【原】Trends in clinical success rates and therapeutic focus

我也不知道为啥NRDD没pdf版本，链接是网页粘贴版的网盘地址

链接:

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Trends in clinical success rates and therapeutic focus

Helen Dowden and Jamie Munro

去年FDA创纪录的批了59个新药（下图），同时EMA也建议通过了42个新活性物质的上市认证，究竟只是短暂的成功还是这种表现可以持续？

Last year was a productive one for the pharmaceutical industry in terms of new drug approvals. A record 59 new drugs were approved by the FDA in 2018, while 42 new active substances were recommended for authorization by the European Medicines Agency. Was this just a fleeting success or are there underlying trends to suggest that such performance can be sustained?

下面展示了CMR的数据，在同比基础上测算并比较了研发表现；覆盖了大中小型公司共30家左右，总的来说代表了全球top20的生物制药公司的研发支出情况；同样也分析了热点治疗领域和新药最初开发者的数据来看看未来的研发趋势。

Here, with this question in mind, we present data from CMR International, which operates a consortium of innovative biopharmaceutical companies to measure and compare R&D performance on a like-for-like basis. This consortium includes ~30 large, mid-sized and small companies, collectively representing ~80% of the top 20 biopharmaceutical companies by global R&D expenditure. We also analyse data on therapeutic area focus and on the originators of new drugs to further illuminate R&D trends.

Fig. 1 | Trends in clinical development. a | Probability of launch from start of phases I, II and III for new active substances (defined as a chemical, biological, biotech or radiopharmaceutical substance that has not been previously available for therapeutic use in humans and is destined to be made available as a ‘prescription-only medicine’, to be used for the cure, alleviation, treatment, prevention or in vivo diagnosis of diseases in humans). The probability of transition from phase II to phase III is also shown. Source: CMR R&D Performance Metrics, applying the progression decision methodology (PDM), which assesses the fate of active substances exiting a phase within a specified year range (such as 2015–2017), and assigns a fate as ‘progressed’ or ‘terminated’ (active substances remaining in-phase are not considered within the PDM). These values can then be used to calculate a probability of success to market. Only new drug projects are included, and the number of projects (n) is >100 for each time point shown in each phase. b | Trends in new drugs entering development. Source: CMR, change in number of new active substances in early development (preclinical, phase I and phase II) and late development (phase III and submission) pipelines, 2009–2017. c | Late-stage development success rate for new active substances targeting rare versus non-rare indications. Source: CMR R&D Performance Metrics, applying the PDM, between phase success rates (phase III to submission and submission to launch), excluding line extensions; n > 90 for non-rare diseases and n = 11–49 for rare diseases. See Supplementary information for details.

图1a是临床各个阶段的成功率，其中2期到3期的成功率只有1/4左右，有人辩护说从成本效益角度来2期失败好于3期失败，因为后者样本更大、临床研究开支更高，也是因为2期到3期的成功率这么低，使得2期到上市的成功率只有1/6不到。最后看横跨整个临床阶段的从1期到上市的概率也一直维持在10%以内。

Meanwhile, phase II success rates have remained relatively static, with only around a quarter of projects successfully progressing through phase II to phase III trials (Fig. 1a). While one can argue that there are cost benefits from failing in phase II rather than phase III given the greater size and expense of late-stage clinical trials, the low phase II success rate reduces the current chance of a molecule making it to market from this point to less than one in six (Fig. 1a). Finally, the probability of launch from entry to phase I has also stayed static at less than 10% (Fig. 1a).

有分析比较16-18年的临床失败原因发现过去3年基本没变：安全或疗效因素79% vs 76%、1% vs 3%因为操作或者技术瓶颈、13% vs 15%是策略调整的结果、7% vs 6%是商业因素。

An analysis of the reasons for clinical failure for the time period 2016–2018 indicates that these are largely unchanged over the previous 3-year time period (Nat. Rev. Drug Discov.15, 817–818; 2016): 79% (versus 76%) were attributable to safety or efficacy; 1% (versus 3%) were due to operational or technical shortcomings; 13% (versus 15%) were the result of strategic realignment; and 7% (versus 6%) were for commercial reasons (Drugs Today53, 117–158: 2017; Drugs Today54, 137–167: 2018; Drugs Today55, 131–160: 2019).

