临床试验计划变化趋势.pdf

临床试验计划变化趋势 来自超过25万项试验的见解 专题报告 1 目录 引言 . 2 最新趋势纵览 . 3 医疗保健支出和制药行业焦点问题 . 3 临床试验持续时间（按不同阶段分列） . 6 受试者招募是限制因素之一 . 7 临床试验设计分析 . 8 多年来，对开展临床试验的国家的选择发生了变化 . 8 适应性临床试验设计的应用越来越广泛 . 9 使用研究主方案可缩短试验持续时间 . 10 基于生物标志物的患者分层可提高试验成功率 . 11 富有试验设计经验的研究中心有助于提高试验成功率 . 13 将历史数据转化为对未来的见解 . 15 参考文献 . 16 2 引言 随着集中化管理数据的普及应用，我们能够对一段时间内临床试验的变化趋势进行评价，也能 够对那些易被忽略的信息进行洞察，如临床试验将在哪里进行、受试者招募进度延迟对研究持 续时间的影响以及研究采用了哪些设计。如果没有这些基于数据的信息，我们对药物研发费用 的认知可能会受到行业出版物和新闻报道中相关热门话题的误导。为了制定切实可行的发展规 划和更明智的战略决策，您需要将最新的变化趋势尽收眼底。在本报告中，我们对来自科睿唯安 旗下Cortellis临床试验情报 TM 和国际药物研究中心 (CMR International)的可靠和全面的数据进行 了汇总，在此基础上分析了过去 5 10年中超过 25万项临床试验的数据，并将这些数据与有关目 前临床试验趋势的一些主流观点进行了对比。 Cortellis临床试验情报汇集了全球范围内的临床试验信息，囊括了来自全球39个临床试验注册 中心以及各家新闻媒体报道、系列出版物、制药公司和其他出版物、会议报告、药政监管信息、公 司网站和药物产品管线的数据，并已被世界范围内的制药公司及相关机构用来制定临床试验计 划，包括研究中心的选择、研究方案的设计、生物标志物的识别和关键竞争情报的获取。 CMR International是科睿唯安的全资子公司，经过20余年的励精图治，已发展成为行业指标和 趋势分析的可靠信息来源。 2019 CMR International全球临床试验计划收集了来自30家制药 公司开展的I IV期临床试验的专有数据，涵盖研究层面、国家层面和研究中心层面的所有信 息，覆盖了8,000余种化合物和35,000余项研究以及100,000项国家层面和640,000余项研究中心 层面的记录。 3 最新趋势纵览 医疗保健支出和制药行业焦点问题 肿瘤适应症即是该行业经常被误解的焦点问题之一；在本报告中，会将其作为全文的基准进行 分析。虽然通常认为肿瘤是导致医疗保健支出和促使制药公司投资的一个主要适应症，但已有 数据显示，肿瘤的排名甚至未进入前三位。 美国医学会杂志（ JAMA）最近发表的一项关于1996 2016年美国154种疾病导致的医疗保健 支出（包括各种医疗、牙科和药房的支出）的研究报告显示，腰部疼痛和颈部疼痛、其他肌肉骨骼 疾病、缺血性心脏病、跌倒和泌尿系统疾病的支出居前六位（按降序排列；图1 ） 1 。 数据来源： Dieleman JL, Cao J, Chapin A, et al. US Health Care Spending by Payer and Health Condition, 1996- 2016.JAMA.2020;323(9):863-884. 图 1. 19962016年医疗保健支出排名前十的医学状况和疾病。 3 Current landscape Health care spending and pharmaceutical industry focus Oncology is one example of a common misperception about the industrys focus, and it will be used as a benchmark throughout this report. While oncology is commonly considered the leading indication for health care spending and pharmaceutical investment, when we look at the available data, we see that oncology is not even in the top three conditions. In a recent study published in the Journal of the American Medical Association (JAMA) regarding health care spending (including expenditure across a range of medical, dental and pharmaceutical settingsnull for nullnullhealth conditions in the nullnited nulltates from nullnull to nullnull, low back and neck pain, other musculoskeletal disorders, ischemic heart disease, falls and urinary diseases were the top five conditions (in descending ordernull nulligure nullnull. null Figure 1. nullop nullnullconditions in health care spending, null null nullnullnull . Source: nullieleman nullnull, nullao null, nullhapin null, et al. nullnull nullealth nullare nullending by nullayer and nullealth nullondition, nullnullnullnull nullnullnullnullnull. nullnullnullnull. nullnullnull3null3(nullnullnullnullnull3null nullnullnull null.null null.null null.null null.null null.null nullnullnull nullnullnull nullnullnull nullnullnull nullypertension nullementias Osteoarthritis nullkin and subcutaneous diseases nullrinary diseases nullalls Ischemic heart disease nulliabetes Other musculoskeletal disorders nullow back and neck pain nullillions nullnull 腰部疼痛和颈部疼痛 其他肌肉骨骼疾病 糖尿病 缺血性心脏病 跌倒 泌尿系统疾病 皮肤和皮下组织类疾病 骨关节炎 痴呆 高血压 10亿美元 4 制药公司的投资趋势与此相同，这一点可由针对每种适应症开展的临床试验的数量得以证实。 