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Issue #56: Vaccination and some basic considerations re Interventional Clinical Trials

10 May 2021

Issue #56: Vaccination and some basic considerations re Interventional Clinical Trials

Anyone who was keeping a close watch on unfolding events through 2020 as the various COVID-19 vaccine candidates (#43, #44) were being tested in humans would be familiar with the idea that the evaluation process requires a progression through ‘graded’ Phase I, Phase 2 and Phase 3 clinical trials. What was so fascinating here was to watch the rapidly emerging stature of novel products (the candidates) as ‘interventions’ to lessen the risk posed to humans by SARS-CoV-2 infection. So far as I’m aware, the ‘intervention’ with all the COVID-19 vaccines tested so far has been to inject 0.5ml or more of fluid containing the candidate vaccine deep into the musculature (the deltoid) of the upper arm (#40).

Medically, an ‘injected vaccine intervention’ is at the low end of what’s termed an ‘invasive’ procedure. The needle first goes through the various layers of skin to a depth where the tip should embed in muscle mass and, with pressure exerted by the vaccinator pushing down on the syringe plunger, the volume in the syringe barrel distributes locally into both the surrounding cells and extravascular fluid. Any tissue damage will be rapidly repaired but, while the monitoring protocol for a vaccine trial will likely require reporting back on effects detected around the injection site – pain, reddening and swelling – there will be no investigation of where the stuff actually goes.

Unlike the situation for ‘small-molecule’ anti-cancer drugs that are injected on a mg/kg basis, no adjustment relative to body weight is made to the ‘adult’ vaccine dose –determined from preliminary studies - of the amount needed (say 10, 50 or 100 mg) to generate an optimal antibody response. In the advanced stages of a vaccine trial, everyone gets the same product given in the same volume in the same way. Keeping to a standard dose removes one ‘variable’ from the trial design. That’s not to say, though, that diversity in gender, body mass, age and so forth is ignored in an Interventional Clinical Trial.

Before people are accepted as participants in a COVID-19 vaccine trial, they must first read, then sign an ‘informed consent’ form (#53, #54) that lays out the available information about personal risk, explanations of how the trial will be conducted and what they will be told when the results are analysed. As potential trial subjects, they will answer questions re their age, sex, current medications, any chronic disease problems (hypertension, diabetes and so forth), a history of adverse vaccine or drug reactions, whether they are persistently infected with (say) HIV or hepatitis C virus (#28) or other issues that might be thought to have a skewing effect on trial outcome. Some of this input may lead to the exclusion of, for instance, people suffering from a particular condition or taking a drug that might negatively impact their capacity to make an optimal immune response. Then there will likely be a requirement for a medical examination. That will include measuring height and weight – to calculate an individual’s body mass index (BMI) – and being bled to supply a blood sample, both to ensure there is no circulating antibody to SARS-CoV-2 (indicating prior infection) and to provide a negative control.

The collection of such information from human subjects will of course, have first been approved by a local, fully independent Human Research Ethics Committee (HREC) that has scrutinised and approved the trial design. In Australia, the HREC process follows national guidelines, though requirements can vary from State to State. And, unlike the situation for Observational Clinical Trials (#54), any Interventional Trial has an absolute requirement for a large ‘control’ group that receives a ‘placebo’ instead of the vaccine candidate. Most commonly, the placebo group – perhaps in equal numbers or 2:1 for test subjects versus controls – is injected with saline, as in the Pfizer/BioNTech vaccine trial, or with some unrelated product like the Meningococcal vaccine (MenACWY) used in one of the AstraZeneca trials (#43, #44). 

Before anyone is given anything, however, it’s obviously essential that the test and placebo groups be as identical as possible. How is that done? Once enough people have been recruited for the trial to begin, the personal data accrued for each individual will be fed into a sophisticated software program that ‘randomises’ the subjects into the two groups. And you’ve no doubt heard emphatic statements to the effect that a legitimate Interventional Trial must be ‘double-blind’. What does that mean?

A double-blind trial is one where neither the organisers of the trial, nor the participants know who has been injected with the test candidate versus the placebo. Obviously, if neither of those groups is aware of who is getting what, there has to be a third partner that can access such information. This is the fully independent DSMB, or Data Safety Monitoring Board, that is constituted separately for each trial and can, if red flags are being raised re what seems to be happening clinically, break into the de-identified (control versus test) data to see whether there is a skewed distribution to one or other group.

Next week we’ll look at more details of the progressive trial process, and also discuss briefly why it is that vaccine trials must be so much bigger, and are much more demanding in many respects, than therapeutic (as distinct from prophylactic) drug trials (#1).

Peter C Doherty 10 May 2021

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