Content gist
“以患者为中心”的药物研发是指基于患者角度开展的药物开发、设计、实施和决策的过程，旨在高效研发更符合患者需求的有临床价值的药物。
After nearly a year, followedExposure Draft (9 August 2022)After that, the CDE issued three guiding principles《亚洲彩票十大平台》，《亚洲彩票十大平台》和《十大靠谱彩票平台》Further emphasis on "patient-centered"。
※ 参照本公众号文章《亚洲彩票十大平台》，将就三个指导原则进行一一对照，红色部分为正文
Iv. Classification of patient experience data
Patient experience data are classified in a variety of ways。Patient experience data may be collected by sponsors or non-sponsors。根据PED的收集方法，可分为预先设计的临床试验、患者偏好研究、自然病史研究、访谈、问卷、专家咨询、患者交流会议总结等。The data nature of PED includes qualitative, semi-quantitative or quantitative。Primary uses of PED in benefit-risk assessment，Including clinical outcome assessment, COA）、提供对获益和风险的患者偏好信息（patient preference information，PPI)，And other insights, needs, or priorities about the disease and its treatment，And support adequate benefit-risk assessment。The following describes COA and PPI。
(I) Clinical Outcome Assessment (COA)
clinical outcome assessment, COA) is from the patient and their caregiver, doctor, or other evaluator，An assessment tool or instrument used to evaluate the feelings, functioning, or survival status of an individual patient，Often a subjective assessment process is required rather than direct presentation of facts。COA was evaluated in terms of symptoms,体征, daily function, overall health status, quality of life and satisfaction。
Depending on the reporter，COA is divided into clinician reported outcomes，ClinRO）、患者报告结局（patient-reported outcome，PRO), observer-reported outcome，ObsRO)，和还包括基于测试评估患者表现的功能结局（performance outcome，PerfO)。
PRO is delivered directly by the patientSelf-reported measurements of symptoms, signs, functions, or other aspectsWithout external correction or explanation by a doctor or other person。The tools for measuring PRO are usually scales, questionnaires, numerical scores, or patient logs。例如，patient global assessment, PGA, numeric rating scale, NRS）、SF-36 健康调查量表（the 36-item short from health survey）等。
ClinRO是专业医护人员基于检查或观察到的患者疾病和健康状态的测量结果，多涉及对于患者体征、症状、Clinical judgments of behavior or other phenomena associated with disease or based on laboratory indicators。例如，格拉斯哥昏迷评分量表（ Glasgow Coma Scale ,GCS）、银屑病面积和严重程度指数（ Psoriasis Area and Severity Index, PASI） 等。
ObsRO is a measure of patient health outcomes reported by caregivers in their daily lives。For example, a diary of the frequency of seizures in children with Dravet syndrome recorded by the caregiver。
PerfO是患者完成一项标准化的功能任务时，由经过适当培训的人员或患者独自评估的测量值。例如，步行速度测定（如6分钟步行试验，6MWT）、记忆重现试验（如单词回忆测验）或其他的认知试验（如数字符号替换测验）等。此外，复合型临床结局评估工具中可能包含多种类型的临床结局评估，如ClinRO 和 PRO 的组合等。
Clinical endpoints based on COA can be used to evaluate clinical benefit。Clinical benefit is defined as the effect of a treatment or intervention on the individual patient's perception, function, or survivalBeneficial effects can be measured by improvement or delay in deterioration。临床结局评估终点可作为评价Clinical benefit的主要终点（单终点或复合终点）或预先定义的次要终点。例如，特发性便秘的关键临床试验中采用平均每周完全自发排便次数（spontaneous complete bowel movement, SCBM）大于等于 3 次作为主要终点；In pivotal clinical trials for myelofibrosis indications，Radiographic findings (reduced spleen volume) were used as the primary endpoint，并将患者日记采集的改良骨髓纤维化症状评分表（Myelofibrosis Symptom Assessment Form, Symptom improvement in MFSAF) as a key secondary PRO endpoint。
In addition, safety can be assessed by the COA tool。例如， 在非小细胞肺癌的临床试验中，采用视觉症状评估问卷(Visual Symptom Assessment Questionnaire ,VSAQ-ALK)评估治疗药物的眼科安全性。
