In good form

1 September 2020

With many Covid-19 patients too ill to make their own decisions, treatment data needed urgently and human challenge trials being mooted as a possible way to expedite the development of a vaccine, the stakes for informed consent are higher than ever. Tim Gunn asks Professor Richard Haynes, clinical trial lead for the Oxford Recovery trial; Professor Nir Eyal, director of the Centre for Population-Level Bioethics at Rutgers University; and Dr Pamela Tenaerts, director of the Clinical Trials Transformation Initiative, how the process can be improved to solve the ethical and administrative quandaries of the pandemic and beyond.

It’s difficult to breathe. It’s difficult to do anything. You have been nailed to a hospital bed by thousands of blood clots, you are drowning in your own lungs – and you appear to have written the date wrong at the top of the sheet.

Some time ago, a hazmat suit handed you a neat stack of what it called ‘patient information’ and ‘informed consent’ documents. Since then, you’ve floundered over the same few sentences and given up trying to understand what the EU’s General Data Protection Regulation has to do with the anvil on your chest. Just sign what they want signed, you think, but using a pen is too much of a challenge.

So you sink into your medically-induced coma, sorry for disappointing that PPE snowman; unsure if you’ll ever wake up.

Thankfully, most Covid-19 trials have streamlined their informed consent processes. But even before the world’s eyes and hopes focused so intently on clinical trials, their regular struggles to recruit enough patients – and the fact that, by some counts, less than half of those they did recruit failed to understand what that meant – suggested something needed to change.

“For various reasons,” says Professor Richard Haynes, the clinical trial lead for Oxford University’s Randomised Evaluation of Covid-19 Therapy (Recovery) trial, “people are getting increasingly risk-averse. They want to try and mitigate that by presenting all the information they possibly can to participants so it couldn’t be said that they didn’t tell somebody about a particular risk.” As a result, US informed consent forms and European participant information leaflets – which essentially amount to the same thing – are filling ever more pages with what Dr Pamela Tenaerts, head of the Clinical Trials Transformation Initiative (CTTI), calls “risk, liability and legalese”, most of which actually diminishes patient understanding.

“Consent forms are erring towards becoming legal documents,” continues Haynes. “Well, in a way, they are legal documents, but they’re almost becoming contractual agreements between patients and researchers, rather than a record of a willingness to take part in a study. I don’t think that’s a helpful trend.”

No routine recovery

Recovery is both the world’s biggest trial of potential treatments for Covid-19 and the fastest-recruiting individually randomised controlled trial in history. Almost as impressively, the patient information sheet is just two sides of A4. Admittedly, that’s helped by the fact that Recovery is testing established treatments for other conditions, which means there are fewer potential legal issues to contend with than there might be with novel drugs. Still, Haynes, a nephrologist by training, thinks consent processes for most clinical trials should be more closely modelled on the consent discussions doctors have with their patients whenever they make changes to routine care.

“For a huge number of the treatments that we use routinely,” he points out, “if we had to put our hands on our hearts, we wouldn’t be able to say to patients, ‘There’s a trial that shows me that the treatment I want to give you is better than not giving you that treatment’. So why should the consent process in the trial be so much more complicated?”

In fact, given the amount of data every trial creates, it wouldn’t be difficult to imagine a world in which the consent processes for established treatments were longer than those for first-in-human drugs.

“When we know a lot about risks,” explains Professor Nir Eyal, director of the Centre for Population-Level Bioethics at Rutgers University, “there is a dilemma about whether to disclose all of them, knowing that disclosing many details of any sort, and certainly of the scary sort like risks, reduces the quality of comprehension.” Routine care and clinical trials often seem to approach this dilemma from opposite directions. Whereas terms of use for participant data increasingly appear in trials’ consent forms, primary care doctors do not solemnly request a signature attesting to the patient’s understanding of all possible side effects when they prescribe new drugs.

Eyal is the lead author of ‘Human challenge studies to accelerate coronavirus vaccine licensure’, the Journal of Infectious Diseases article that effectively launched the movement for Covid-19 human challenge trials (HCTs). As he sees it, our lack of understanding about Covid-19 helps sidestep the disclosure-comprehension dilemma for possible HCTs – simply because there’s less information with which to bombard potential participants.

“Some doctors and bioethicists criticise the idea of challenge trials by saying, ‘We don’t have an adequate understanding of this disease, so how is it possible that consent can be informed?’” says Eyal. “That is a flawed understanding of when consent is valid. Informed consent means, ideally, making you as informed as scientists might be at that point in time about the major facts relevant to your decision.”

Paper jam

HCT discussions aren’t the only things helping to refine our understanding of consent. Tenaerts has been deeply impressed by how well Recovery has used the urgency of the pandemic to “boil the process down to its essence”, and match it to the needs of its target population. That emphasis has made it possible for the patient information sheet to be replicated on the trial website and adapted for an animation, thus making it even more accessible.

“There is not one approach to this,” Tenaerts emphasises. “You need to think about who your population is, what your study is, and what you really need to convey in a way that people understand, so when participants enter a trial, they have a really good sense of what that means for them.”