在相近的时间段内，疼痛和糖尿病也高居前三位（图2 和图3 ） 2 。临床试验的成功率可能增加制药 公司的投资；而且制药公司更有可能对成功率更高的疗法进行投资。例如，在针对肿瘤适应症进 行的临床试验中，能够将在研药物成功上市（从I 期至获批）的概率仅有3.4%；相比之下，针对心 血管类、代谢 /内分泌类和自身免疫 /炎症类适应症的临床试验的这一概率分别为 25.5%、 19.6%和 15.1% 3 。 数据来源： Cortellis临床试验情报 TM 数据来源： Cortellis临床试验情报 图 2. 20002005年间临床试验完成数量排名前十的适应症。 图 3. 20102014年间临床试验完成数量排名前十的适应症 2 。 4 Pharma investment follows this same trend, as evidenced by the number of clinical trials conducted for each condition. Over a similar timeframe, pain and diabetes are also in the top three conditions (Figures 2 and 3). 2 nullhe success rate of trials could contribute to investment choicesnull pharmaceutical companies are more linullely to invest in therapies that have a greater chance of success. For enullample, oncology trials only have a 3.4null probability of success of manulling it to marnullet (from Phase null to approval), compared with 2nullnull for cardiovascular trials, null.null for metabolicnullendocrinology trials and null.null for autoimmunenullinflammatio n trials. 3 Figure 2. nullop nullnull conditions in number of trials with end dates during 2nullnullnullnull2nullnull Source: nullortellis nulllinical nullrials nullntelligencenull Figure 3. nullop nullnull conditions in number of trials with end dates during 2nullnullnullnull2null4. 2 Source: nullortellis nulllinical nullrials nullntelligence null null nullnull nullnull 2null 2null 3null 3null 4null nullronic obstructive pulmonary disease nullheumatoid arthritis nulllid tumor nullypertension nullchinullophrenia nullreast tumor nullsthma Pain nullnullnull infection nullonnullinsulin dependent diabetes nullumber of clinical trials null on d i t i on null nullnull nullnull nullnull 2nullnull 2nullnull nullronic obstructive pulmonary disease nullheumatoid arthritis nullepatitis null infection nullypertension Obesity nullreast tumor nullnesthesia nullsthma nullonnullinsulin dependent diabetes Pain nullumber of clinical trials null on d i t i on 4 Pharma investment follows this same trend, as evidenced by the number of clinical trials conducted for each condition. Over a similar timeframe, pain and diabetes are also in the top three conditions (Figures 2 and 3). 2 nullhe success rate of trials could contribute to investment choicesnull pharmaceutical companies are more linullely to invest in therapies that have a greater chance of success. For enullample, oncology trials only have a 3.4null probability of success of manulling it to marnullet (from Phase null to approval), compared with 2nullnull for cardiovascular trials, null.null for metabolicnullendocrinology trials and null.null for autoimmunenullinfla matio n trials. 3 Figure 2. nullop nullnull conditions in number of trials with end dates during 2nullnullnullnull2nullnull Source: nullortellis nulllinical nullrials nullntelligencenull Figure 3. nullop nullnull conditions in number of trials with end dates during 2nullnullnullnull2null4. 