未來臨床試驗的方向是哪？探討臨床試驗去中心化

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　　Assessing the opportunities, considerations, and implications of decentralized trials—and why they’re here to stay.
　　評估去中心化試驗的機會、考慮因素和影響——以及為什么它們會存在保留.

　　For many pharmaceutical organizations, decentralized clinical trials （DCTs） have quickly become a strategic priority, one that is expected to endure long after the COVID-19 pandemic ends. Once viewed as nice-to-have pilot projects, DCTs—trials conducted remotely or through local healthcare providers to improve the patient experience—arrived when Pfizer launched a virtual trial1in 2011. While drug-based interventional DCTs only experienced a 7% CAGR between 2014 and 2019, they jumped to 77% between the second halves of 2019 and 2020 after the onset of COVID-19, according to ZS’s DCT database, referencing data from more than 1,000 trials.
　　對于許多制藥企業而言，去中心化臨床試驗 （DCT） 已迅速成為其重點戰略，并預計在 COVID-19 大流行結束后仍將持續很長時間。DCT（遠程或通過當地醫療保健提供者進行的試驗以改善患者體驗）在輝瑞于 2011 年啟動虛擬試驗1時出現時，曾經被視為不錯的試點項目。根據 ZS 的 DCT 數據庫中參考1,000 多項試驗的數據，在 2014 年和 2019 年，基于藥物的介入性 DCT 僅有7%CAGR，在 COVID-19 爆發后的 2019 年下半年和 2020 年之間，一躍攀升至 77%。

　　Decentralized trials offer a patient-centric approach, addressing various patient needs that often go unmet in traditional designs. DCTs benefit sponsors by accelerating clinical development, enabling more representative patient access and developing a stronger evidence package than traditional trials. Yet, DCT implementation doesn’t have to be all or nothing； trial decentralization can be viewed as a spectrum, with most DCTs combining in-person and remote activities to make clinical trial participation easier for patients. But one thing is certain: COVID-19 has shifted the balance of tradeoffs for the pharma industry, and despite operational challenges that may arise during decentralization, the benefits outweigh the investment. In the era of disruption, now is the time to take the risk.
　　去中心化臨床試驗提供了一種以患者為中心的方法，解決了傳統設計中經常無法滿足的各種患者需求。DCT通過加速臨床研發、賦能典型患者接觸，并發展比傳統試驗更有力的證據包，來使申辦方受益。然而，DCT的實施并不一定是1或0；試驗去中心話可以被視為一個范圍，大多數 DCT 結合了面對面和遠程活動，使患者更容易參與臨床試驗。但有一件事是肯定的：COVID-19 改變了制藥行業的平衡，盡管去中心化可能會出現運營挑戰，但其收益大于投資。在顛覆的時代，現在是承擔風險的時候了。

　　DCTs are here to stay
　　DCT 將繼續存在

　　Through our work with pharma clients, we have observed four primary drivers that suggest DCTs are here to stay, even in a post-pandemic society:
　　通過我們與制藥客戶的合作，我們觀察到四個主要驅動因素表明 DCT 將繼續存在，即使是在大流行之后的社會：

　　Regulatory direction:As a result of COVID-19, regulatory agencies including the FDA and European Medicines Agency have clarified their guidance on key decentralized modalities, such as telemedicine across state lines, direct-to-patient investigational product shipments, and more. The FDA’s new Digital Health Center of Excellence2and legislative direction3to advance the use of DCTs indicate a smoother regulatory landscape through 2021 and beyond.
　　• 監管方向：由于 COVID-19，包括 FDA 和歐洲藥品管理局在內的監管機構已經明確了他們對關鍵分散模式的指導，例如跨州遠程醫療、直接面向患者的研究產品運輸等。FDA 新的數字健康卓越中心和立法方向以推進 DCT 的使用，表明到 2021 年及以后監管環境將更加順暢。

　　Technology maturity:Evolving technology—fueled by record-level venture capital investments4in digital health—is enabling trial decentralization. Furthermore, horizontal and vertical integration among technology solution providers is creating more end-to-end technology solutions to deliver DCTs.
　　• 技術成熟度：不斷發展的技術——在數字健康領域創紀錄的風險資本投資的推動下——正在驅動試驗去中心化。此外，技術解決方案提供商之間的橫向和縱向整合正在創造更多的端到端技術解決方案來實現DCT。

　　Pharma investment and capability development:Pharma is creating focused DCT capability groups with dedicated leadership and investing in processes and technology to operate DCTs at scale.
　　• 制藥投資和能力開發：制藥公司正在創建專注于DCT的小組，具有專門的領導人員，并投入流程和技術以大規模運營DCT。

　　Patient experience:Patients’ increasing use of digital healthcare, such as telemedicine and digital pharmacies, have enhanced expectations of their clinical trial experience, which we don’t expect to revert moving forward.
　　• 患者體驗：患者越來越多地使用數字醫療保健，例如遠程醫療和數字藥房，提高了對其臨床試驗體驗的期望，這種情況我們預計未來不會逆轉。

