Abstract
For any therapeutic intervention in an individual, there is a balance between the potential benefits and the possible harms. The extent to which the benefits are desirable in a given condition depends on the efficacy of the intervention, the chance of obtaining it and the seriousness and intensity of the condition. The extent to which the harms are undesirable depends on the nature of the hazard that can lead to harm, the chance that the harm will occur and its seriousness and intensity. Rational therapeutic decisions require clinicians to consider competing courses of action, with potential benefits of different desirability and potential harms of different undesirability. They also have a duty to explain to the patient, for the contemplated interventions, both the possible benefits and the potential harms that the patient may consider significant. In an individual patient, it is necessary to consider (a) the probabilities of benefit from both intervention and non-intervention and (b) the probabilities of harm from both intervention and non-intervention. However, there are several potential problems. Here, we consider how failure to distinguish maximum benefits from probable benefits, or hazards (potential harms) from probable harms, and failure to consider all the competing probabilities may lead to imperfect therapeutic decisions. We also briefly discuss methods to assess the benefit to harm balance.
Similar content being viewed by others
References
Ferner RE. Hazards, risks and reality. Br J Clin Pharmacol. 1992. https://doi.org/10.1111/j.1365-2125.1992.tb04013.x.
Royal Society Study Group. Risk assessment. London: The Royal Society; 1983.
Aronson JK. Adjusting therapeutic dosage regimens to optimise the balance of benefit to harm. Clin Med (Lond). 2005. https://doi.org/10.7861/clinmedicine.5-1-16.
Montgomery (Appellant) v Lanarkshire Health Board (Respondent) (Scotland). 11 March 2015. https://www.supremecourt.uk/cases/uksc-2013-0136.html. Accessed 7 Apr 2024.
Smith RL. The Paton Prize Award: the discovery of the debrisoquine hydroxylation polymorphism: scientific and clinical impact and consequences. Toxicology. 2001. https://doi.org/10.1097/00008571-199111000-00013.
Juhaeri J. Benefit-risk evaluation: the past, present and future. Ther Adv Drug Saf. 2019. https://doi.org/10.1177/2042098619871180.
Coplan PM, Noel RA, Levitan BS, Ferguson J, Mussen F. Development of a framework for enhancing the transparency, reproducibility and communication of the benefit-risk balance of medicines. Clin Pharmacol Ther. 2011. https://doi.org/10.1038/clpt.2010.291.
US Food and Drug Administration. Benefit–risk assessment in drug regulatory decision-making 2018: draft PDUFA VI implementation plan (FY 2018-2022). Rockville, MD: U.S. Department of Health and Human Services, Food and Drug Administration, 2018. https://www.fda.gov/media/112570/download. Accessed 6 Feb 2024.
Kürzinger ML, Douarin L, Uzun I, El-Haddad C, Hurst W, Juhaeri J, et al. Structured benefit-risk evaluation for medicinal products: review of quantitative benefit-risk assessment findings in the literature. Ther Adv Drug Saf. 2020. https://doi.org/10.1177/2042098620976951.
Hughes D, Waddingham E, Mt-Isa S, Goginsky A, Chan E, Downey GF, et al. PROTECT Benefit-Risk Group. Recommendations for benefit-risk assessment methodologies and visual representations. Pharmacoepidemiol Drug Saf. 2016. https://doi.org/10.1002/pds.3958.
Grabias B, Kumar S. Adverse neuropsychiatric effects of antimalarial drugs. Expert Opin Drug Saf. 2016. https://doi.org/10.1080/14740338.2016.1175428.
Gogtay NJ, Ferner RE. Mefloquine for malarial prophylaxis in military personnel. BMJ. 2015. https://doi.org/10.1136/bmj.h5797.
Aronson JK. "Collaborative care” is preferable to “patient centred care. BMJ. 2016. https://doi.org/10.1136/bmj.i2926.
World Health Organization (WHO). Antibiotic resistance. 31 July 2020. https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance. Accessed 6 Feb 2024.
Medicines and Healthcare products Regulatory Agency (MHRA). Patient involvement strategy. 2021. https://www.gov.uk/government/publications/patientinvolvement-strategy. Accessed 6 Feb 2024.
European Medicines Agency. Stakeholders and Communication Division. The patient’s voice in the evaluation of medicines. 18 October 2013 EMA/607864/2013. https://www.ema.europa.eu/en/documents/report/report-workshop-patients-voice-evaluation-medicines_en.pdf. Accessed 6 Feb 2024.
Cashin AG, Wand BM, O’Connell NE, Lee H, Rizzo RRN, Bagg MK, et al. Pharmacological treatments for low back pain in adults: an overview of Cochrane reviews. Cochrane Database Systc Rev. 2023. https://doi.org/10.1002/14651858.CD013815.pub2.