2 Source: nullortellis nulllinical nullrials nullntelligence null null nullnull nullnull 2null 2null 3null 3null 4null nullronic obstructive pulmonary disease nullheumatoid arthritis nulllid tumor nullypertension nullchinullophrenia nullreast tumor nullsthma Pain nullnullnull infection nullonnullinsulin dependent diabetes nullumber of clinical trials null on d i t i on null nullnull nullnull nullnull 2nullnull 2nullnull nullronic obstructive pulmonary disease nullheumatoid arthritis nullepatitis null infection nullypertension Obesity nullreast tumor nullnesthesia nullsthma nullonnullinsulin dependent diabetes Pain nullumber of clinical trials null on d i t i on 非胰岛素依赖型糖尿病 HIV感染 疼痛 哮喘 乳腺肿瘤 精神分裂症 高血压 实体瘤 类风湿性关节炎 慢性阻塞性肺疾病 疼痛 非胰岛素依赖型糖尿病 哮喘 麻醉 乳腺肿瘤 肥胖 高血压 丙型肝炎感染 类风湿性关节炎 慢性阻塞性肺疾病 身体状况 身体状况 临床试验数量 临床试验数量 5 有趣的是，根据截至2020年6月的过去五年的数据， COVID-19已成为研究数量排名第四位的适应 症（图 4）。仅 2020年的数据即显示，针对 COVID-19开展的临床试验的数量比疼痛多达 8倍，使疼痛 成为了第二大适应症，这凸显了制药行业对这种在短时间内即对全世界人口造成严重影响的疾 病进行防治的决心。 以上示例表明，某个时间段的汇总数据将帮助您获得对临床试验变化趋势的洞察，而这些趋势 往往会由于错误认知而被忽略。然而，为了充分了解影响临床试验总体趋势的因素，对临床试验 费用支出和临床试验数量以外的其他因素进行关注非常重要，如临床试验的持续时间和受试者 招募进度。 数据来源： Cortellis临床试验情报 图 4. 20152020年6月30日期间临床试验完成数量排名前十的适应症。 5 Interestingly, according to the data for the last five years to June 2020, COVID-19 has already beconulle the fourth nullost studied indication nullnulligure nullnullnull Data for only 2020 shonull that there are eight tinulles nullore clinical trials being conducted for COVID-19 than for nullain, nullhich is the second leading condition, highlighting the nullharnullaceutical industrynulls deternullination to nullrevent and treat a disease that has significantly affected the nullorldnulls nullonullulation in a short anullount of tinullenull nullhese enullanullnullles denullonstrate honullaggregated data over tinulle can nullrovide insight into trends in clinical trials that are tynullcally overloonulled due to nullrcenullionnull null ever, to fully understand the factors shanullng the clinical trial landscanull, it is inullnullortant to loonull beyond enullnullnditure and nunullber of trials to other factors such as clinical trial length and nullrticinullnt enrollnullentnull Figure 4. nullonull 10 conditions in nunullber of trials nullith end dates during 2015-June null, 2020null Source: Cortellis Clinical nullrials Intelligence 0 1000 2000 null00 null00 5000 null00 null00 null00 nulldvanced solid tunullor nullreast tunullor nulletastatic non-snullall cell lung cancer nullnesthesia nulldenocarcinonulla nulletastasis COVID-19 Obesity nullon-insulin denullendent diabetes nullain nullunullber of clinical trials C on d i t i on 疼痛 非胰岛素依赖型糖尿病 肥胖 COVID-19 恶性肿瘤转移 腺癌 麻醉 转移性非小细胞肺癌 乳腺肿瘤 晚期实体瘤 身体状况 临床试验数量 6 临床试验持续时间（按不同阶段分列） 临床试验持续时间的长短与药物研发的财务成本和潜在收益直接相关。因此，制药公司和生物 技术公司尤其注重于对缩短临床试验持续时间方法的探索。与5 10年前相比，目前已观察到临 床试验持续时间缩短的总体趋势（图5 ）。但 III期临床试验例外。这并不奇怪，因为该研究阶段通常 需要获得非常大的研究样本量。 可缩短临床试验持续时间的因素可包括使用药政监管机构的加速审评流程。例如， 2020年发表 的一项研究结果表明， FDA的药物审评时间从1983年的3 年以上缩短至2017年的1 年以内 4 。 