1、淺談藥物之臨床試驗楊蕙瑛, M.S., RPh.,大綱,藥物之發展與研究何謂臨床試驗歷史緣由醫學研究的準則試驗醫師之責任與義務,Quiz,How long will it take?Probability? Profit? vs. Cost?Luck vs. Effort?,Statistics,New Drugs Begin in the Laboratory , Discovering and Bringing One New Drug to the public Typically Costs a Pharmaceutical or Biotechnology Company Nearl
2、y $900 Million USDTakes an Average of 10 to 12 YearsOut of Every 5,000 New Compounds Identified during the Discovery ProcessOnly 5 are Considered Safe for Testing in Human Volunteers after Preclinical Evaluations. After 3 to 6 Years of Further Clinical Testing in Patients, Only 1 of these Compounds
3、is Ultimately Approved as a Marketed Drug for Treatment.,About Clinical Research,Clinical Research is Essential to New Drug Discovery and Development. Through research, new drugs are tested for Effectiveness SafetyPurpose: Be designed to ensure that only those pharmaceutical products that are both s
4、afe and effective are brought to market.,About Clinical Research (Cont.),Before a patient learns that a new drug is available for their condition, many patients have taken the drug on an investigational basis. Patients who participate in clinical research help in the development of new treatments wh
5、ich help people to live longer and feel better.,About Clinical Research (Cont.),The final phases of clinical research, involving patients with chronic or acute illness, follow years of research in the laboratory as well as testing of the drug in people who have no illnesses. Only after all phases of
6、 research are complete can the Food and Drug Administration approve drugs for use by the general public.,About Drug Discovery and Development,Pre-Clinical Stage(IND/CTX/CTA)Phase I 第一期之臨床試驗Phase II 第二期之臨床試驗Phase IIIa 第三期之臨床試驗(NDA/MAA)Phase IIIb/IV 第四期之臨床試驗Post-Marketing 藥品上市後之試驗,In General.,Clinical
7、 testing is usually described as consisting of Phase I, Phase II and Phase III clinical studies. In each successive phase, increasing numbers of patients are tested.,What is Required before an Investigational Drug can be Tested in Human Volunteers?,In Preclinical Stage of Drug Development An investi
8、gational drug (ID) must be tested extensively in the laboratory to ensure it will be safe to administer to humans. Testing can take from 1 to 5 years Must provide information about the drugPharmaceutical Composition (e.g. PK)SafetyHow the drug will be formulated & manufacturedHow it will be administ
9、ered to the first human subjects,Pre-Clinical Stage,Preclinical TechnologyLaboratory tests document the effect of the investigational drugin living organisms (in vivo) and in cells in the test tube (in vitro)Pharmacology/ToxicologyPharmacological testing determines effects of the candidate drug on t
10、he body. Toxicology studies are conducted to identify potential risks to humans.,Pre-Clinical Stage (Cont.),Chemistry Manufacturing and Controls (CMC)/PharmaceuticsThe results of preclinical testing are used by experts in pharmaceutical methods to determine how to best formulate the drug for its int
11、ended clinical use.e.g. A drug intended to act on the sinuses may be formulated as a time-release capsule or as a nasal spray. Regulatory agencies require testing that documents the characteristics Chemical Composition Purity Quality Potency: the drugs active ingredient and of the formulated drug,Pr
12、e-Clinical Stage (Cont.),Results of all testing must be provided to the FDA in USA and/or other appropriate regulatory agencies (e.g. EMEA in Europe) in order to obtain permission prior to begin clinical testing in humans. Regulatory agencies review the specific tests and documentation that are requ