　　Pros and cons of DCTs
　　DCT的優缺點

　　DCTs offer patients a more streamlined experience, reduce the burden of time-consuming in-person visits and enable wider patient access, especially in rural and underrepresented communities.
　　DCT 為患者提供了更簡化的體驗，減少了耗時就診的負擔，并能更廣泛地接觸患者，尤其是在農村和社區。

　　Like patients, sponsors also benefit from DCTs. As of 2016, 85% of trials failed to finish on time, financially impacting sponsors by up to $8 million per day, according to Pharmafile.5Decentralization can reduce these hurdles for sponsors by speeding up recruitment, increasing compliance, and reducing drop-out rates. Additionally, collecting high-quality clinical and real-world data through DCTs can build stronger evidence packages and better reflect the value created for patients. Sponsors can use novel digital endpoints to generate differentiated label claims through DCTs as well.
　　與患者一樣，申辦方也受益于DCT。根據 Pharmafile 的數據，截至 2016 年85% 的試驗未能按時完成，對申辦方每天的財務影響高達 800 萬美元。去中心臨床試驗可以通過加快招募、提高合規性和降低退出率來減少申辦方面臨的這些障礙. 此外，通過 DCT 收集高質量的臨床和現實世界數據，可以構建更強大的證據包，并更好地反映為患者創造的價值。通過DCT,申辦方也可以使用新穎的數字端點生成差異化的標簽聲明。

　　Still, decentralization—like most new innovations—adds complexity to the clinical trial process. It requires stakeholders to devote time and resources before the benefits can be realized. Sponsors must learn how to effectively and flexibly implement DCTs, as well as support patients and sites on their respective learning journeys. From a regulatory perspective, DCTs are still nascent and without consistent standards, meaning sponsors may have to initially focus on select priority markets. Lastly, while initial proof points to DCTs providing value are emerging—especially for increasing recruitment speed6and enhancing patient retention7—more work is needed to understand their impact. Sponsors should consider ways to benchmark DCT performance versus traditional trials to understand and capture the value of DCT.
　　盡管如此，去中心化——與大多數新的創新一樣——增加了臨床試驗過程的復雜性。它需要利益相關者投入時間和資源才能實現收益。申辦方必須學習如何有效和靈活地實施 DCT，并在各自的學習過程中支持患者和site。從監管的角度來看，DCT仍處于起步階段沒有一致的標準，這意味著申辦方可能必須首先關注特定的優先市場。最后，雖然 DCT提供價值的初步證據正在出現——尤其是在提高招募速度 6 和提高患者保留率方面——但還需要做更多的工作來了解它們的影響。申辦方應考慮對 DCT 性能與傳統試驗進行基準測試的方法，以了解和獲取 DCT 的價值。

　　Key considerations and implications
　　主要考慮因素和影響

　　Sponsors considering DCTs must root their approach in a deep understanding of patient needs and experiences. Designing approaches and solutions that reduce the patient burden and provide the right behavioral incentives for patients will lead to better patient engagement and improved trial performance. It’s also important to recognize that sites will remain key to patient experiences: As sponsors develop DCT solutions, providing options that are adaptive to site workflow and capability will be critical.
　　考慮 DCT 的申辦方,必須將他們的方法基于對患者需求和體驗的深刻理解。設計減輕患者負擔并為患者提供正確行為激勵的方法和解決方案將引導更好的患者參與及改進臨床試驗績效。意識到site仍是患者體驗的關鍵也很重要：隨著申辦方開發DCT解決方案，提供適合site工作流程和能力的選擇將是至關重要的。

　　It’s easy to assume solely decentralizing trials and introducing new technology will improve the patient experience, but this isn’t necessarily true. In fact, a multitude of disjointed study apps may even increase the burden, while home nurse visits may be more stressful than visiting a community center. Sponsors must first listen to patients and understand their needs, and then create a more personalized trial experience that meets those needs. It’s important for sponsors with diverse clinical development pipelines to tailor this exercise to specific trial patient populations, endpoints and intervention modalities. Furthermore, within each trial, sponsors should strive to enable optionality for individual patients based on their engagement preferences.
　　很容易假設僅去中心化臨床試驗和引入新技術將改善患者體驗，但這不一定是真的。事實上，大量雜亂無章的學習應用程序甚至可能會增加負擔，而家庭護士訪問可能比訪問社區中心更具壓力。申辦方首先必須聽取患者的意見并了解他們的需求，然后創建可以滿足這些需求的更加個性化的試驗體驗。對于擁有不同臨床開發渠道的申辦方來說，根據特定的試驗患者群體、終點和干預方式定制這項練習非常重要。此外，在每項試驗中，申辦方應努力根據個別患者的參與偏好為他們提供選擇權。