2018 年，有 81%（ 48/59）的临床试验受益于至少一项FDA 的加速审评计划（加速审批、快速通道或优先 审评），这一比例较前几年有所增加。然而，部分研究阶段持续时间的缩短以及监管机构的加速 审批并未转化为从获得新药临床试验批准至新药获批上市之间的间隔时间的缩短，这一时间间 隔始终为8 年左右（ 1983 2017年期间）。值得注意的是，针对肿瘤适应症进行的临床试验的中位 持续时间为13.1年，而针对非肿瘤适应症进行的临床试验的中位持续时间为5.9 7.2年，这表明 有关肿瘤适应症临床试验的风险更高 3 。 图 5. 按研究阶段和临床试验启动年份列出的平均试验持续时间（20102012年、20132016年和 20172020年）。临床试验持续时间按试验启动日期和试验结束日期之间的时间间隔计算。 6 Clinical trial duration by phase Trial length is directly correlated with the financial cost and potential return of drug development. Therefore, pharmaceutical and biotech companies particularly focus on identifying methods to reduce trial duration, and there has been a general trend of shorter durations vs. 5-10 years ago (Figure 5). The exceptions to this are Phase 3 trials, which is not surprising given that this phase typically requires the largest sample sizes. Factors contributing to shorter trial timelines could include faster regulatory approval processes. For example, a study published in 2020 found that FDA drug review times declined from more than three years in 1983 to less than one year in 2017. 4 In 2018, 81% (48/59) benefitted from at least one expedited FDA program (accelerated approval, fast-track or priority review), which is an increase from previous years. However, shorter durations for some phases and faster approval times by the regulatory bodies have not translated to shorter total time from authorization of clinical testing to approval, which has consistently been approximately eight years (in the timeframe from 1983 to 2017). Interestingly, oncology trials last a median of 13.1 years, compared with 5.9-7.2 years for non- oncology trials, which suggests higher risk for oncology trials. 3 Figure 5. Average trial duration, by phase and year the trial started (2010-2012, 2013-2016, 2017-2020). Trial duration was calculated by trial start date and trial end date. Source: Cortellis Clinical Trials Intelligence 0 10 20 30 40 50 60 2017-2020 2013-2016 2010-2012 2017-2020 2013-2016 2010-2012 2017-2020 2013-2016 2010-2012 2017-2020 2013-2016 2010-2012 2017-2020 2013-2016 2010-2012 2017-2020 2013-2016 2010-2012 2017-2020 2013-2016 2010-2012 2017-2020 2013-2016 2010-2012 2017-2020 2013-2016 2010-2012 数据来源： Cortellis临床试验情报 临床试验平均持续时间（月） 0 期临床 试验 I 期临床 试验 I/II 期临床 试验 I 期临床 试验 II/III 期临床 试验 III 期临床 试验 IV 期临床 试验 非常规的 试验阶段 试验阶段 未说明 7 受试者招募是限制因素之一 该行业面临的一个问题是受试者招募进度，这仍然是影响临床试验持续时间的一个限制因素。 在临床试验的所有阶段中，受试者招募的持续时间最长（图6 ），针对肿瘤适应症进行的临床试验 尤其如此（图7 ）。 在 PubMed中进行快速检索，会检索到近20万篇与“受试者/ 患者招募中面临的挑战”相关的文 章。这不仅是一个持续存在的挑战，也是在临床试验中最有可能提高效率和缩短试验持续时间 的一个因素。 数据来源： 科睿唯安国际药物研究中心（ CMR International） 数据来源： 科睿唯安国际药物研究中心（ CMR International） 图 6. 20152017年完成的临床试验的中位持续时间（按不同阶段分列）。 图 7. 20152017年完成的临床试验的中位持续时间（按治疗领域分列）。 