10th October 2020
[But concern may be in order]
I suppose most people believe the trials on vaccines for COVID19 will be looking to demonstrate that they reduce the risk of infection, death, or serious illness – or suchlike.
Also, you may have heard that several vaccines could be ready for use early next year 2021. Maybe even later this year.
As Dilbert may retort: Hahahahahahahahahahahaha! Oh, let me pause and wipe away my tears of mirth.
Really. Think about it. Then think a bit more…
AstraZeneca (AZ) is thought to be leading the pack with their vaccine AZD1222. Their major clinical trial will recruit 30,000 participants – which is good. You can find the trial description on Clinicaltrials.gov. It goes by the snappy title ‘Phase III Double-blind, Placebo-controlled Study of AZD1222 for the Prevention of COVID-19 in Adults.’ 1
You may be interested in the start and end date of this AZ trial:
Estimated Study Start Date: August 17, 2020
Estimated Primary Completion Date*: December 2, 2020
Estimated Study Completion Date: October 5, 2022
*date when all volunteers have been recruited onto the trial.
As you can see, even if all goes to plan, their study will not be completed until two years from now. Then they will have to analyse the data and suchlike, which will take a couple of months, even as a rush job. Which means they are unlikely to have everything sorted before early 2023.
For those who were claiming, a few months ago, that a vaccine would be ready by September this year i.e. a month ago, this would be stretching the word ‘ready’ far beyond its natural boundaries.
As for studying deaths from COVID19, this trial will not be looking at anything as tricky as that. Preventing deaths from COVID19 is not an end-point they are aiming for.
Below I have listed the primary end-points for study NCT04516746. By primary end-points, I mean those outcomes that will be used to determine if the trial has been a success or failure.
Sorry, jargon alert, and boring but also necessary, I feel, just so you know I am not making this stuff up. My comments in brackets [ ].
PRIMARY END-POINTS OF AZ STUDY
1: To estimate the efficacy of 2 IM doses of AZD1222 compared to placebo for the prevention of COVID-19 in adults ≥ 18 years of age [Time Frame: 1 year]
A binary response, whereby a participant is defined as a COVID-19 case if their first case of SARS-CoV-2 RT-PCR-positive symptomatic illness occurs ≥ 15 days post second dose of study intervention. Otherwise, a participant is not defined as a COVID-19 case.
[You may note that a positive SARS-Cov-2 RT-PCR test is not sufficient to define someone as having been infected with the virus – they must also have symptoms.]
2: To assess the safety and tolerability of 2 IM doses of AZD1222 compared to placebo in adults ≥ 18 years of age [ Time Frame: a: 28 days post each dose of study Intervention. / b: from Day 1 post-treatment through Day 730.]
a: Incidence of adverse events.
b: Incidence of serious adverse events, medically attended adverse events, and adverse events of special interest.
3: To assess the reactogenicity* of 2 IM doses of AZD1222 compared to placebo in adults ≥ 18 years of age (Substudy only) [ Time Frame: 7 days post each dose of study intervention.]
Incidence of local and systemic solicited adverse events.
*In vaccine clinical trials, the term reactogenicity refers to the property of a vaccine of being able to produce common, “expected” adverse reactions, especially excessive immunological responses and associated signs and symptoms, including fever and sore arm at injection site.
At this point I feel the need to point out that preventing deaths from COVID19 is not even a secondary end-point for this trial either. So, whatever else we will find out, we are not going to know if AZD1222 saves any lives. Or, to be technical, the trial is not sufficiently ‘powered’ to reach statistical significance for overall mortality.
Anyway, getting back to the timelines, you may now be thinking, how on earth are they planning to launch a vaccine next year, if they are not going to complete their key clinical trial until October 2022? Do they have a time machine?
Well, it goes like this.
Clinical trials – before a drug is approved – normally go through three clinical phases.
- Phase I: Evaluate safety, determine safe dosage, identify side effects (in a small group of human volunteers, maybe twenty or thirty)
- Phase II: Test effectiveness, further evaluate safety (maybe a couple of hundred volunteers).
- Phase III: Confirm effectiveness, monitor side-effects, compare to other treatments (up to tens of thousands of volunteers).
Following completion of the Phase III trial, the data are sent to the regulatory authorities, who will then determine if the ‘drug’ is both safe and effective. Or at least safe and effective enough to recommend approval.
The AZ trial I have been talking about up to now, is a phase III trial, with 30,000 participants.
However, clearly, with SARS-Cov-2 vaccines, they are not going to (and cannot) wait for Phase III trials to complete. Instead, they are planning to launch directly after (what would normally be called phase II trials) to finish.
Regarding this, I was sent an e-mail by a friend regarding these phase II trials, and what they are trying to achieve. The e-mail is summary of an article by William A Haseltine who writes this, of himself.
‘For nearly two decades, [William A. Haseltine] was a professor at Harvard Medical School and Harvard School of Public Health where I founded two academic research departments, the Division of Biochemical Pharmacology and the Division of Human Retrovirology. I am perhaps most well-known for my work on cancer, HIV/AIDS, and genomics.’