　　Beyond the approach itself, sponsors also must ensure that decentralization options are considered early in clinical development planning, allowing sufficient time for patient research, endpoint validation and vendor selection activities. If decentralization is an operational afterthought, the process will be more difficult to incorporate and, moreover, the extent to which the trial can be decentralized will be constrained by traditional, site-centered protocols. Shifting this thinking upstream will enable study teams to assess how decentralization can improve the patient experience.
　　除了方法本身，申辦方還必須確保在臨床開發計劃的早期考慮去中心化的選擇，為患者研究、終點驗證和供應商選擇活動留出足夠的時間。如果去中心化是事后的想法，則該過程將更難以納入，而且，試驗的去中心化程度將受到傳統的、以site為中心的協議的限制。將這種想法向上游轉移將使研究團隊能夠評估去中心化如何改善患者體驗。

　　Developing the digital capabilities needed for DCTs is also critical. There are new types of data collected in DCTs and oftentimes new insight generation opportunities from continuous data collection. Digital solutions must enable a unified user experience and one source of truth for data integration. Additionally, while the infrastructure can be gradually built—with numerous digital solutions and providers in the market—sponsors must have an enterprise architecture blueprint to guide the development to enable connectivity and optionality. Developing the DCT infrastructure without a plan would lead to future challenges with technological integration and agility.
　　發展DCT所需的數字能力也很關鍵。在 DCT 中收集了新類型的數據，并且經常從連續數據收集中獲得新的視角及機會。數字解決方案必須支持統一的用戶體驗和數據集成的一個真實來源。此外，雖然基礎設施可以逐步構建——市場上有許多數字解決方案和供應商——但申辦方必須有一個企業架構藍圖來指導開發以實現連接性和可選性。在沒有計劃的情況下開發 DCT 基礎設施將導致未來的技術集成和敏捷性挑戰。

　　Finally, since DCTs are cross-functional in nature, they require collaboration across sponsors’ trial design, trial operations, regulatory, digital health and innovation functions. These teams must overcome functional silos and establish new ways of working to successfully drive DCTs. Sponsors must also establish consistent processes to facilitate scaling DCTs from a proof-of-concept to an organizational capability. One key step here is organizational knowledge sharing: applying learnings rapidly and efficiently across study teams.
　　最后，由于 DCT 本質上是跨職能的，因此它們需要在申辦方的試驗設計、試驗運營、監管、數字健康和創新職能之間進行協作。這些團隊必須克服功能孤島并建立新的工作方式以成功推動 DCT。申辦方還必須建立統一的流程，以促進 DCT 從概念驗證到組織能力的擴展。這里的一個關鍵步驟是組織知識共享：跨研究團隊快速有效地應用學習。

　　Where to start?
　　從哪里開始？

　　For sponsors wondering where to begin or focus DCT efforts across a portfolio, a combination of their business needs and the feasibility of decentralization between therapy areas can act as a guide. Some therapy areas are a better fit for decentralized trials, based on factors such as the investigational medicinal product’s administration route （e.g., oral vs. infusion）, type of assessment procedure （e.g., non-invasive vs. invasive biopsy）, and whether the condition being studied is chronic or acute. Although ZS’s DCT database found cardiovascular, neurology, and diabetes as the most common therapy areas for DCTs, they can also be applied in other therapeutic areas. In fact, oncology and infectious diseases makeup 5% and 4%, respectively, of all DCTs historically. That said, for many therapy areas, full decentralization may not be feasible or right for patients； instead, identifying specific procedures that can be decentralized or combined into a single visit can drive valuable improvements to the patient experience.
　　對于想知道從哪里開始或在整個投資組合中集中 DCT工作的發起人來說，他們的業務需求和治療領域之間去中心化的可行性的組合可以作為指導。一些治療領域更適合分散試驗，這取決于研究藥物的給藥途徑（例如，口服與輸注）、評估程序類型（例如，非侵入性與侵入性活檢）以及病情是否正在研究的是慢性的或急性的。盡管 ZS 的 DCT 數據庫發現心血管、神經病學和糖尿病是 DCT 最常見的治療領域，但它們也可以應用于其他治療領域。事實上，腫瘤學和傳染病歷來分別占所有 DCT 的 5% 和 4%。也就是說，對于許多治療領域，完全分散對患者來說可能不可行或不正確。相反，確定可以分散或合并到單次訪問中的特定程序可以推動對患者體驗的寶貴改進。

　　As DCTs become more common, they will raise the bar for patient experience and patient data collection. They offer an opportunity to fundamentally change how we perform clinical research. As pharma companies embark on this journey, they can’t do it alone. The good news is that patients, investigators, sites and regulators are prepared to make the change and unlock the value of moving clinical trials closer to patients.
　　隨著 DCT變得越來越普遍，它們將提高患者體驗和患者數據收集的標準。它們提供了從根本上改變我們進行臨床研究的方式的機會。隨著制藥公司踏上這一旅程，他們無法獨自完成。好消息是，患者、研究人員、研究中心和監管機構已準備好做出改變并釋放讓臨床試驗更貼近患者的價值。

　　Fan Gaois aPrincipal；Maurice Solomonis a Principal；Arnab Royis a Manager； andWilliam Chaplinis a Consultant, all withZS

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　　來源：煎茶員日記