13、ired to proceed to the next stages of development.,How are ID Tested in Humans?,Testing of an investigational new drug (IND) Begins with submission of information about the drug, andApplication for permission to begin administration to healthy volunteers or patients.,Applications,Investigational New
14、 Drug (IND)-USAClinical Trial Exception (CTX)-UKClinical Trial Authorization (CTA) - Australiaare examples of requests submitted to appropriate regulatory authorities for permission to conduct investigational research. These researches can include testing of A new dosage form, or New use of a drug a
15、lready approved to be marketed,Phase I Study,Phase I Study,These are the first studies conducted in humans. Designed to verify safety and tolerability of the candidate drug in humans and typically take 6 to 9 months. A small number of subjects, usually from 20 to 100 healthy volunteers, take the inv
16、estigational drug for short periods of time.Testing includes observation and careful documentation of how the drug acts in the bodyhow it is absorbed, distributed, metabolized and excreted,Before Start Running.,Should Obtain Permission from Appropriate Regulatory Authorities (e.g. FDA of USA; DOH of
17、 Taiwan) andAn institutional or independent review board (IRB) or ethical review/advisory board (ERB)Must approve the protocol for testing as well as the informed consent documents (ICFs) that volunteers sign prior to participating in a clinical study.,Why?,Many laws and safeguards are in place to p
18、rotect the rights and safety of patients who volunteer for clinical research. Clinical research trials are carefully designed to protect and monitor patients who receive investigational drugs. Before the first participant enrolls, every trial is reviewed/approved by DOH of TWN (FDA in USA) and IRB.,
19、Purpose of IRB/IEC,ICH GCP Guideline, Section 3.衛生署藥政處頒佈-藥品優良臨床試驗規範第參章、人體試驗委員會獨立倫理委員會 An Independent Committee of Physicians, Community Advocates and Others Ensures a Clinical Trial is Ethical and the Rights of Study Participants are ProtectedAn Important Part of IRB Approval is:to review the inform
20、ed consent for the trial to ensure that it lists all information that a patient needs to make a decision about participating.,Responsibilities of IRB/IEC,ICH GCP Guideline, Section 3.1.1第參章第一節責任Should Safeguard the Rights, Safety, and Well-being of all trial subjects. Special Attention Should be Pai
21、d to Trials that May Include Vulnerable Subjects.人體試驗委員會獨立倫理委員會應確保受試者的權利，安全以及福祉受到保護。對可能包括易受傷害的受試者之試驗應特別留意-衛生署藥政處公告之藥品優良臨床試驗規範(九十一年八月),Composition of IRB/IEC,ICH GCP Guideline, Section 3.2第參章第二節第八十五條組成、功能及運作 人體試驗委員會獨立倫理委員會應由合理人數組成，其成員應具備審查及評估試驗之科學、醫學層面及倫理之資格與經驗。 人體試驗委員會獨立倫理委員會應保留成員及其資格之名單。,Compositio
22、n of IRB/IEC (Cont.),建議人體試驗委員會獨立倫理委員會組成人員應包含：（一）至少五位成員（二）至少一位專業為非科學背景人士（三）至少一位醫療機構試驗機構外人士人體試驗委員會獨立倫理委員會成員中唯有非試驗主持人與試驗委託者身分者能夠參與表決或提出試驗相關事宜之意見。,IRB審查須包括:,計畫書是否符合優床試驗規範？試驗學依據是否合？研究設計和統計是否適當？受試者隱私的保護是否足夠？主持人和研究地點是否合適？是否為當地文化所能接受？副作用和安全性是否可接受？,Phase II Study,Phase II Study,Designed to determine effectiv
23、eness and further study the safety of the candidate drug in humans. Depending upon the type of investigational drug and the condition it treats, this phase of development generally takes from 6 months up to 3 years. Testing is conducted with up to several hundred patients suffering from the conditio
24、n the investigational drug is designed to treat. This testing determines safety and effectiveness of the drug in treating the condition and establishes the minimum and maximum effective dose.,Phase II Study (Cont.),Most Phase II Clinical Trials are:Randomized 隨機分配Randomly Divided into Groups One gro
