临床试验：临床终点(1)

What is an Endpoint?

  As defined in the FDA-NIH Biomarker Working Group’s Biomarkers, EndpointS, and other Tools (BEST) glossary, an endpoint is “a precisely defined variable intended to reflect an outcome of interest that is statistically analyzed to address a particular research question.”

Clinical Outcomes vs Clinical Endpoints

• Clinical Outcomes
  Clinical outcomes are medical events that occur as a result of a disease or treatment. They are measurable changes in health, function or quality of life that result from giving care to patients. The term “outcome” in clinical trials refers to a measured variable (e.g., peak volume of oxygen or PROMIS Fatigue score).

• Clinical Endpoints
  An endpoint refers to the analyzed parameter (e.g., change-from-baseline at 6 weeks in mean PROMIS Fatigue score). A clinical endpoint generally refers to one of the target outcomes of the trial, but may also refer to any disease or sign that strongly motivates the withdrawal of the patient from the trial, then often termed humane (clinical) endpoint.

There is a delicate equilibrium between an endpoint and an outcome measure, rather than a simple alternative: difference vs synonyms. Just look through basis several clinical circumstances surrounding these terms, in their application to each individual clinical situation.

  治疗或疾病最终对于人体健康的影响叫结局，英文为outcome；而用于测量结局的指标称为终点，英文为endpoint。

  临床试验设计常讲主要终点（primary endpoint）和次要终点（secondary endpoint），实际上就是要设计者根据研究目的确定主要（次要）结局的指标（变量）[primary (secondary) outcome measure (variable)]。而我们有时会混淆上述概念，说成试验的主要结局是什么，次要结局是什么，而实际想表达的是主要结局测量选用的指标是什么。结局是带有方向和判断的结果表达，如恶化、加重或好转，它是通过选择的终点测量比较得出的结果。

  临床终点指在一个特定时间段内发现的症状或功能水平的变化，或反映患者感觉、功能或生存状态的临床特点或变化的观测与评价指标。终点（endpoint）是一种用于评价一个临床试验中不同治疗组间治疗效果统计学比较结果的一种评价方法，终点往往被解释为通过测量的评估；但实际完整的终点指标应该包括资料收集的全面描述，以及支持特定研究目的的分析比较方法。

  临床结局主要是反映对疾病干预治疗产生的结果，而临床终点更强调在特定时限内的临床试验中，对临床结局的观测与评价。

Clinical Outcomes vs Surrogate Endpoints

  A clinical trial’s endpoints measure the outcomes in the trial. When a trial evaluates the efficacy of a new medical product or a new use for an approved product, investigators may choose endpoints that directly measure the clinical outcome they want to study. Alternatively, they may choose an endpoint that is a substitute, or “surrogate”, for the outcome they want to study:

• Clinical outcomes directly measure whether people in a trial feel or function better, or live longer. The benefit or likely benefit of a therapy, as measured by clinical outcomes (e.g., improvement in symptoms), is assessed to determine whether it outweighs any adverse effects (e.g., drug-induced liver injury).

• Surrogate endpoints may be used instead of clinical outcomes in some clinical trials. For example, surrogate endpoints are used when the clinical outcomes, like strokes, might take a very long time to study, or in cases where the clinical benefit of improving the surrogate endpoint, such as controlling blood pressure, is well understood. They are also used in cases where conducing a clinical endpoint study would be unethical.

Surrogate Endpoints

  A surrogate endpoint is a laboratory measure or a physical sign that is intended to be used as a substitute for a clinically meaningful endpoint. Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in a clinically meaningful endpoint.

  Surrogate endpoints “does not measure the clinical benefit of primary interest in and of itself, but rather is expected to predict that clinical benefit or harm based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence” and is used as a “substitute for a direct measure of how a patient feels, functions, or survives.”
  FDA uses surrogate endpoints, including markers such as laboratory measurements, radiographic images, or physical signs, to predict clinical benefit. Surrogate endpoints can be classified by their level of validation: validated surrogate endpoints, reasonably likely surrogate endpoints, and candidate surrogate endpoints. For an accelerated approval, a surrogate endpoint that is “reasonably likely to predict clinical benefit” can be used in place of a validated surrogate endpoint.

Types of Endpoints

  Endpoints are characterized by the type of research question they aim to answer, the outcomes they capture, and how they are used in the study design (Table 1). Effectiveness endpoints answer research questions that intend to demonstrate that an intervention or exposure results in a clinical benefit, defined as “a positive effect on how an individual feels, functions, or survives.

Characterized by the manner in which the outcomes are captured

• single-measure endpoint is a single variable that reflects a single outcome of interest.

• composite endpoint, multiple clinical outcomes are combined into a single variable and a single statistical test is performed.

• Intermediate endpoints measure “a clinical outcome that can be measured earlier than an effect on irreversible morbidity or mortality (IMM) and that is considered reasonably likely to predict the medical product’s effect on IMM or other clinical benefit.

Grouped within the statistical hierarchy

  The critical determination for grouping endpoints is whether they are intended to establish effectiveness to support approval or intended to demonstrate additional meaningful effects.

• Endpoints essential to establish effectiveness for approval are called primary endpoints.

• Secondary endpoints may be used to support the primary endpoint(s) and/or demonstrate additional effects.

• The third category in the hierarchy includes all other endpoints, which are referred to as exploratory. Exploratory endpoints may include clinically important events that are expected to occur too infrequently to show a treatment effect or endpoints that for other reasons are thought to be less likely to show an effect but are included to explore new hypotheses.

参考资料

1. https://rethinkingclinicaltrials.org/chapters/design/choosing-specifying-end-points-outcomes/choosing-and-specifying-endpoints-and-outcomes-introduction/
2. https://www.researchgate.net/post/What-is-the-difference-between-an-end-point-and-an-outcome-measure
3. https://www.fda.gov/media/84987/download
4. https://zhuanlan.zhihu.com/p/31523055
5. https://www.fda.gov/files/drugs/published/Multiple-Endpoints-in-Clinical-Trials-Guidance-for-Industry.pdf
6. https://www.fda.gov/drugs/development-resources/surrogate-endpoint-resources-drug-and-biologic-development