Drug trial consent: Ethically and legally sound without triggering a nocebo effect

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Patients need to be able to make informed consent when taking part in drug trials, writes University of Oxford's Jeremy Howick in The Conversation. But information must be provided in a way that doesn't scare them off unnecessarily.

Jeremy Howick, faculty of philosophy, University of Oxford writes in The Conversation: It has been illegal to treat humans like guinea pigs since the Nuremberg trials, in which Nazi doctors were punished for doing unspeakable things to prisoners. These days, we have to explain the experiment to the people taking part in trials for new treatments and get their permission (their “informed consent”).

Specifically, we have to tell them about the risks of taking part. So in a trial of a new drug, we have to tell patients about all the possible side-effects. In ethical geek-speak, we have to preserve patients’ autonomy by giving them enough information to make an autonomous decision. Which is fine, up to a point.

It is also an ethical requirement to avoid unnecessarily harming patients. A recent study shows that the relatively recent discovery of so-called nocebo effects – a result of the patient’s expectation that the treatment will harm them – means that harm is being done by the way we inform patients about the trial in which they are taking part.

The study describes a multicentre randomised trial of aspirin versus sulfinpyrazone for treating unstable angina. Because of differences in individual hospital review processes, patients either received or did not receive a statement outlining possible gastrointestinal side-effects. This resulted in a six-fold increase in the number of people withdrawing from the study because of subjective, minor gastrointestinal symptoms, which suggests that the warning about side-effects may prompt patients to expect and subsequently experience them (nocebo effects).

An earlier very large study with over 250,000 patients who took placebo pills in clinical trials found that half of them reported some side-effect, such as pain or nausea, but also more serious things. One in 20 dropped out of the trial because of a side-effect. Some of these were common things, such as back pain, that can happen whether or not someone is in a trial. But our analysis showed that the way patients were told about the side-effects caused many of them.

How can we stop harming patients with nocebo effects while respecting their autonomy? The answer is simple: tell them everything they want to know about side-effects, but tell them in the right way.

In the trials I have been involved in, patients have reported being scared by the way potential side-effects are shared. Yet the ethics committee usually insists that we keep the scary language. The ethics committee’s insistence is understandable from a medico-legal perspective. They are concerned about outlier cases where a patient might say they were not sufficiently well informed about the potential harm they experienced.

The problem with this approach is that it violates the other patients’ right to choose how to be communicated with – their autonomy. Changing the ethics committee’s worries may require that they be equally scared of a court case where a patient decided not to enrol in a trial because of the scary way risks were presented and subsequently sued for missing an opportunity.

I hope my recent study addresses this problem without court cases. Violating autonomy by force-feeding risk information to patients shows that the debate about presenting risk information requires balancing different aspects of autonomy with other ethical principles.

How to avoid nocebo harms
Nobody believes we should prevent patients from learning about all the negative side-effects of their treatment. These are all available on the internet, so attempts to hide them would fail anyway.

What they don’t know won’t hurt ‘em. Don’t tell patients about unlikely risks if telling them outweighs the benefits. Most of us volunteer for this option by not reading the small print of over-the-counter drugs we take. I bet you didn’t you know that rare side-effects of aspirin include ruptures in the wall of the stomach or intestine, bleeding in the skull, hives, seizures, trouble breathing and black tarry stools. Yet these are described on the small print of every aspirin pack you buy.

Personalised consent. As much as it is their right to know about them if they want to, it is a patient’s right not to know if they don’t. Doctors and researchers can ask patients how much they want to know and tell them as much. They can tell them where to get more information later on (for example, on a website).

Positive framing. Just over 200 healthy adult volunteers were given a placebo described as “a well-known tablet available without prescription”. They were randomly assigned to either be told about a risk in the standard way, such as “Common, one in 10 people will experience this side-effect”). Or they received positively framed wording, such as “Uncommon, 90% of people will not get this side-effect”. Those who received the positively framed information reported fewer side-effects. Other studies have reported similar findings. The content of the information is the same in both cases, but the way it is conveyed seems to affect the risk of harm.

We don’t want to be treated like guinea pigs. And we don’t want to be harmed if it can be avoided. Let’s make informed consent more ethical by balancing the need to tell with the need to tell the right way.

Abstract 1
Background: Trial participants in placebo groups report experiencing adverse events (AEs). Existing systematic reviews have not been synthesized, leaving questions about why these events occur as well as their prevalence across different conditions unanswered.
Objectives: (1) To synthesize the evidence of prevalence of AEs in trial placebo groups across different conditions. (2) To compare AEs in trial placebo groups with AEs reported in untreated groups within a subset of randomized trials.

Search Methods: We searched PubMed for records with the word "nocebo" in the title and "systematic" in any field. We also contacted experts and hand-searched references of included studies.
Study Eligibility: We included any systematic review of randomized trials where nocebo effects were reported. We excluded systematic reviews of non-randomized studies.
Participants and Interventions: We included studies in any disease area.
Study Appraisal and Synthesis Methods: We appraised the quality of the studies using a shortened version of the Assessment of Multiple Systematic Reviews tool (AMSTAR) tool. We reported medians and interquartile ranges (IQRs) of AEs. Among the trials within the review that included untreated groups, we compared the prevalence of AEs in untreated groups with the prevalence of AEs in placebo groups.

Results: We identified 20 systematic reviews. These included 1271 randomized trials and 250,726 placebo-treated patients. The median prevalence of AEs in trial placebo groups was 49.1% (IQR 25.7-64.4%). The median rate of dropouts due to AEs was 5% (IQR 2.28-8.4%). Within the 15 of trials that reported AEs in untreated groups, we found that the AE rate in placebo groups (6.51%) was higher than that reported in untreated groups (4.25%).
Limitations: This study was limited by the quality of included reviews and the small number of trials that included untreated groups.
Conclusions and Implications of Key Findings: AEs in trial placebo groups are common and cannot be attributed entirely to natural history. Trial methodologies that reduce AEs in placebo groups while satisfying the requirement of informed consent should be developed and implemented.

Howick J, Webster R, Kirby N, Hood K

Abstract 2
Unlike its friendly cousin the placebo effect, the nocebo effect (the effect of expecting a negative outcome) has been almost ignored. Epistemic and ethical confusions related to its existence have gone all but unnoticed. Contrary to what is often asserted, adverse events following from taking placebo interventions are not necessarily nocebo effects; they could have arisen due to natural history. Meanwhile, ethical informed consent (in clinical trials and clinical practice) has centred almost exclusively on the need to inform patients about intervention risks with patients to preserve their autonomy. Researchers have failed to consider the harm caused by the way in which the information is conveyed. In this paper, I argue that the magnitude of nocebo effects must be measured using control groups consisting of untreated patients. And, because the nocebo effect can produce harm, the principle of non-maleficence must be taken into account alongside autonomy when obtaining (ethical) informed consent and communicating intervention risks with patients.

Jeremy Howick

The Conversation report

Journal of Clinical Pharmacology abstract

BMJ Journal of Medical Ethics abstract

Trials abstract

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