(II) Patient Preference Information (PPI)
患者偏好信息是指患者针对特定治疗的不同临床结局或其他特性的选择意愿和接受程度的定性或定量的评估。In benefit-risk assessment, PPIs can provide patients' preference for benefits and tolerance for risks。例如，询问患者对不同用法（如外用、口服或注射）药物的使用倾向，或询问患者是否为了可能的获益而愿意接受潜在的风险。
在药物研发的不同阶段，PPI可能对于Treatment background、终点选择和动态获益-风险评价等方面都有一定的指导作用。For example, PPI helps with clarityClinical benefit as measured by the trial endpoint对于患者的重要性，了解患者对于特定药物的获益和风险的权衡，了解患者群体对于各种治疗方案的Selection preferenceAnd heterogeneity。
The application of PPI in benefit-risk assessment should fully consider the indication background,The application value of patient preference informationPPI collection methods and representativeness of patients' views。The value of patient preference information should be carefully considered in the following cases:①药物疗效明确但存在严重或不确定的安全性风险， 而患者愿意承受更高的风险以获得可能的获益；②患者之间对于最重要的获益和/或风险的观点有较大差异；③患者观点与医疗专业人员观点不一致。一般而言，对于疗效不佳或存在严重安全性问题的药物，不能仅依据患者偏好信息进行Benefit - Risk assessment。
Iv. Patient experience data support benefit-risk assessment
(1) Overview of important factors in benefit risk assessment
Patient experience data can provide key considerations for drug benefit-risk assessment。在药物Benefit - Risk assessment整体框架下，可将患者体验数据纳入其中予以完善，关注患者临床需求和患者观点，确保以患者为中心进行Benefit - Risk assessment。
The benefit-risk assessment framework and concerns based on patient experience data include the following aspects (see Table 1)：“Therapeutic background analysis”（疾病的发病情况、严重性与预后、现有可用疗法的特点、未满足临床需求等）、具体药物“获益”和“风险及风险管理”。对上述每个方面均需要评估相关的证据（包括数据质量和可信度）以及不确定因素及其潜在影响。最后，Combine the severity of the disease with the current unmet clinical need，并综合有关药物获益和风险的证据和不确定性，并Combine the severity of the disease with the current unmet clinical need，得出获益风险评估的具体结论。
表1. Patient-centered benefit-risk assessment framework
Evaluation dimension | Application scenarios of patient experience data |
Therapeutic background analysis | Identify and measure the patient's most significant symptoms and burden of the disease * Understand the natural history of the disease, including the occurrence and development of the disease, the severity of the disease, and the prognosis Identify significant risks and benefits for patients from existing treatments and assess unmet clinical needs Understand the treatment characteristics that are most important to patients and determine the level of need for new therapies |
获益 | The evaluation results of patient experience data, patient preference information, and other patient experience data information were included in the evaluation of benefits • Evaluate the clinical benefit of the drug based on the clinical outcome evaluation endpoint • Determine clinical relevance of study assessment endpoints and measures • Evaluate whether the change value of the measure (threshold) is clinically significant,The minimum clinically significant difference between the groups and the threshold of change at the individual level were included Patient preference information indicates the patient's tendency to benefit |
Risk and risk management | The assessment results of the clinical outcome assessment, patient preference information, and other patient experience data were incorporated into the risk assessment • Evaluation of drug safety and tolerability based on COA endpoints • Evaluate the clinical significance of the severity and frequency of safety events • Understand patient awareness of risk and the perceived impact of risk on quality of life • 如出现不良事件并采取了相应管理措施，了解该风险管理措施对患者造成的负担 • Patient preference information provides a patient's acceptance of risk |
