On the ethical requirement to inform patients about potential treatment benefits

Dear Editor,

Patients must understand both potential benefits and potential harms of trial treatments in order to provide informed consent.[1, 2] It is therefore worrying that Davis et al. found that “None of the patient information leaflets in [their] sample communicated any information about the types of drug benefits that patients might expect.”[3] Similar findings have been reported for trials: an analysis of 33 patient information leaflets (PILs) found that whereas all PILs mentioned potential harms, many (67%) failed to mention potential benefits.[4]

Beyond standing in the way of ethical informed consent, failure to mention potential benefits raises concerns of avoidable harm. [5] Especially for more subjective symptoms such as pain, informing patients of all the bad things a treatment might do, without telling them about the potential benefits, can lead to high expectations of something bad happening. In some cases, the high expectation can actually cause the symptom (such as pain) to arise. This is called a “nocebo” effect.[5]

Paradoxically, the opposite can also be true, in which potential trial participants over-estimate potential benefits. Trials set out to test hypotheses and these hypotheses incorporate assumptions about the expected magnitude of treatment effect irrespective of what actual results show. Without knowing exactly what endpoint is being studied and the hypothesized size of the treatment effect (generally incorporated into sample size calculations), potential trial participants can over-estimate the nature and magnitude of potential benefit or underestimate the harm, a phenomenon known as therapeutic optimism.[6, 7] For trials with “noninferiority” hypotheses, the problem is even more concerning, for patients may (mistakenly) assume the new intervention is being studied to evaluate improved efficacy whereas the primary study hypothesis relates to ruling out a degree of inferior efficacy deemed “clinically acceptable.”[7] The variation in the extent to which potential benefits are mentioned is also indicative of research waste. Without clear guidance regarding when and how to explain potential benefits to patients, individual researchers and ethics committee members must devise the right way to explain potential benefits (or not) from first principles.

Davis et al. stated that “information about a drug’s benefits is not required by EU or UK legislation.”[3] This is true but should change. Within clinical trials, mentioning potential benefits is required (but not always done[4]). The Declaration of Helsinki states that: “each potential subject must be adequately informed of … the anticipated benefits and potential risks of the study and the discomfort it may entail.”[8] Meanwhile the relevant regulations in the UK, EU, and US all state that mentioning potential benefits to trial participants is required. [9-12] For example, the UK legislation states: “Before the trial is initiated, foreseeable risks and inconveniences have been weighed against the anticipated benefit for the individual trial subject and other present and future patients.”[9]

In a clinical trial, the benefits of treatments are usually less certain than clinical practice, since in clinical practice the treatments have already passed through trials. And if they have passed through trials, the benefits (whatever they are) are more certain than they were before the trial. The knowledge produced by trials about how treatments work should not be restricted to curious academics; there is an ethical imperative that it be provided to patients to make informed decisions.

Fortunately, the problem with the variation in the way potential trial treatment benefits are explained to trial participants is being addressed. An MRC funded study has generated consensus that a number of principles—which include the need to mention both potential benefits and potential harms—can be followed.[13] This project will harmonize whether and how potential benefits of trial participants are informed about potential trial treatment benefits. The Davis et al. paper identifies that more needs to be done for information about treatment benefits outside the trial setting.[14]

References

1. Howick J: Unethical informed consent caused by overlooking poorly measured nocebo effects. J Med Ethics 2020.
2. Paterick TJ, Carson GV, Allen MC, Paterick TE: Medical informed consent: general considerations for physicians. Mayo Clin Proc 2008, 83(3):313-319.
3. Davis C, Wagner AK, Salcher-Konrad M, Scowcroft H, Mintzes B, Pokorny AMJ, Lew J, Naci H: Communication of anticancer drug benefits and related uncertainties to patients and clinicians: document analysis of regulated information on prescription drugs in Europe. BMJ 2023, 380:e073711.
4. Kirby N, Shepherd V, Howick J, Betteridge S, Hood K: Nocebo effects and participant information leaflets: evaluating information provided on adverse effects in UK clinical trials. Trials 2020, 21(1):658.
5. Howick J, Webster R, Kirby N, Hood K: Rapid overview of systematic reviews of nocebo effects reported by patients taking placebos in clinical trials. Trials 2018, 19(1):674.
6. Horng S, Grady C: Misunderstanding in clinical research: distinguishing therapeutic misconception, therapeutic misestimation, and therapeutic optimism. IRB 2003, 25(1):11-16.
7. Doshi P, Hur P, Jones M, Albarmawi H, Jefferson T, Morgan DJ, Spears PA, Powers JH, 3rd: Informed Consent to Study Purpose in Randomized Clinical Trials of Antibiotics, 1991 Through 2011. JAMA Intern Med 2017, 177(10):1452-1459.
8. The Declaration of Helsinki [https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-pr…
9. The Medicines for Human Use (Clinical Trials) Regulations 2004 [https://www.legislation.gov.uk/uksi/2004/1031/schedule/1/made]
10. Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC Text with EEA relevance [https://eur-lex.europa.eu/eli/reg/2014/536/oj]
11. 2018 Requirements (2018 Common Rule) [https://www.hhs.gov/ohrp/regulations-and-policy/regulations/45-cfr-46/re…
12. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. In. Edited by Services DoHaH.
13. Sovoboda M, Jacob N, Treweek S, Gillies K, Bower P, Edwards A, Hood K, Howick J: Developing principles for sharing information about potential trial intervention benefits and harms with patients: report of a modified Delphi survey. Trials 2022, 23( 863):TBA.
14. Schwartz LM, Woloshin S, Welch HG: Using a drug facts box to communicate drug benefits and harms: two randomized trials. Ann Intern Med 2009, 150(8):516-527.