7 Enrollment as a limiting factor One aspect the industry struggles with is participant enrollment, which continues to be a limiting factor for trial durations. Across all trial phases, the enrollment period represents the longest duration (Figure 6), especially for oncology trials (Figure 7). A quick search of PubMed returns nearly 200,000 articles related to “challenges with participant or patient recruitment.” Not only is this an ongoing challenge, it is also an area of clinical trials with the greatest opportunity to increase efficiency and decrease trial duration. Figure 6. Median duration of clinical trials completed during 2015-2017, by phase. Source: The Centre for Medicines Research (CMR) International Figure 7. Median duration of clinical trials completed during 2015-2017, by therapeutic area. Source: The Centre for Medicines Research (CMR) International 85 154 150 114 393 435 48 216 277 51 52 48 158 168 142 0 200 400 600 800 1000 1200 Phase 1 Phase 2 Phase 3 Median duration (days) Study start-up Subject enrollment Treatment duration Data management Report writing 124 107 147 99 139 254 260 293 394 524 129 126 103 99 275 51 56 44 46 56 148 159 123 147 162 0 200 400 600 800 1000 1200 1400 Respiratory Musculoskeletal Alimentary tract Genitourinary and kidney Oncology Median duration (days) III期 II期 I期 肿瘤 泌尿生殖系统和肾脏疾病 消化道疾病 肌肉骨骼系统疾病 呼吸系统疾病 中位持续时间（天） 中位持续时间（天） 7 Enrollment as a limiting factor One aspect the indust y struggles with is participant enrollment, which continues to be a limiting factor for trial durations. Across all trial phases, the enrollment period represents the longest duration (Figure 6), especially for oncology trials (Figure 7). A quick search of PubMed returns nearly 200,000 articles related o “challenges with participant or patient recruitment.” Not only is this an ongoing challenge, it is also an area of clinical trials with the greatest opportunity to increase efficiency and decrease trial duration. Figure 6. Median duration of clinical trials completed during 2015-2017, by phase. Source: The Centre for Medicines Research (CMR) International Figure 7. Median duration of clinical trials completed during 2015-2017, by therapeutic area. Source: The Centre for Medicines Research (CMR) International 85 154 150 114 393 435 48 216 277 51 52 48 158 168 142 0 200 400 600 800 1000 1200 Phase 1 Phase 2 Phase 3 Median duration (days) Study start-up Subject enrollment Treatment duration Data management Report writing 124 107 147 99 139 254 260 293 394 524 129 126 103 99 275 51 56 44 46 56 148 159 123 147 162 0 200 400 600 800 1000 1200 1400 Respiratory Musculoskeletal Alimentary tract Genitourinary and kidney Oncology Median duration (days) 7 Enrollment as a limiting factor One aspect the industry struggles with is participant enrollment, which continues to be a limiting factor for trial durations. Across all trial phases, the enrollment period represents the longest duration (Figure 6), especially for oncology trials (Figure 7). A quick search of PubMed returns nearly 200,000 articles related to “challenges with participant or patient recruitment.” Not only is this an ongoing challenge, it is also an area of clinical trials with the greatest opportunity to increase efficiency and decrease trial duration. Figure 6. Median dur