The impact of uncertainty on benefit-risk assessment | For uncertainty, patient preference information may indicate a patient's overall preference for a benefit-risk assessment |
Benefit-risk conclusion | |
(二) Patient experience data support key considerations in benefit-risk assessment
在Benefit - Risk assessment中，患者的体验数据可以为以下一系列考量指标提供有用的信息，例如疾病的自然史、疾病Main symptoms, signs and diseasesThe impact on the patient's life, the patient's experience of treatment or perspective on unmet needs,Patient-reported efficacy or safety outcomes, patient preferences for treatment options or outcome measures, etc. (see Table 1 for details)。According to the purpose of data collection, data type and data quality, the scope and function of PED are different。
1.Treatment background
PED can provide a patient's perspective on the impact of the disease and their existing treatment experience。例如，PED有助于更清晰地理解疾病对患者的影响，哪些症状和体征是患者最在意的、最困扰的、最影响日常生活质量的。PED亦有助于了解目前可用治疗方法对患者群体的医疗需求的满足程度，包括有效性、安全性、耐受性、便利性、可及性等。
For the pathogenesis, clinical symptomsAnd/or clinical benefitThe evaluation indicators of diseases are not fully understood, and PED data also provides insight into the natural history of diseases。For example, some rare diseases have low incidence and complex phenotypes,Lack of effective treatment, clinical trial design for drug research and developmentDrug efficacy and safetyPose a great challenge。患者的体验和观点可为疾病发生发展、疾病严重性、治疗的有效性和安全性、预后等方面的评估提供重要的参考。
2.Clinical benefit
Clinical benefit需关注其有效性指标的临床相关性、是否契合患者需求、获益程度是否具有临床意义等，患者体检数据可以为Clinical benefit的评估提供患者观点和偏好信息。
2.1 Clinical relevance of efficacy outcomes
Descriptions of clinical benefits usually include有效性（如生存率、重要临床结果的变化、症状和体征的减轻、功能的改善、生活质量改善）、效应强度和不确定性，The distribution of therapeutic effect in the population, the duration of therapeutic effect, etc。对于有效性指标的选择，建议根据目前对于疾病的认知以及已获得的患者体验数据，判断试验终点和测量指标的临床相关性，即是否为患者最在意或对患者影响最大的临床指标，或该测量指标是否可预测Clinical benefit。
对于以直接或相对直接测量Clinical benefit（如症状和体征的减轻、功能的改善、生活质量的提高）为研究终点的临床试验，Clinical outcome assessment endpoint can be selected。该终点如作为主要或关键次要终点指标，应充分说明选择依据，并提供COA数据的采集方式、度量性能（如信度、效度）、详尽数据分析及结果判读。
Benefits in addition to clinical benefits (e.g., ease of medication, compliance, etc.)It may also affect patient preferences and should be given appropriate weight in the benefit-risk assessment。
2.2 Clinical significance of benefit
需要评估Clinical benefit的程度是否具有临床意义，这亦是以患者为中心的Benefit - Risk assessment的重要考量因素之一。
基 于 有 临 床 意 义 的 最 小 差 别 （minimally clinically important difference, MCID）或最小有意义差别（minimum important difference, MID) to set a clinically valuable benefit threshold，Represents the smallest improvement that the patient finds valuable。
When determining the MCID，It should be based on patient experience data，At the same time, it can refer to the relevant guidelines, expert consensus and other recognized standards, and communicate with the review agency in a timely manner to reach a consensus。
When a meaningful difference is shown between groups, it does not represent a meaningful clinical benefit for an individual。Can be considered based on MCID/MID预设一个有临床意义的患者个体内的指标变化阈值（clinically meaningful within-patient change），对患者是否达到治疗目标进行判断，该值可作为评价获益的支持性证据。
2.3. Risk tolerance and acceptance