Haynes uses the word ‘proportionate’ to get at the same point, but that particular concept looks a little different during Covid-19. Informed consent in the age of social distancing can involve one healthcare professional explaining the key points of a trial to a patient, another streaming the discussion on FaceTime, and a third watching from outside the room with a witnessed version of the consent form.

With many hospitals treating Covid wards as ‘hot zones’ where everything should be considered infected, getting even one sheet of A4 to a patient and back is no mean feat. In the most extreme cases, doctors independent of the trial can act as legal representatives for patients too sick to make their own decisions, who are free to opt in or out of continuing if and when they recover their faculties. Other hospitals have scanned signed documents from inside the ward, or left them in plastic document holders until investigators could be confident there was no surviving virus residue on the paper.

That’s a lot of extra site work, and as much as Haynes appreciates investigators’ ingenuity, he wishes it wasn’t so necessary. “The key point is that too often the piece of paper becomes the focus of the whole thing,” he laments. “Where’s the piece of paper? Has it been filled in properly? Silly things like that become the focus of consent, whereas actually the focus should really be: did the patient have an adequate explanation of the benefits and risks of going into the trial, and did they come to a free decision as to whether they wanted to take part?”

He’s talking about HCTs in particular, but Eyal puts the disjunction well: “Sure, a form is consent enough to sign certain financial contracts, but it’s absolutely inadequate in this setting.”

Haynes was thinking about this issue long before Covid-19 highlighted how obstructive paper documentation can become. “I was absolutely determined that we would use an electronic consent form for the next trial,” he says. “I have sat through countless training sessions for other trials where somebody explains how to complete the consent form, and pleads with the research coordinators to make sure they do it properly so we don’t have to go back and do lots of corrections later. But despite all of that, despite the best training, you end up having to go back and do lots of corrections later.”

It’s not the most exciting selling point, but e-consent might just mean the end of missed tick boxes and incorrect dates. Beyond that, however, both Haynes and Tenaerts think digital tools are an opportunity to refocus the consent process. It can’t completely replace written documentation, but Recovery’s two-minute patient information animation, for instance, spares investigators from having detailed consent conversations with patients who simply aren’t interested.

“And if, after watching, they did want to take part, they could digest the consent form more quickly, because a lot of what they heard in the animation was actually lifted straight from the information leaflet,” explains Haynes, who intends to use a sequence of animations to break up consent for more complex future trials into something more manageable. “If you combine those animations with an e-consent form, then I think we are moving forward.”

Read the room

That’s not the only way to do so. Already, instead of focusing on checking that all the forms have been properly filled in and filed, monitoring staff on Haynes’ chronic disease trials prioritise sitting in on consent discussions to ensure patients are actually well informed when they make their decisions.

However digital the informed consent process might be, Tenaerts and the CTTI also emphasise that the best way to improve it is by engaging with patient populations. Vaccine challenge trials obviously complicate that, but Eyal has worked closely with the 1Day Sooner HCT volunteer movement to get the best possible information on to its website, which, like the Recovery animation, helps ensure that only those who properly understand what a trial would entail sign up to possibly join one.

From there, both Eyal and Haynes see potential for using e-consent testing tools to better verify patient understanding. For Haynes, the results of these “gentle quizzes” don’t necessarily need to prompt immediate action from investigators. They’re as valuable for the feedback they give on how to improve future consent processes as anything else, and they help to reframe the process as something closer to the classroom than the court.

“A form is consent enough to sign certain financial contracts, but it’s absolutely inadequate in this setting [of Covid-19 human challenge trials].”
Professor Nir Eyal

Given the high stakes of HCTs, however, Eyal sees them as a way for investigators to ensure that only those who properly comprehend the risks and key facts are signed up to the trial. “And you would ask questions in many different ways,” he explains, “because it’s possible that someone could give the correct answer if questioned in one way, but not act on that understanding, as would be shown if the question were asked differently.”

That’s possible for a trial that needs comparatively few participants from the tens of thousands that have gone out of their way to find out about it and register their interest. Usually, participants are scarcer than they are savvy. There’s no way unfriendly, increasingly complex informed consent processes are addressing that. The CTTI has a range of valuable recommendations for tiered document structures and ongoing consultation, but Tenaerts repeatedly hammers home the fact that, first and foremost, informed consent needs to consider its audience.

Haynes agrees. “We often read manuals that say ‘get consent’ or ‘take consent’,” he says, before contrasting them with a quote from a senior nurse colleague. “Actually, that’s not the way it should be: it’s about patients giving their consent. We’ve got to make that as easy and understandable a process for them as we can.”

19 Average length, in pages, of informed consent documents for multicentre phase-III RCTs conducted at the German Brain Tumor Centre.
European Journal of Cancer
Length, in pages, of the Oxford Recovery trial’s patient information sheet.
Oxford Recovery trial
Proportion of patients in one survey of oncology studies that recognised the goal of the trial was to benefit future patients.
The Lancet


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