Department of Psychiatry, University of Oxford, Oxford, UK; Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK.
Meta-Research Innovation Center at Stanford, and Departments of Medicine, Departments of Health Research and Policy, Departments of Biomedical Data Science, and Departments of Statistics, Stanford University, Palo Alto, CA, USA.
Lancet. 2020 Mar 21;395(10228):998-1010. doi: 10.1016/S0140-6736(19)33177-0.
Certain limitations of evidence available on drugs and devices at the time of market approval often persist in the post-marketing period. Often, post-marketing research landscape is fragmented. When regulatory agencies require pharmaceutical and device manufacturers to conduct studies in the post-marketing period, these studies might remain incomplete many years after approval. Even when completed, many post-marketing studies lack meaningful active comparators, have observational designs, and might not collect patient-relevant outcomes. Regulators, in collaboration with the industry and patients, ought to ensure that the key questions unanswered at the time of drug and device approval are resolved in a timely fashion during the post-marketing phase. We propose a set of seven key guiding principles that we believe will provide the necessary incentives for pharmaceutical and device manufacturers to generate comparative data in the post-marketing period. First, regulators (for drugs and devices), notified bodies (for devices in Europe), health technology assessment organisations, and payers should develop customised evidence generation plans, ensuring that future post-approval studies address any limitations of the data available at the time of market entry impacting the benefit-risk profiles of drugs and devices. Second, post-marketing studies should be designed hierarchically: priority should be given to efforts aimed at evaluating a product's net clinical benefit in randomised trials compared with current known effective therapy, whenever possible, to address common decisional dilemmas. Third, post-marketing studies should incorporate active comparators as appropriate. Fourth, use of non-randomised studies for the evaluation of clinical benefit in the post-marketing period should be limited to instances when the magnitude of effect is deemed to be large or when it is possible to reasonably infer the comparative benefits or risks in settings, in which doing a randomised trial is not feasible. Fifth, efficiency of randomised trials should be improved by streamlining patient recruitment and data collection through innovative design elements. Sixth, governments should directly support and facilitate the production of comparative post-marketing data by investing in the development of collaborative research networks and data systems that reduce the complexity, cost, and waste of rigorous post-marketing research efforts. Last, financial incentives and penalties should be developed or more actively reinforced.
在药物和器械获得市场批准时，可用证据通常存在一定局限性，而这些局限性在上市后阶段仍持续存在。通常，上市后研究格局较为零散。当监管机构要求制药和器械制造商在上市后阶段开展研究时，这些研究在获得批准多年后仍可能未完成。即使完成，许多上市后研究仍缺乏有意义的活性对照，采用观察性设计，并且可能未收集与患者相关的结局。监管机构应与行业和患者合作，确保在药物和器械批准时未解决的关键问题能在上市后阶段及时得到解决。我们提出了一套共 7 项关键指导原则，我们相信这些原则将为制药和器械制造商提供必要的激励，使其在上市后阶段生成比较数据。第一，监管机构（药物）、通知机构（欧洲器械）、卫生技术评估组织和支付方应制定定制化的证据生成计划，确保未来的上市后研究能解决在进入市场时影响药物和器械获益-风险概况的可用数据的任何局限性。第二，上市后研究应进行层级设计：应优先考虑在随机试验中评估产品相对于现有已知有效疗法的净临床获益的研究，只要有可能，应解决常见的决策困境。第三，上市后研究应酌情纳入活性对照。第四，在上市后评估临床获益时，应将非随机研究的使用限制在效应幅度被认为较大的情况下，或者在进行随机试验不可行的情况下，有可能合理推断出比较获益或风险的情况下。第五，通过创新设计元素简化患者招募和数据收集，提高随机试验的效率。第六，政府应通过投资开发协作研究网络和数据系统，减少严格的上市后研究工作的复杂性、成本和浪费，直接支持和促进比较上市后数据的生成。最后，应制定或更积极地强化财务激励和处罚措施。
