精準醫療分子檢測產業分析與發展策略

Abstract

精準醫療系考慮個體或特定族群之基因組成、背景環境及生活型態等因素，訂出合適的疾病預防、診斷與治療計畫，目標是希望在對的時間，給予目標個體最適當的治療方針，期盼醫療診斷和治療用藥能夠準確，最終目的是減少族群罹病率，提升疾病緩解率及治癒率，減少治療產生的副作用，減少病患死亡率，甚至提升病患的生活品質，減少國家社會的醫療經濟負擔。近年來，次世代定序（Next-generation Sequencing, NGS）技術的應用，讓精準醫療的發展更為蓬勃，過去的理念逐漸成為現實世界可行的方案。目前多數精準醫療分子檢測是以「實驗室開發的測試（Laboratory Developed Tests, LDTs）」的形式進行。在美國，精準醫療分級檢測LDTs可由符合臨床實驗室精進修正案（Clinical Laboratory Improvement Amendments, CLIA）規範，並獲得醫療保健和醫療補助服務中心（Centers for Medicare and Medicaid Services, CMS）認證的實驗室來執行。然而，由於檢測結果不準確和誤判的案例時有發生，而這些失誤會創造病人許多傷害，所以美國食品藥物管理局（Food and Drug Administration, FDA）於2014年10月公告精準醫療分子檢測LDTs的管理指引草案，並期望將其全面納入體外診斷醫療器材（In Vitro Diagnostic Medical Devices, IVD）的管理模式中，以確保病人安全。該草案公告後，在具有符合CLIA管理規範資格的業者抗議下，美國FDA，在2017年初，宣佈將延後發佈精準醫療分子檢測LDTs管理指引的最終版本，暫時維持現行管理模式，希望續做修正、協商，未來再另行啟動修法。以此為前車之鑒，本研究之目的乃為政府提出適用於臺灣精準醫療分子檢測之管理建議，以利精準醫療分子檢測之政策擬定並促進精準醫療分子檢測相關產業之發展。本研究計畫於2017年開始精細評估美國精準醫療分子檢測LDTs的發展背景與監管機制，參考其他先進國家精準醫療分子檢測LDTs與IVD的相關法規，再藉由多次會議，彙集臺灣本土產、官、學、研、醫界先進學者專家等之建議，以統整臺灣精準醫療分子檢測產業現況，發展出介於LDT與IVD之間的LDTS（Laboratory Developed Tests and Services）之概念，並以此為主體提出一個管理綱要草案。LDTS系以實驗室發展之測試服務為主體，在發展的初期，試辦管理物件將以非醫療機構之生技業者為目標。為了要讓未來精準醫療分子檢測產業之發展能以病患安全與民眾權益為優先，LDTS參考美國CLIA之實驗室測試方法的分類標準、初期建議采鼓勵性（非強制性）的列冊管理機制、建立與國際接軌的品質管制系統（參照CLIA或ISO 15189或ISO/IEC 17025國際標準的要求），逐步建立不良事件的通報機制。為促使業者自願納入本管理機制，並能增進產業創新研發動能，本研究建議主管機關訂定LDTS發展IVCT之相關獎勵措施（例如：「利基審查方案」）,希望此評估計畫之研究成果與建議，能夠成為主管機關後續管理辦法撰擬與系統建置的有效依據。 承此，臺灣食品藥物管理署於2018年同意辦理「分子檢測先期計畫-建立精準醫療分子檢測實驗室管理指引及其輔導試行計畫」。本研究接力2017年計畫，持續更新與彙整各先進國家（美國、歐盟、澳洲、日本）與中國大陸對於臨床分子檢測實驗室品質與服務相關之最新法規、管理機制與發展趨勢，並加比較與分析做為臺灣政府施政的參考。此外，本研究計畫邀請國內產、官、學、研、醫、生物資訊（人工智慧）、各領域相關工作者，成立專家學者委員會，研擬臺灣臨床分子檢測實驗室之「管理與品質指引」與「輔導暨查核試行基準」。專家小組委員會經4次分組會議與2次專家會議後針對LDTS指引之定義、品質系統、分級、列冊、查核、通報等架構基礎，擬定管理與技術指引草案。為瞭解國際實際執行臨床分子檢測實驗室品質提升相關方案，本研究計畫亦組隊參加美國BIO International Convention國際研討會，並參訪FDA及通過CLIA認證之實驗室，汲取美國經驗，提出報告，作為本研究計畫後續「實驗室輔導暨查核試行作業」的參考。 為促進精準醫療分子檢測產業同仁深度暸解政府政策，並鼓勵國內相關生技產業之分子檢測實驗室所有工作人員有機會參與本LDTS試辦研究，本研究舉辦3場次說明會（台南、台中、臺北）、2場次輔導訓練課程及1場次「精準醫療分子檢測產業檢測與服務國際研討會」。國際研討會邀請美國與大陸相關領域專家學者來台參與，針對法規管理、技術交流、品質提升等主題，與國際專家學者們作了深度探討，冀能提升臺灣分子檢測實驗室品質及產業競爭力。 本研究為鼓勵精準醫療分子檢測「產業」之發展，研究物件為非醫療機構之實驗室。本研究參考美國CLIA規範中實驗室測試方法之分類分級標準，邀請國內12家分子檢測產業實驗室參加輔導暨查核試行作業；其中，2家參與輔導試行作業，10家參與查核試行作業。於輔導暨查核過程中，專家學者深入瞭解試行流程、評量方式、查核模式、相關書表之內涵並提供調整之建議，以作為未來正式實施之參考基礎。 精準醫療服務于未來全球醫療產業中扮演不可或缺的角色。制訂完善規範及運作模式讓臺灣相關「產業實驗室」於此新興領域有可依循之「服務標準與品質標準」已成為當務之急。藉由上述執行內容，本研究之成果將能提供主管機關作為日後參考，作為後續有效管理相關「產業實驗室」之可行模式，加速提升臺灣精準醫療領域相關產業之國際競爭力。