25、up: Receives the Investigational DrugAnother Group: Gets a Placebo Containing no Medication, and Sometimes a Third Group that Receives a Current Standard Treatment to which the New Investigational Drug will be Compared. Double-Blinded 雙盲Neither Patients Nor Researchers Evaluating the Compound Know w
26、ho is Receiving the Investigational Drug or Placebo.,Phase III Study,Phase III Study,Provide Expanded Testing of Effectiveness/ Efficacy and Safety of an Investigational Drug, They are usually:Randomized and Blinded Clinical Trials 隨機雙盲Multi-Center, Multi-Nation 多國多中心Requires 1 to 4 years of testing
27、, depending upon the type of drug candidate and the condition it treats Several hundred to thousands of volunteer patients suffering from the condition the investigational drug treats.,Applications to Market a New Drug,New Drug Application (NDA): in the U.S.Marketing Authorization Application (MAA)
28、: in the U.K.Applications Need to Present:Document Safety and Efficacy of the Investigational Drug and Contain All the Information Collected during the Drug Development ProcessConclusion of Successful Preclinical and Clinical TestingSubstantial Evidence that the Drug will have the Effect it is Repre
29、sented to have when People Use it or under the Conditions for which it is Prescribed, Recommended or Suggested in the Labeling (in-Label Use). Obtaining Approval (e.g. by FDA in USA) to Market a New Drug frequently takes between 6 months and 2 years,Does Testing Continue After A New Drug is Approved
30、?,Yes,After the FDA (or other Regulatory Agency for Drugs Marketed outside the U.S.) Approves a New Drug, Pharmaceutical Companies may Conduct Additional Studies.Late-Stage Drug Development Studies of Approved, Marketed Drugs may Continue for Several Months to Several Years.,They are,Phase IIIb Stud
31、yPhase IV StudyPost-Marketing Study上市後監測調查(Post-Marketing Surveillance Study, PMS study)為進一步了解病患長期的治療經驗，收集病患資料之研究。,Phase IIIb Study,Often Begin before ApprovalMay Supplement or Complete Earlier Trials by Providing Additional Safety Data, or May Test the Approved Drug for Additional Conditions for wh
32、ich it may Prove Useful.,Phase IV Study,To Expand Testing of a Proven Drug to Broader Patient Populations To Compare the Long-Term Effectiveness and/or Cost of the Drug to other Marketed Drugs available to Treat the Same Condition.Post-Marketing Surveillance (PMS),To Test a Marketed Drug in New Age
33、Groups or Different Patient Types. Some Studies Focus on Previously Unknown Side Effects or Related Risk Factors. As with All Stages of Drug Development Testing, the Purpose is to Ensure the Safety and Effectiveness of Marketed Drugs,Post-Marketing Study,Conclusion,Guidelines in Research Ethnics醫學研究
34、的準則,Pre-Nuremberg Research Scandals,1796: Edward Jenner (discovered smallpox vaccine) -injected healthy eight-year-old James Phillips first with cowpox then three months later with smallpox 1845-1849:J. Marion Sims, father of gynecology”-performed multiple experimental surgeries on enslaved African
35、women without the benefit of anesthesia.-After suffering unimaginable pain, many lost their lives to infection.,Pre-Nuremberg Research Scandals (cont.),1900:Walter Reed-injected 22 Spanish immigrant workers in Cuba with the agent for yellow fever paying them $100 if they survive and $200 if they con
36、tract the disease. 1906:Dr. Richard Strong, Harvard professor of tropical medicine-experimented with cholera on prisoners in the Philippines killing thirteen.,Nuremberg War Crimes- Nov 20, 1945,Nazi doctorstrials for medical experimentsConducted among civilians and Allied forces under the custody of
37、 the German ReichWithout subject consentCommitted murders, brutalities, cruelties, tortures, atrocities and other inhuman acts,Principles of Research Ethics -Nuremberg Code 1947,Informed ConsentRequirement of Prior Animal ExperimentAnticipated Scientific Findings to Result from the ExperimentOnly Qu