在药物安全性评估时需要重视患者的感受和体验，例如，某些患者在用药过程中可能出现一些较轻的不良反应，但长期用药亦可能对其生活质量产生明显影响。
In determining the risk of a drug, characteristics such as severity, frequency, and reversibility of adverse events should be considered, as well asAfter the patient had an adverse reactionEffects and potential consequences on medication adherence。PED可以是安全性结局本身（即基于COA的安全性终点），也可作为其它支持性证据，如风险知情情况（Whether the patient understands each type of risk and the severity of the risk occurrence and its likelihood), clinical importance (which risk patients perceive to have the greatest impact on quality of life), tolerance of adverse events,The acceptability of risk management measures and the burden of risk management measures on patients。
Patient preference data can provide information on patient risk acceptance, that is, the likelihood of clinical benefit,Whether patients are willing to accept predictable and unknown risks。For example, whether the patient is willing to accept a potential risk for the possible benefit;而某些慢性疾病患者，其患者已适应所患疾病及其对日常生活的影响，现有治疗可稳定病情，相比之下，其对新疗法可能会期待更大的受益，而不可承受较高的风险。
3.Benefit - Risk assessment
当药物有明确的Clinical benefit，且安全性特征良好、未发现严重的安全性风险时，可判断其获益大于风险。
当药物有明确的Clinical benefit、但存在安全性风险时，需权衡获益-风险比，考虑是否可通过合理的风险管理措施控制风险。
When the drug presents a potentially serious safety risk (e.g., life-threatening) and/or may have limited benefit,Or when there is uncertainty, benefit-risk assessment can be challenging。在这种情况下，符合特定目的且可靠的患者体验数据，对评估药物获益-风险将有所助益。
整体人群的Benefit - Risk assessment是对临床试验受试者的整体评价；而亚组评估是针对部分患者亚组的评估。当整体Benefit - Risk assessment与亚组评估之间存在不一致时，需要仔细权衡来自两部分的支持性数据，亦可纳入患者的观点。例如，经评估药物对整体适应症人群的预期风险超过获益时，如果PED能够帮助识别具有良好获益风险比的亚组人群，则可在后续研发中以该人群为试验对象开展研究，以证明药物是否在该人群具有有利的获益-风险比。
(三) Drug life cycle considerations
1.Pre-market research and development
The collection and application of patient experience data is an accumulation process。临床开发过程中，患者体验数据的不断积累，用以指导更广泛的Benefit - Risk assessment，从而支持药物研发继续/终止的决策。
早期收集的患者体验数据多以定性数据为主，可为Benefit - Risk assessment和药物开发决策提供的信息包括发现未满足的临床需求、确定目标患者群体、确定试验设计的关键要素等。例如，Patient experience data collected early in clinical development can be analyzed in an open-ended question format or against patient health data，了解疾病的自然病史、临床实践的偏好、患者亚群的差异等，从而识别未满足的患者需求，确定目标患者群体。
With the continuous accumulation of PED, the scope of patient experience data was gradually focused and the method was gradually quantified in the later stage。例如，开发定量的COA评估工具，以更直接地测量对患者最关注的临床结局，并验证该工具的临床相关性，确定有临床意义的变化阈值；可以收集量化Information about patient preferences,以确定患者使用药物的意愿，量化风险接受度并基于临床和患者偏好证据对药物进行Benefit - Risk assessment。
这些后期收集的定量PED信息可作为临床有效性和安全性数据的直接证据或补充信息，支持动态地评估获益-风险。当面临重大开发决策需要与审评机构讨论时，PED的收集与应用也可作为与审评机构沟通交流的重要内容之一。
2.Post-marketing use phase
During the post-marketing use of the drug, it should be based on the accumulation of new information (including PED),Continuous evaluationThe benefit-risk status of a drug,If new risks are discovered, decide whether to take appropriate regulatory measures，包括修改风险管理计划、增加上市后研究要求、说明书变更或撤市等，以期将患者的获益最大化和风险最小化。鼓励上市后收集更多的PED，这类信息可以由申办者为回应特定的上市后要求为目的而收集，也可以通过申办者、研究者或患者组织自愿发起的各类研究（如访谈、问卷调研、患者使用偏好研究等）而收集。这些患者体验数据既可以真实地向广大患者、医护人员和相关人员传达反映患者关于药物使用的体验和感受，也可以为获益风险的动态评估提供新证据。
5. Communication
当申办者计划收集和利用患者体验数据作为Benefit - Risk assessment的一部分时，鼓励在这类研究的设计阶段与审评机构早期沟通，以获得关于研究设计、数据采集和监管是否符合要求的及时反馈。
当申办者计划采用PRO或其它COA作为确证性研究的主要或关键次要终点时，应与审评机构及时沟通。另外，在临床试验过程中，如果因为更改PRO或其它COA而使临床试验方案做出重大调整，应与审评机构及时沟通。具体参见《亚洲彩票十大平台》《亚洲彩票十大平台》《亚洲彩票十大平台》等相关指导原则。
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