Precision Medicine is one of the key items for development in the global biomedical field. Through molecular testing and gene sequencing, precise diagnosis and therapy are provided to the patients, and significantly reduces ineffective utilization and waste of medical resources. At the 2017 BioTaiwan Committee, the Executive Yuan concluded that “to establish appropriate precision medicine-related regulations, and to meet the international standard for the management of molecular testing laboratories” were of foremost importance in expediting the development of biotech industry in Taiwan. In 2017, this study conducted the “Precision Medicine Molecular Testing Management and Evaluation Project” in Taiwan. In this project, the development background and management mechanism of LDTs in the US was studied, and the trend of development and related regulations in other advanced countries were examined. Through multiple meetings, advice and recommendations were compiled from experts of various sectors-industry, government, academia, research, and medicine. Through investigation of current developmental status of molecular testing in Taiwan, a novel mode of operation, Laboratory-developed Tests and Services （LDTS）, was proposed, and its implementation resembles something in between the LTDs and IVD. With LDTS as the center, a management guideline was drafted for the regulatory authority. These management guidelines adopted the consensus from the various sectors of industry, government, academia, research, and medicines, and aim to promote the development of biotech industry and to incubate an “industrial ecosystem” for LDTS in Taiwan. LDTS focuses on “laboratory-developed tests and services” and targets the non-medical laboratories as the object for management. In LDTS, Clinical Laboratory Improvement Amendments （CLIA） serves as a regulatory reference, and a voluntary, incentive-oriented mechanism of management was adopted in the hope of building up systems for quality management and adverse event reports that are in line with international standard, and thereby elevating the quality of tests and services provided by the non-medical labs, safeguarding the welfare and safety of the patients and the general public, and expediting the development of the Industry of precision medicine and molecular testing in Taiwan. With such a view, in 2018, this study conducted the “Molecular Testing Early Phase Project-development of Precision Medicine Molecular Testing Laboratory Management Guidance and Trial Consultation Project”. Succedent to the project in 2017, this project continues to update and compile recent clinical molecular testing laboratory-related regulations, management mechanism, and developmental trends from numerous advanced countries （such as the US, EU, Australia, and Japan） and China. The information obtained from each country were compared and analyzed to provide a basis for the government in the formulation of relevant policies. In addition, this project invited experts from the sectors of industry, government, academia, research, medicines, and bioinformatics （AI）, and established an expert committee to investigate and draft the “Management and Quality Guidelines” and “Trial Consultation and Inspection Standard” for clinical molecular testing laboratories. After four group sessions and two committee meetings, fundamental structures of the LDTS guidelines, such as the definition, quality system, classification, registration and listing, inspection, and reporting, etc., were outlined into a management and technical draft guidance. To comprehend how the other countries improve the quality of clinical molecular testing laboratories and what programs were enforced for such purpose, committee members from this project were sent by this project to participate in the US BIO International Convention and visited US FDA and CLIA-accredited laboratories, from which experience the members drafted a report to be serve as the reference for “Laboratory Consultation and Trial Assessment”, the latter part of this project. To provide a more thorough understanding of government policies to the precision medicine and molecular testing industry, and to encourage the participation of the LDTS trial projects from molecular testing laboratories in local biotech industry, three open seminars （at Tainan, Taichung and Taipei）, two consultation and training courses, and one “International Conference for the Elevation of the Quality of Clinical Molecular Testing Laboratory” were held. Experts and scholars from the US and Mainland China were invited to the conference for an in-depth discussion with local experts on topics such as regulations, technology advancement, and quality elevation, etc., in the hope of improving the quality and competitiveness of the molecular testing laboratories in Taiwan. This project provides incentives for the development of the precision medicine and molecular testing industry and manages the non-medical laboratories. Twelve molecular testing laboratories from the industry, classified in accordance to the criteria of CLIA, were invited to participate in the “Trial Consultation and Inspection Program”: two of the laboratories participated in trial consultation, while ten participated in the trial inspection. During this program, experts from the project committee gained a deeper knowledge regarding the trial process, evaluation methods, mode of inspection, and the contents of related documentations, and provided recommendations and advice for improvements and adjustments on each aspect. Services in precision medicine industry will play an indispensable role in the future global medical industry. There is an urgent need to set up a standard for services and test quality for the “industrial laboratories” in Taiwan by drafting a complete and thorough guidance. The outcomes from various activities executed in this project offer the regulatory authority a reference for building a standard model of effective management of the “industrial laboratories”, thereby increasing the global competitiveness of Taiwan’s Precision Medicine Industry.