled since Feb. 20, to $23 billion from $7 billion, turning its chief executive into an overnight billionaire (although it was interesting to note the amount of insider sales after the successful phase I tests were announced):
“While Moderna’s vaccine is regarded as a strong contender, the company has never brought a successful drug to market.” (From https://khn.org/news/analysis-how-a-covid-19-vaccine-could-cost-americans-dearly/)
…and that’s just the tip of the iceberg in the ongoing and escalating ripoff of the taxpayer, all of it cloaked in the manufactured COVID hysteria fueled by Wall Street, Big Pharma and Bill Gates.
No way a vaccine couid cost so much and specially vaccines designed for massive deployment which benefit from economies of scale. (From memory, I think J&J’s vaccine would go to about 5$ per course).
It is insane from the very beginning asserting that some trials will be finished before the end of the year, having started in July the earliest. One thing is ‘green-lighting’ that might be tried to be accelerated (erroneously IMO) and another thing is terminating the trial too soon which would be an enormous mistake of unimaginable scale. The standards for safety assessment require longer term follow up of the volunteers to check for any potential adverse effect (that might take several months to be evident), so the trials must last for at least a year. This article cites overoptimistic takes that go beyond common sense. For instance that of Redfield is insane to the bones. How can one seriously say that you need only a small number of events? It is true that you don’t need large numbers to estimate efficacy but this is not the only point of Phase III trials. Yet to need to check whether the efficacy is kept over time, for 6 months to say the least. Safety assessment is a requisite also and requires much larger numbers to identify possible adverse effects that could have low probability or even be rare (but yet significant when we are talking about the population at large).
The press has been criticizing the lower safety standards of Chinese or Russian candidates and then they come with this insanity? Making vaccine development political could be one of the biggest mistakes of this administration.
If you see that a vaccine is approved ONLY in the US, be wary.
I took the Redfield quote to mean “as few as 150 infections indicate that the vaccine is garbage and we can stop the trial.” That seems perfectly reasonable to me.
If you read the link in the quote you’ll see that 150 infectious observations is related to a vaccine efficacy of 50% with a 95% statistical confidence level. That number goes higher and higher as the efficacy level improves. A 50/50 chance that the vaccine is ineffective will encourage those vulnerable to the worse medical outcomes to avoid it; like the plague.
Are you disagreeing with me? That sounds like exactly what I wrote: if your target is 50% efficacy, and a “surprisingly” small number (150) of infections can show you haven’t met that target, then the trial can be abandoned early.
No. This is bad interpretation. In the trial you have vaccinated and non vaccinated, then you see the infections in both arms, compare and determine efficacy. To do this calculation you don’t need too many being infected, but at least a few hundreds in the unvaccinated arm, and whatever results in the vaccinated arm.
And even if you find the vaccine doesn’t fulfil the requirements the trial cannot be terminated as you have to go on checking other possible adverse effects.
I think you might have missed a critical part of the article:
There doesn’t seem to be any room for ambiguity here: the trials will be halted early if the vaccines are overwhelmingly shown to be ineffective. It doesn’t seem like much of a stretch to imagine that Redfield is referring to this possibility.
You missed a word
…end the trials weeks early if interim results are overwhelmingly positive or negative.
So, besides what you said, he is also saying unambiguously that if the results are overwhelmingly positive the trials could be terminated and the vaccine approved. For that, not so many cases of infection would be needed.
Both, Fauci and Redfield, are sowing the seeds in public opinion for fast approval and because the public at large ignores the process of vaccine trials/approval they are succeeding. Your interpretation is good example IMO. It seems to me that you are willing to read only part of the quote.
Family members that are ER docs and other heath prof and of quick vaccine everyone said I will wait and see.
I used to work with heroin addicts.
The secret to being an old junkie was to be very geonerous and let someone else shoot up first and see what happens.
Would you buy a used car from gangsters? I trust in the idea and science of vaccines, but I don’t trust the US govenrment or corporations as far as I can spit: they constantly lie, conceal information, cheat, and steal, like Pompeo, Clapper, Schiff, and the rest of fascists.
Would you inject a small F-35, or glyphosate, Russiagate, or a war on Libya, into your arm? would you swallow the latest unemployment and economy numbers?
Well, that’s the problem, isn’t it? We have no trust in our institutions anymore so people don’t trust anything that comes from them either.
That’s maybe not the end of the world with official statistics but it will prove to be a huge challenge if no one healthy will accept whatever vaccine is produced :/
Folks, folks, folks, folks!!
There are literally millions and millions of high risk people all over the world who will be clamoring for vaccine protection so that they can go on with their lives. Medical people, obese people and other people with pre-existing medical conditions, nursing home patients, immuno-compromised patients.
So sit back and wait while those of us with high risk spouses get our vaccines first!
But that’s not how this works? You don’t give the vaccine to the high risk population until after you’ve shown it’s not a problem in the healthy population. You accomplish two things with that approach. 1, you decrease likelihood of transmission to the high risk population. 2, you test the vaccine to make sure you understand any complications before the higher risk people get the vaccine. The people with serious comorbidities should be last in line for any vaccine.
By the time the vaccine is widely available there should be enough short term side effect results so that high risk populations will be given the option. Many with serious risks and terrible lifestyles will take that risk. Many will volunteer their risk. Like nursing home patients.
Because of some of the large numbers being bandied about as potential profits, I am just as concerned about the accuracy and transparency of the reporting of adverse effects.
If I recall correctly, adverse side effects is reported through the FDA, which has its problems with regulatory capture.
It would be wise if any vaccine maker liability immunity was tied to accurate reporting of bad outcomes and side effects.