最後更新日期：2021 年 10 月 09 日
「臨床試驗(Clinical trial)」是將試驗用藥物(IMP)施用於人體的介入性臨床研究，主要是觀察其安全性與有效性。
Clinical trial is an experiment which is conducted in human beings. It’s a type of interventional clinical research (介入性臨床研究) which aims to investigate research questions about safety and efficacy of one or more health interventions.
Clinical trail’s life cycle can be broadly divided into 3 stages (臨床試驗可大致分成三個階段):
- Stage 1: Study Initiation (起始)
- Stage 2: Study Conduct (執行)
- Stage 3: Study Closeout (結案)
整個臨床試驗的生命週期又包括：
- Study initiation (試驗起始)
- Plan/preparation (準備)
- RA/EC submission (試驗送審)
- Execution (Site initiation & Enrollment) 試驗執行(開Site與招募受試者)
- Last Subject Last Visit (LSLV) 最後一個受試者的最後一次訪問 /Database lock (DBL) 資料庫鎖定
- Closure (Site close-out) 結案關Site
- Ongoing subject follow-up (後續進行中受試者追蹤)
Study Initiation
Clinical trial follows a specific research plan which is known as “Clinical Trial Protocol (臨床試驗計畫書)” developed by researcher or manufacturer. Clinical trial protocol explains how the trial will be conducted, including the objectives(目的), design(設計), methodology(方法) and organization(組織).
研究人員或藥商想要執行臨床試驗，就需要研發出該項臨床試驗的「試驗計畫書(Protocol)」，裡頭得清楚闡述研究目的、設計、方法與組織等規劃。
Before a clinical trial begins, researchers review prior information about the medicinal product to develop research questions & objectives. Then they decide about selection criteria, number of participants, what drugs will be tested, duration of study, type of data to be collected, data analysis method, etc.
執行試驗前，研究人員會參考過去的經驗及相關資訊來訂定接受試驗的人需要符合的標準、需要多少人參加、什麼藥物會被用來測試、試驗要執行多長時間、需要收集哪些資料，以及這些資料該怎麼分析等等。
Study protocol often explains what statistics will be used in the trial. The details are provided in stand-alone document that is statistical analysis plan (SAP). It includes details about how data will be handled, specific analysis of all measures/values, what would be the meaningful outcome, and so on.
After the creation of study protocol, case report form (CRF) or eCRF is created. With the help of case report form that is CRF database is created to store and manage the clinical data. Parallelly, research sites are selected which in turn gets approval to conduct the trial and begins to identify and recruit the research participants for the trial.
試驗計畫書生出來後，接著就是要來做個案報告表啦，除了紙本形式以外，使用電子形式的個案報告表(eCRF)也已漸漸成為現今臨床試驗的趨勢。同時，試驗團隊也會開始尋找適合作為臨床試驗開展的醫院(試驗中心Site)，並準備開始收案，納入適合的受試者。
Before starting the trial, approval from appropriate regulatory authorities (RA) and institutional review board (IRB) or ethics committee (EC) is required. During trial initiation stage, other aspects of the trial such as budgeting, business development, feasibility assessment, financial planning is also finalized.
當然，在執行一項臨床試驗前，必須要先取得衛生主管機關(TFDA)與人體試驗委員會(IRB)審查通過的核准，才能順利開始執行試驗。
Study Conduct
During this stage, the first thing to happen is inform consent (知情同意) process. In this process, volunteers will be educated by research staff about the purpose of the study, possible benefits and risks of study, duration of participation, what all procedures will be involved, what the participants would be expected to do during the study, etc.
試驗執行階段的第一件事，就是知情同意的過程。招募受試者的方式有很多，一般會由醫師在門診期間詢問來診的病人(如果醫師判斷該名病患或許能夠符合試驗計畫書的受試者納入條件)，如果病人有意願的話，就會安排時間由試驗團隊人員詳細解說試驗的目標、潛在效益與風險、參與時間與試驗執行程序，以及參與研究的受試者被期望需要遵守的地方。
After becoming well aware about all the study information, volunteers decide whether to participate or not to participate in the trial. If volunteers decide to participate in the trial, they sign informed consent form (ICF；受試者同意書) agreeing to take part in the study. Volunteers will be screened to make sure that they qualify for the trial. Each trial protocol has guidelines about who can or who cannot participate in the trial. These are called eligibility criteria (資格標準).