You can look him up on Wikipedia if you like.2 Basically, it sounds like he knows what he is talking about, with regard to science, viruses and suchlike. Although when it comes to research on vaccines for COVID19 he seems to have spotted commercial reality for the first time in his life.
Here was the e-mail, sent to me:
Here is an interesting article about the COVID-19 vaccine trials written by William A. Haseltine, who was a professor at Harvard Medical School and Harvard School of Public Health, and who founded two academic research departments, the Division of Biochemical Pharmacology and the Division of Human Retrovirology.
Here are the two most important points he makes, which summarizes what he says in his article, are:
“These [vaccine] protocols do not emphasize the most important ramifications of COVID-19 that people are most interested in preventing: overall infection, hospitalization, and death.”
[The COVID-19 vaccine trials are only looking to see if these vaccines reduce symptoms that may be as mild as cough and headache. They are NOT requiring that the vaccines reduce the risk of infection, hospitalization or death.]
“It boggles the mind and defies common sense that the National Institute of Health, the Center for Disease Control, the National Institute of Allergy and Infectious Disease, and the rest would consider the approval of a vaccine that would be distributed to hundreds of millions on such slender threads of success.”
He also notes how few people there are in each of these studies for their interim analysis, which he says the companies will probably use to try and get Emergency Use Authorization from the FDA:
- “For Moderna, the interim analysis includes giving the vaccine to only 53 people.”
- “For Johnson & Johnson, their interim analysis includes [only] 77 vaccine recipients “
- “For AstraZeneca, their interim analysis includes [only] 50 vaccine recipients”
- “For Pfizer, their interim analysis includes only 32 people getting the vaccine.”
“These companies likely intend to apply for an emergency use authorization (EUA)
The full article was published in Forbes magazine, and can be seen there 3 .
In super-short form, the current plan is these vaccines will be launched after giving them to around fifty people – each. At which point we will have no idea if they prevent infection, hospitalisation, or death. In addition, we will not really know if they are safe, as the numbers involved are simply too small – and the timelines too short.
I hope you can now see my scepticism earlier this year, when people were claiming a vaccine could be made available six months after the start of the outbreak. I was aware – as is everyone else who knows how clinical trials are done – that this simply cannot be done. Or to be more accurate, the only way to do it is by cutting some essentially corners. The corners called ‘safety’, and ‘efficacy’.
Yes, I fully accept these are not normal times, and there is certainly a need for speed. Yes, I also accept that we probably should be willing to accept an increased level of risk to tackle the enormous problems caused by COVID19.
However, for the average person, between the ages of twenty and fifty, the upper range estimate of the risk of dying of COVID19, if you get infected, is 0.0003 = 0.03%, which is 3 in 10,000.4 This figure comes from the CDC in the US, which continues to stick to a higher estimated Infection Fatality Rate (IFR), than almost anyone else.
Their lower level estimated IFR for this age group is around one in 15,000. Either way, these are very low risk levels indeed. Under the age of twenty, the risk is almost incalculably small. So, for the majority of the population, under the age of fifty (realistically under sixty), we really should not be in a mad rush to vaccinate. We need the type evidence for both safety and efficacy that can only be provided by a Phase III trial.
However, I fear that such is the clamour for a vaccine, so desperate the need, we are going to be launching vaccine after vaccine, based on extremely thin evidence indeed. Not only that, it seems that in some countries, whilst reluctantly backing away from suggesting that COVID19 vaccination would be compulsory, are going to make it almost impossible to refuse.
Here is one headline, discussing the ideas being talked about in Australia ‘No overseas travel, and no welfare payments: The way the government will force people to get a COVID-19 jab – even as the PM insists the vaccine will NOT be compulsory.’
- Australians could face being banned from travelling overseas for refusing jab
- Federal Health Minister Greg Hunt said he would ‘not rule out’ strict measures
- Echoed prime minister saying he’d make vaccine ‘as mandatory as possible’
- Scott Morrison said later on Wednesday he had no power to enforce a vaccine
- Mr Hunt said government was not considering making inoculation compulsory
- But said authorities would have option of enforcing policies like ‘no jab, no pay’5
As mandatory as possible? Sorry, but mandatory is binary. It is, or it isn’t. As for the concept of compulsory vaccination. According to the Australian Prime Minister compulsory vaccination would mean pinning people to the floor and vaccinating them. However, telling people that they cannot travel, or work, or receive welfare payments, is tantamount to compulsion.
In my opinion, if we had fully tested vaccines, that were known to be both safe and effective, contemplating such actions would still be several steps too far. However, compelling people to get vaccinated, when all we have is Phase II studies to go on, ventures into extremely worrying territory.
We will effectively be compelling people to become participants in a massive medical research trial. It is my understanding that actions such as this would lie directly within the Nuremberg Code.
Point one: The voluntary consent of the human subject is absolutely essential.
This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, overreaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment. 6
The Nuremburg Code was written after the Second World War to ensure that nothing like the unethical human experimentation carried out then on prisoners would ever happen again.
If people want to take these vaccines, of their own free will, that is up to them, and they may be right to make that decision.
However, I am deeply concerned that many others will be coerced, one way or another, to be vaccinated against their will.