Data from: Retrospective harm benefit analysis of pre-clinical animal research for six treatment interventions

Background: The harm benefit analysis (HBA) is the cornerstone of animal research regulation and is considered to be a key ethical safeguard for animals. The HBA involves weighing the anticipated benefits of animal research against its predicted harms to animals but there are doubts about how objective and accountable this process is. Objectives: i. To explore the harms to animals involved in pre-clinical animal studies and to assess these against the benefits for humans accruing from these studies; ii. To test the feasibility of conducting this type of retrospective HBA. Methods: Data on harms were systematically extracted from a sample of pre-clinical animal studies whose clinical relevance had already been investigated by comparing systematic reviews of the animal studies with systematic reviews of human studies for the same interventions (antifibrinolytics for haemorrhage, bisphosphonates for osteoporosis, corticosteroids for brain injury, Tirilazad for stroke, antenatal corticosteroids for neonatal respiratory distress and thrombolytics for stroke). Clinical relevance was also explored in terms of current clinical practice. Harms were categorised for severity using an expert panel. The quality of the research and its impact were considered. Bateson's Cube was used to conduct the HBA. Results: The most common assessment of animal harms by the expert panel was 'severe'. Reported use of analgesia was rare and some animals (including most neonates) endured significant procedures with no, or only light, anaesthesia reported. Some animals suffered iatrogenic harms. Many were kept alive for long periods post-experimentally but only 1% of studies reported post-operative care. A third of studies reported that some animals died prior to endpoints. All the studies were of poor quality. Having weighed the actual harms to animals against the actual clinical benefits accruing from these studies, and taking into account the quality of the research and its impact, less than 7% of the studies were permissible according to Bateson's Cube: only the moderate bisphosphonate studies appeared to minimise harms to animals whilst being associated with benefit for humans. Conclusions: This is the first time the accountability of the HBA has been systematically explored across a range of pre-clinical animal studies. The regulatory systems in place when these studies were conducted failed to safeguard animals from severe suffering or to ensure that only beneficial, scientifically rigorous research was conducted. Our findings indicate a pressing need to: i. review regulations, particularly those that permit animals to suffer severe harms; ii. reform the processes of prospectively assessing pre-clinical animal studies to make them fit for purpose; and iii. systematically evaluate the benefits of pre-clinical animal research to permit a more realistic assessment of its likely future benefits.研究背景：伤害收益分析（Harm Benefit Analysis, HBA）是动物研究监管的基石，亦被视为保障动物权益的核心伦理防线。该分析需权衡动物研究所预期获得的收益与动物面临的可预见伤害，但学界对该流程的客观性与可问责性尚存疑虑。 研究目标：① 梳理临床前动物研究（pre-clinical animal studies）中动物所遭受的伤害，并对照此类研究为人类带来的潜在收益进行评估；② 验证开展此类回顾性伤害收益分析的可行性。 研究方法：研究人员通过将动物研究的系统综述（systematic reviews）与同一干预措施的人类研究系统综述进行比对，从一批已被评估过临床相关性的临床前动物研究样本中系统性提取伤害相关数据，涉及的干预措施包括：用于出血治疗的抗纤溶药物（antifibrinolytics）、用于骨质疏松症的双膦酸盐类药物（bisphosphonates）、用于脑损伤的糖皮质激素（corticosteroids）、用于脑卒中的梯利拉扎（Tirilazad）、用于新生儿呼吸窘迫的产前糖皮质激素，以及用于脑卒中的溶栓药物。同时结合当前临床实践对研究的临床相关性进行探讨。研究团队通过专家小组将伤害按严重程度进行分级，并考量了研究质量及其影响。本次分析采用贝茨立方体（Bateson's Cube）开展伤害收益分析。 研究结果：专家小组对动物伤害最常见的分级为“重度”。研究中镇痛药物的使用极为罕见，部分动物（包括绝大多数新生动物）在未接受麻醉或仅接受轻度麻醉的情况下承受了重度操作。部分动物出现了医源性伤害（iatrogenic harms）。多数动物在实验结束后被长期饲养，但仅1%的研究提及了术后护理措施。三分之一的研究报告称部分动物在实验终点前死亡。所有纳入研究的质量均较差。在综合考量动物实际遭受的伤害、此类研究实际为人类带来的临床收益，以及研究质量与影响后，依据贝茨立方体（Bateson's Cube）的评判标准，仅有不足7%的研究符合伦理许可标准：仅针对双膦酸盐类药物的中等质量研究，似乎在将动物伤害降至最低的同时，为人类带来了收益。 研究结论：本研究首次在一系列临床前动物研究中系统性探讨了伤害收益分析的可问责性。在这些研究开展之时，现行监管体系未能有效保障动物免受重度痛苦，亦未能确保仅开展具备临床价值且科学严谨的研究。本研究结果凸显了三项亟需推进的工作：① 修订现有监管规范，尤其是允许动物遭受重度伤害的相关条款；② 改革临床前动物研究的前瞻性评估流程，使其适配实际应用需求；③ 系统性评估临床前动物研究的收益，以更客观地预判其未来潜在价值。