38、alified ScientistAvoidance of Physical and Mental Suffering No Death or Disabling Injury,Nuremberg Code (堡宣言),1948公佈Voluntary Participation/自願與Informed Consent/知情同意Benefits Overweight Risks/Risks should not exceed benefits超過風險,醫學研究的準則 (Codes of Research Ethnics),Nuremberg Code for Human Experimentat
39、ion 堡宣言 - 1948發表Declaration of Helsinki 赫爾辛基宣言1964發表The Nuremberg Code had little or no influence on the actual conduct of research.The medical and research community realized that the Code did not provide adequate guidance for most of the research activities carried out by medical doctors,赫爾辛基宣言之,自
40、主：受試者是在被充分告知相關訊息後，自由決定要加的。有：加試驗的風險相對於可能有的好處，是可以接受的。受試驗者加試驗後，並會犧牲其權，仍會受到已證明有效的最佳照顧附註：中文有台榮總江晨恩醫師翻譯，成大醫學院創院院長黃崑巖教授修訂版,Declaration of Helsinki * Principles,Research must Conform to Scientific Principles Protocol and Independent Ethics Committees Supervision and Conduct of Trial by Suitably Qualified Pe
41、rsons Objectives and Possible Benefits Balanced against Risk to Subjects Privacy Respected and Minimal Physical and Mental Impact on the Subject Informed Consent * (1996, 2000, 2002 and 2004),Ethical Research,Requires Scientific Validity and Careful Thought and Planning to Protect Human Subjects,ICH
42、 GCP Guideline,“International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use”USA, EU and Japan (plus Australia, Canada, the Nordic countries & WHO)The World Medical Association（WMA）世界醫學協會The Good Clinical Practice (GCP) guideline is Topic E6Ad
43、opted:17 January, 1997 in the EU (guideline, as CPMP / ICH /135/95)1 April, 1997 in Japan (law)9 May, 1997 in the USA (guideline, in the Federal register),藥品優良臨床試驗規範,本規範係依據八十五年十一月二十日衛生署藥政處公告之藥品優良臨床試驗規範(九十一年八月)，並參考國際醫藥法規協合會之ICH E6 Guidance for Industry（E6 Good Clinical Practice: Consolidated Guidance
44、）所修訂的。,藥品優良臨床試驗規範 (GCP),第壹章、名辭解釋 第貳章、基本方針 第參章、人體試驗委員會獨立倫理委員會 第肆章、試驗主持人 第伍章、試驗委託者 第陸章、臨床試驗計畫書 第柒章、主持人手冊 第捌章、執行臨床試驗的必要文件,緒論,其為臨床試驗設計、執行、記錄與報告之倫理與科學品質的國際標準。遵守此標準可確保受試者的權利、安全與福祉，使臨床試驗執行與赫爾辛基宣言的原則相符，並可保證臨床試驗數據的可信度。凡供查驗登記用之藥品臨床試驗均應符合本規範；凡供學術研究用之藥品臨床試驗及其他有關人類安全與福祉之臨床研究亦應參考本規範。,Good Clinical Practice (GCP),
45、An International Ethical and Scientific Quality Standard for Designing, Conducting, Recording, and Reporting Trials that Involve the Participation of Human Subjects Public assurance that the Rights, Safety, and Well-being of trial subjects are protected well-Results in Credible Data Consistent with
46、the Declaration of Helsinki,Principles of ICH GCP,Conduct Trials according to GCP Weigh Risks vs. Benefits Protect the Subjects Have Adequate Information to Justify Trial Write a Sound Protocol Receive IRB/IEC Approval Use Qualified Physicians,Principles of ICH GCP (cont.),Use Qualified Support Staf
47、f Obtain Informed Consent Record Information Appropriately Protect Confidentiality Handle Investigational Products Appropriately Implement Quality Systems,何謂 Qualified 的 Physicians 呢？,ICH GCP Guideline, Section 4.1藥品優良臨床試驗規範第四章第一節 第一二條:試驗主持人的資格與認定,藥品優良臨床試驗規範 (GCP),第壹章、名辭解釋 第貳章、基本方針 第參章、人體試驗委員會獨立倫理委員
48、會 第肆章、試驗主持人 第伍章、試驗委託者 第陸章、臨床試驗計畫書 第柒章、主持人手冊 第捌章、執行臨床試驗的必要文件,試驗主持人的資格與認定,試驗主持人合格與否應藉由教育、訓練課程、和具備適當執行臨床試驗的經驗來判定。除了需符合所有衛生主管機關規定的資格和能力，並且需提供試驗委託者、人體試驗委員會獨立倫理委員會和衛生主管機關最新的學經歷資料或其他相關文件，以證明其符合試驗主持人的資格。,但自97年5月18日起,責任?義務?,共十三節,一、試驗主持人的資格與認定二、足夠的資源三、受試者的醫療四、與人體試驗委員會獨立倫理委員會的聯繫五、遵從試驗計畫書六、研究用藥品七、隨機分配過程及盲性解碼八、受試者的受試者同意書九、紀錄和報告十、進度報告十一、安全性通報十二、試驗提早中止或撤銷十三、試驗主持人機構之總結報告,GCP Conduct Standards,IRB & Regulatory Approval Compliance with Protocol Informed Consent Confidentiality of Data Medical Management of Adverse Events Product Accountability Qualification & Training,
