Issue #54: Ethics and observational clinical trials

Written by Nobel Laureate Professor Peter Doherty

Though I’ve now been involved in basic biomedical research for almost 50 years, that’s largely been spent as a laboratory-based experimentalist working with mouse model systems (#32, #33, #34). Now, all such studies are rigorously evaluated by Animal Ethics Committees comprised of scientists, other academics and lay people from diverse backgrounds. Comparable, but separate Human Ethics Committees play the same role with any systematic analysis involving people. Back when I started in science there was no requirement for any such scrutiny and approval process. The reason this change came about, especially on the medical side, rests in some appalling abuses that, as late as the 1970s, were perpetrated on vulnerable people. I reviewed some of that ‘horrible history’ in The Knowledge Wars and may also write about it later in this series.

Last week I discussed the fact that I’d enrolled as a research participant in two separate observational studies as part of studies aimed at getting much better data on immune responses to the Pfizer/BioNtech (PB) and Astra Zeneca vaccines. That’s my first experience of being a trial participant and, as I discuss clinical trials, you should also be aware that I’ve never designed one. As a consequence, some of the questions I’ve been asking informed colleagues have been pretty naïve and I’m a commentator, not an an authority, on the subject.

As I write this, I’ve just agreed to sign-up to a further study that, conducted by immunology colleague Sammy Bedoui, is ‘piggy-backing’ on Siddhartha Mahanty’s trial. So far as I’m concerned as a participant, Sammy’s initiative will further require that, on the day that I’m due to be bled for serum and white blood cells (WBCs), I will also need to supply a faecal sample. If you work at The Royal Melbourne Hospital (RMH) or the Doherty Institute, to enrol in Sammy’s study, you are required to be signed up for Siddhartha’s trial – which is looking for volunteers!

The overall aim is to see if an individual’s vaccine-induced immune response correlates in any way with the bacterial populations, the ‘microbiome’, in that person’s gastrointestinal tract. The interface between microbiome, health and immunity is a ‘hot topic’ in biomedicine though, as you can imagine, with the diversity of gut microflora, it is an immensely complex equation to unravel. Remembering back to my early veterinary research days, I recall that colleagues who were interested in animal nutrition would insert a large rubber ‘portal’, or rumen fistula, to connect that big fermentation vat, the fourth stomach of the sheep, to the outside world. In order to study the bacterial flora (the rumen microbiome) the investigator just had to remove the plug and scoop out some of the macerated green contents for analysis. No doubt the same technology is being used today as researchers ask if modifying the rumen microbiome can reduce the amounts of methane (CH4 a prominent greenhouse gas) that sheep and cattle produce.

With those sheep in mind, it didn’t seem too big a sacrifice on my part to provide a faecal sample for Sammy’s study. Still, as we discussed informally on one of our most recent Zoom meetings, why is it that even professional healthcare workers are much more comfortable with a regular needle puncture to provide 10ml of or so of blood than with – given that the participants are supplied with spatulas and bottles – than providing a much more readily accessed sample? And yes I will have to sign yet another informed consent before yielding-up that additional, valuable resource for research purposes!

My participation In Sammy’s sub-study will be flawed in the sense that, joining late, I didn’t provide a pre-vaccination faecal sample. Still, while my pre-bleed is a genuine control for the antibody and WBC analyses that, with our precise antibody and T cell assays, clearly differentiate elements of the ongoing, SARS-CoV-2 spike specific immune response from the ‘naïve’ background, I don’t know that an early faecal sample would indeed define a stable, pre-vaccination microbiome. It will be interesting to find out.

With such observational studies, participants are not randomised into different treatment groups. They can, though, have more than one ‘arm’ and compare, say, immune responses in people who do, or do not, suffer from a defined, underlying disease. Additional to that, working from the information provided by the trial participants at the time of enrolment, it is possible in retrospect to separate the results into different categories based on age, sex, smoker versus non-smoker, and so forth. And there is no mandatory need for a ‘placebo’ group. In the context discussed here, it would be unethical to require that some should be injected with saline rather than with a vaccine. The control is the individual’s own pre-bleed and there is no point in exposing people to even a minimal risk (from venepuncture) that has zero benefit for, yet some cost to, the research program.

Detailed observational studies are also used to assess health outcomes in groups of participants who may or may not be receiving an ‘intervention’ (whether medical device or drug) or as part of their routine medical care. Otherwise, Interventional, or random-controlled trials with clinically healthy subjects are the major, and mandated research tool for evaluating the safety and efficacy of any drug or vaccine that might end the toll of the current COVID-19 pandemic. That’s where we’ll go next week.