Makary MA, Overton HN, Wang P. Overprescribing is major contributor to opioid crisis. BMJ. 2017. https://doi.org/10.1136/bmj.j4792.
Islam A, Butler T, Nath SK, Alam NH, Stoeckel K, Houser HB, et al. Randomized treatment of patients with typhoid fever by using ceftriaxone or chloramphenicol. J Infect Dis. 1988. https://doi.org/10.1128/AAC.37.8.1572.
Pullar T, Wright V, Feely M. What do patients and rheumatologists regard as an ‘acceptable’ risk in the treatment of rheumatic disease? Br J Rheumatol. 1990. https://doi.org/10.1093/rheumatology/29.3.215.
Aronson JK, Derry S, Loke YK. Assessing perceptions of benefit and harm of common drug therapies using therapeutic scenarios. Br J Clin Pharmacol. 2003;55(4):438.
Aronson JK, Ferner RE. Biomarkers: a general review. Curr Protoc Pharmacol. 2017. https://doi.org/10.1002/cpph.19.
Hingorani AD, Windt DA, Riley RD, Abrams K, Moons KG, Steyerberg EW, et al. PROGRESS Group. Prognosis research strategy (PROGRESS) 4: stratified medicine research. BMJ. 2013. https://doi.org/10.1136/bmj.e5793.
Kent DM, Paulus JK, van Klaveren D, D’Agostino R, Goodman S, Hayward R, et al. The predictive approaches to treatment effect heterogeneity (PATH) statement. Ann Intern Med. 2020. https://doi.org/10.7326/M18-3667.
Report of the Committee of Principal Investigators. WHO cooperative trial on primary prevention of ischaemic heart disease with clofibrate to lower serum cholesterol: final mortality follow-up. Lancet. 1984;2(8403):600–4.
Aronson JK, Ferner RE. Clarification of terminology in drug safety. Drug Saf. 2005. https://doi.org/10.2165/00002018-200528100-00003.
Ferner R, Aronson J. Susceptibility to adverse drug reactions. Br J Clin Pharmacol. 2019. https://doi.org/10.1111/bcp.14015.
Campagna JD, Bond MC, Schabelman E, Hayes BD. The use of cephalosporins in penicillin-allergic patients: a literature review. J Emerg Med. 2012. https://doi.org/10.1016/j.jemermed.2011.05.035.
Køster-Rasmussen R, Korshin A, Meyer CN. Antibiotic treatment delay and outcome in acute bacterial meningitis. J Infect. 2008. https://doi.org/10.1016/j.jinf.2008.09.033.
Moran R, Devchand M, Smibert O, Trubiano JA. Antibiotic allergy labels in hospitalized and critically ill adults: a review of current impacts of inaccurate labelling. Br J Clin Pharmacol. 2019. https://doi.org/10.1111/bcp.13830.
Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, et al. PREDICT-1 Study Team. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008. https://doi.org/10.1056/NEJMoa0706135.
Evans DA, Manley KA, McKusick VA. Genetic control of isoniazid metabolism in man. BMJ. 1960. https://doi.org/10.1136/bmj.2.5197.485.
Gutiérrez-Virgen JE, Piña-Pozas M, Hernández-Tobías EA, Taja-Chayeb L, López-González ML, Meraz-Ríos MA, et al. NAT2 global landscape: genetic diversity and acetylation statuses from a systematic review. PLoS One. 2023. https://doi.org/10.1371/journal.pone.0283726.
Lennard L, Cartwright CS, Wade R, Richards SM, Vora A. Thiopurine methyltransferase genotype-phenotype discordance and thiopurine active metabolite formation in childhood acute lymphoblastic leukaemia. Br J Clin Pharmacol. 2013. https://doi.org/10.1111/bcp.12066.
Relling MV, Schwab M, Whirl-Carrillo M, Suarez-Kurtz G, Pui CH, Stein CM, et al. Clinical Pharmacogenetics Implementation Consortium guideline for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018 update. Clin Pharmacol Ther. 2019. https://doi.org/10.1002/cpt.1304.
Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC, et al. Medical genetics: a marker for Stevens–Johnson syndrome. Nature. 2004. https://doi.org/10.1038/428486a.
Lonjou C, Thomas L, Borot N, Ledger N, de Toma C, LeLouet H, et al. RegiSCAR Group. A marker for Stevens–Johnson syndrome: ethnicity matters. Pharmacogenom J. 2006. https://doi.org/10.1038/sj.tpj.6500356.
Camacho Arroyo MT, Rivas Paterna AB, Meneses Monroy A, Cabrera García L, Blázquez González P, Mancebo Salas N, et al. Off-label and unlicensed drug use in a pediatric intensive care unit of a tertiary care Spanish hospital: a descriptive study. Arch Argent Pediatr. 2023. https://doi.org/10.5546/aap.2021-02550.eng.