受試者在全盤瞭解試驗相關資訊後，可決定是否要參與該項臨床試驗。如果決定要參與，就需要簽署「受試者同意書(ICF)」，然後依循試驗計畫書的指引來進行篩選，確保納入試驗的受試者符合納入標準。
Volunteers will undergo all necessary medical evaluation to meet all inclusion and exclusion criteria for the trial. Researcher will collect all the medical data from the volunteers and their previous doctors and then extract the relevant information. If the volunteers qualify for the trial, they will be administered with the investigational drug. Once the volunteers qualify for the participation in the trial, they become research subjects (受試者).
這些自願參加臨床試驗的人，會被安排一些必要的醫療檢測，以確保符合試驗的納入排除條件。在這過程中，研究人員還會向病人或其先前的醫師收集相關醫療病歷資訊。一旦符合條件的受試者，就可以開始施用試驗用藥物。
Clinical trial data are generated from research subjects. Data are collected from the time of first participant enrollment till study completion. Research subjects are asked to do the site visits, tests and other procedures according to the study protocol. At each visit, most of the procedures and results are first documented by research staff on source document such as subject’s medical record. Site staff transcribe each subject’s data to the paper CRF (pCRF) or electronic CRF (eCRF) after the subject’s visit.
臨床試驗的資料是來自受試者的受試狀況，基本上資料的收集會從首位納入的受試者開始，直至試驗結束為止。受試者會被要求在規定的時間內前往門診接受試驗用藥、醫療檢測或其他相關程序，在每次門診時，試驗團隊會將試驗大部分的程序與結果先記錄與歸檔在來源文件(source document)中，像是病歷報告。於門診後，再將每個受試者的資料抄寫到個案報告表中或是輸入到電子個案報告表內。
Site monitor appointed by Sponsor or CRO ensures that trial is conducted according to the study protocol, prescribed guidelines and applicable regulatory requirements. Clinical research associates (CRA) do source data verification (SDV) which involve CRF or eCRF comparison against the source document.
試驗監測者是由試驗委託者或是CRO公司指派，以確保試驗依循試驗計畫書、規範指引與適用的當地法規要求。臨床試驗專員(CRA)會於試驗中心(Site)針對研究人員所收集的試驗數據進行原始資料的核對(Source Data Verification，SDV)，比對病例報告表(CRF)和來源文件(source document) ，確保資料被準確記錄、更正並按規定執行。
| *監測(Monitoring)的目的有三個： 1. 確保受試者之權利及福祉受到保護(Subject protection) 2. 確保試驗數據準確與完整且可查證(Data accuracy) 3. 確保試驗之執行符合計畫書及其他相關法規之規定(GCP compliance) *監測者(Monitor)應擔任試驗委託者(Sponsor)及試驗主持人(PI)之間的主要溝通聯繫者。因此，CRA需要與下列各單位都有所聯繫，包括：試驗團隊(Study teams)、試驗中心(Site)、試驗主持人(PI)與試驗助理 (SC)，此外還有人體試驗委員會(IRB)、食藥署(TFDA)，及其他官方單位或是國外合作對象(Global associates)等。 |
Paper CRFs are sent to data entry center where all the data are transcribed into a database. Data from other sources such as lab data are also collected in the database. During the course of the trial, the raw data are abstracted, coded and transcribed. After participant activities have ended and all the data is in a computer database, data is checked and cleaned for final study analysis.
Study Closeout
Once the trial is completed, the analysis of clinical data takes place. Researchers analyze the information collected during the investigation to make decisions about the findings. They also check if any further testing is required.
試驗完成後，就會開始對臨床數據進行分析。 研究人員會分析試驗期間所收集到的資料，以對試驗結果做出決定，並檢查是否需要進一步進行其他測試。
Decisions depend on the phase of the trial. For instance, after phase I or phase II trial, research team decides whether to continue testing the treatment in the next phase or to stop because results are not promising enough. And if phase III trial is completed, research team analyzes whether the new product is effective and safe to use in general population. Then they submit new drug application (NDA) to the TFDA so the new product can be launched in the market.
Results of clinical trial are shared with appropriate parties through publication, conferences and posting to trial registration record. Data will be archived according to the prescribed rules.
Conclusion
Clinical trial is a complex process which needs a well-coordinated team of experts to achieve a meaningful outcome.
本篇僅為個人臨床研究深耕手札，不作為任何其他用途。