图1b是新药的进入开发阶段的趋势变化，给的指标是进入早期和后期开发阶段的NAS的数量变化，其中早期指的是临床前、1期及2期，后期指的是3期和申报上市。21世纪早期在shots on goal的浪射策略下很多项目得以进入管线，但是现在进入早期开发的项目会更加有选择性，近十年来急剧下降——当然某种程度也是有合并的因素在里面，比如辉瑞和惠氏、默克和先灵葆雅，但是还是能够得出结论：药企正积极应对公众诉求，在所选之经营领域建立卓越中心，即便是最大的那些药企也将研发集中在特定的领域。另外药企还采取了多种更有效率的策略，比如阿斯利康的5R，确认候选药物有着预期的效用后才进入后期阶段。

A popular model espoused in the early 2000s to counter attrition — the ‘shots on goal’ approach — was to push a greater number of projects into the pipeline. Data suggest that companies are now more selective about projects taken into  early development, with a sharp decline in early-stage project numbers over the decade (Fig. 1b). Some of this decline can be attributed to consolidation within the industry, particularly at the start of the decade following the mega-mergers of Pfizer with Wyeth and Merck & Co. with Schering-Plough. However, it seems reasonable to conclude that companies are also making good on their public aspirations to build ‘centres of excellence’ around their chosen franchises, with even the largest pharma companies sharpening their focus on particular therapeutic areas. Furthermore, companies are typically employing various productivity strategies, such as AstraZeneca’s ‘5Rs’ to ensure that a drug candidate is acting as intended before advancing it into later-stage clinical development (Nat. Rev. Drug Discov.17, 167–181; 2018).

处于后期开发的候选药物数量逐渐上升，15-17年有下降，这其实就是反映了早期开发阶段项目更加聚焦的策略，同样也可以预见到未来后期开发成功率的进一步提升的希望。

The number of candidates in late-stage development has risen gradually until recently. However, the dip in 2015–2017 (Fig. 1b) could signal that the result of a more focused and strategic approach about progressing candidates in early-stage development is working its way through the pipeline, and that we will now see the hoped-for outcome of a further boost in late-stage success rates.

治疗领域的选择也会影响成功率，图2可以看出10-17年心血管和神经系统疾病领域的成功率最低

The choice of which therapy area to focus on can also affect success rates. Cardiovascular and nervous system disorders are among those areas with the lowest probability of success over the 2010–2017 time period (Fig. 2), and could be a contributor to the deprioritization of such assets in several companies’ pipelines.

Fig. 2 | Probability of launch from phases I, II and III by therapeutic area from 2010–2017. Source: CMR R&D Performance Metrics, applying the progression decision methodology (PDM), between phase success rates (phase I to phase II, phase II to phase III, phase III to submission and submission to launch). Only projects for new active substances are included. See Supplementary information for details.

另一个影响成功率的治疗领域的考虑因素就是管线中孤儿药适应症或罕见病的药物的数量增长，主要是肿瘤领域分类的增加贡献了这部分趋势。罕见病的研究占了整个2期和3期试验的1/4，图1c中显示这类分子的后期开发成功率落后于非罕见病药物，但是gap正在收窄。这种提升是宣传提高患者意识、开发患者注册中心和引入额外监管支持机制的共同努力的结果。

Another therapeutic area consideration with the potential to influence development success rates is the growth in the number of drugs for orphan indications or rare diseases in company pipelines, a trend to which the increasing fragmentation of the oncology area has strongly contributed. Data from the CMR 2018 Global Clinical Performance Metrics Program reveal that rare disease studies now account for nearly a quarter of all phase II and phase III trials combined. Improvement in the late-stage success rates for such molecules has lagged those for non-rare diseases over the last decade, but the gap is narrowing (Fig. 1c). The concerted efforts of patient advocacy groups to raise disease awareness and develop patient registries, as well as the introduction of additional regulatory support mechanisms, are likely factors behind this improvement.

自从1983年美国引入孤儿药注册项目后，获批的罕见病新药就急剧增长，2018年FDA批准的新药中创纪录的58%（34/59）有孤儿药认证，其中27个来自小型公司。罕见病上更小的临床规模、更专业的商业化策略心音了大量新的生物制药企业的投入，在这个领域可能会使他们和大公司开展更有效的竞争。

Since the introduction of the first orphan drug designation programme in 1983 in the US, the number of new drugs approved for a rare disease has grown rapidly, and in 2018 a record 34 (58%) of the new drugs approved by the FDA had an orphan drug designation. Notably, 27 of these 34 approvals were from smaller companies. The reduced scale of the clinical programmes and more specialized commercialization methods associated with rare disease therapies have attracted investment from a slew of new biopharma companies, which may able to compete more effectively with larger companies in this field.

Fig. 3 | Percentage of FDA new drug approvals sponsored by major biopharma companies. The data include the top 20 companies as ranked according to 2017 pharmaceutical revenues. Sources: FDA and Cortellis Competitive Intelligence.

图3是是FDA批准的新药中大型药企申办的比例，可以看出近年来整体上下降。其实更进一步分析这些新药的最初开发者就可以发现是否是小型公司主导了新药的开发，或者小公司是否在和大公司的合作中有着更大的职责。同样有趣的是可以发现参与者的变化会对未来开发的成功率构成什么影响。

Indeed, there has been an overall decline in the number of new drugs brought through the US regulatory process by large pharma company sponsors in recent years (Fig. 3). A more detailed look at the originators of these new drugs could provide more insight into whether we are truly seeing smaller companies take the lead in new drug development or whether they are engaged in large pharma partnerships structured in such a way as to allow them greater responsibilities. It will also be interesting to observe what impact this change in the landscape of players will have on development success rates in the future.