Tang L, Zhao K, Hou N. Off-label use of antimicrobials among hospitalized children: a retrospective study of 3,406 patients. Front Microbiol. 2023. https://doi.org/10.3389/fmicb.2023.1173042.
Bateman DN, Rawlins MD, Simpson JM. Extrapyramidal reactions with metoclopramide. Br Med J (Clin Res Ed). 1985. https://doi.org/10.1136/bmj.291.6500.930.
Martin RM, Biswas PN, Freemantle SN, Pearce GL, Mann RD. Age and sex distribution of suspected adverse drug reactions to newly marketed drugs in general practice in England: analysis of 48 cohort studies. Br J Clin Pharmacol. 1998. https://doi.org/10.1046/j.1365-2125.1998.00817.x.
Zucker I, Prendergast BJ. Sex differences in pharmacokinetics predict adverse drug reactions in women. Biol Sex Differ. 2020. https://doi.org/10.1186/s13293-020-00308-5.
Funck-Brentano C, Salem JE. Influence of baseline QTc on sotalol-induced prolongation of ventricular repolarization in men and women. Br J Clin Pharmacol. 2022. https://doi.org/10.1111/bcp.15188.
Ferner RE, Dunstan JA, Chaplin S, Baird GM. Drugs in donated blood. Lancet. 1989. https://doi.org/10.1016/s0140-6736(89)90326-7.
Cheymol G. Effects of obesity on pharmacokinetics implications for drug therapy. Clin Pharmacokinet. 2000. https://doi.org/10.2165/00003088-200039030-00004.
British National Formulary (BNF), National Institute for Health and Care Excellence (NICE). Phenelzine interactions. https://bnf.nice.org.uk/interactions/phenelzine. Accessed 6 Feb 2024.
Floor-Schreudering A, Geerts AF, Aronson JK, Bouvy ML, Ferner RE, De Smet PA. Checklist for standardized reporting of drug–drug interaction management guidelines. Eur J Clin Pharmacol. 2014. https://doi.org/10.1007/s00228-013-1612-7.
Ferner RE, Aronson JK. Communicating information about drug safety. BMJ. 2006. https://doi.org/10.1136/bmj.333.7559.143.
Threapleton CJD, Kimpton JE, Carey IM, DeWilde S, Cook DG, Harris T, et al. Development of a structured clinical pharmacology review for specialist support for management of complex polypharmacy in primary care. Br J Clin Pharmacol. 2020. https://doi.org/10.1111/bcp.14243.
Hijazi Z, Hohnloser SH, Oldgren J, Andersson U, Connolly SJ, Eikelboom JW, et al. Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis. Circulation. 2014. https://doi.org/10.1161/CIRCULATIONAHA.113.003628.
Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med. 1989. https://doi.org/10.1056/NEJM198908103210629.
Pasquali S, Hadjinicolaou AV, Chiarion Sileni V, Rossi CR, Mocellin S. Systemic treatments for metastatic cutaneous melanoma. Cochrane Database Syst Rev. 2018. https://doi.org/10.1002/14651858.CD011123.pub2.
Prasad K, Kumar A, Gupta PK, Singhal T. Third generation cephalosporins versus conventional antibiotics for treating acute bacterial meningitis. Cochrane Database Syst Rev. 2007. https://doi.org/10.1002/14651858.CD001832.pub3.
Warrell DA, Looareesuwan S, Warrell MJ, Kasemsarn P, Intaraprasert R, Bunnag D, et al. Dexamethasone proves deleterious in cerebral malaria: a double-blind trial in 100 comatose patients. N Engl J Med. 1982. https://doi.org/10.1056/NEJM198202113060601.
WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JAC, Murthy S, Diaz JV, Slutsky AS, Villar J, Angus DC, et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA. 2020. https://doi.org/10.1001/jama.2020.17023.
Acknowledgements
We thank Prof. Aroon Hingorani and anonymous reviewers for helpful comments on a draft of this paper.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
No funding was received for the preparation of this article.
Conflict of interest
Robin E. Ferner has undertaken research and published on adverse drug reactions and medication errors and has acted as an expert witness in legal cases related to these. Jeffrey K. Aronson has published papers in bioscience journals and edited textbooks on adverse drug reactions; he has often acted as an expert witness in civil actions relating to suspected adverse drug reactions and in coroners’ courts.
Ethics approval
Not applicable.
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Availability of data and material
Not applicable.
Code availability
Not applicable.
Authors’ contributions
REF and JKA contributed equally to the intellectual content; REF wrote the first draft. Both authors have read and agreed upon the final version.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Ferner, R.E., Aronson, J.K. Competing Benefits and Competing Hazards: The Benefit to Harm Balance in Individual Patients in Rational Therapeutics. Drug Saf (2024). https://doi.org/10.1007/s40264-024-01428-2
Accepted:
Published:
DOI: https://doi.org/10.1007/s40264-024-01428-2