淺談藥物之臨床試驗(yàn)

1、淺談藥物之臨床試驗(yàn)楊蕙瑛, M.S., RPh.,大綱,藥物之發(fā)展與研究何謂臨床試驗(yàn)歷史緣由醫(yī)學(xué)研究的倫理準(zhǔn)則試驗(yàn)醫(yī)師之責(zé)任與義務(wù),Quiz,How long will it take?Probability? Profit? vs. Cost?Luck vs. Effort?,Statistics,New Drugs Begin in the Laboratory , Discovering and Bringing

2、 One New Drug to the public Typically Costs a Pharmaceutical or Biotechnology Company Nearly $900 Million USDTakes an Average of 10 to 12 YearsOut of Every 5,000 New Compounds Identified during the Discovery ProcessO

3、nly 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 is Ultimately Approved as a Marketed Drug fo

4、r 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 thos

5、e pharmaceutical products that are both safe 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 dru

6、g on an investigational basis. Patients who participate in clinical research help in the development of new treatments which help people to live longer and feel better.,About Clinical Research (Cont.),The final phases o

7、f 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 research are co

8、mplete 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(yàn)Phase II 第二期之臨床試驗(yàn)Phase IIIa

9、 第三期之臨床試驗(yàn)(NDA/MAA)Phase IIIb/IV 第四期之臨床試驗(yàn)Post-Marketing 藥品上市後之試驗(yàn),In General…..,Clinical testing is usually described as consisting of Phase I, Phase II and Phase III clinical studies. In each successive phase, inc

10、reasing 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 investigational drug (ID) must be tested extensively

11、 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 formulat

12、ed & manufacturedHow it will be administered to the first human subjects,Pre-Clinical Stage,Preclinical TechnologyLaboratory tests document the effect of the investigational drugin living organisms (in vivo) and

13、in cells in the test tube (in vitro)Pharmacology/ToxicologyPharmacological testing determines effects of the candidate drug on the body. Toxicology studies are conducted to identify potential risks to humans.,Pre-Cli

14、nical 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 intended c

15、linical 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 Puri

16、ty Quality Potency: the drug's active ingredient and of the formulated drug,Pre-Clinical Stage (Cont.),Results of all testing must be provided to the FDA in USA and/or other appropriate regulatory agencies (e.g. EM

17、EA in Europe) in order to obtain permission prior to begin clinical testing in humans. Regulatory agencies review the specific tests and documentation that are required to proceed to the next stages of development.,How

18、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.,Appli

19、cations,Investigational New Drug (IND)-USAClinical Trial Exception (CTX)-UKClinical Trial Authorization (CTA) - Australiaare examples of requests submitted to appropriate regulatory authorities for permission to condu

20、ct investigational research. These researches can include testing of A new dosage form, or New use of a drug already approved to be marketed,,Phase I Study,Phase I Study,These are the first studies conducted in humans

21、. 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 investigational drug for sh

22、ort 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 fro

23、m Appropriate Regulatory Authorities (e.g. FDA of USA; DOH of Taiwan) andAn institutional or independent review board (IRB) or ethical review/advisory board (ERB)Must approve the protocol for testing as well as the in

24、formed consent documents (ICFs) that volunteers sign prior to participating in a clinical study.,Why?,Many laws and safeguards are in place to protect the rights and safety of patients who volunteer for clinical research

25、. 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) a

26、nd IRB.,Purpose of IRB/IEC,ICH GCP Guideline, Section 3.衛(wèi)生署藥政處頒佈-藥品優(yōu)良臨床試驗(yàn)規(guī)範(fàn)\第參章、人體試驗(yàn)委員會(huì)\獨(dú)立倫理委員會(huì) An Independent Committee of Physicians, Community Advocates and Others Ensures a Clinical Trial is Ethical and the Right

27、s of Study Participants are ProtectedAn Important Part of IRB Approval is:to review the informed consent for the trial to ensure that it lists all information that a patient needs to make a decision about participating

28、.,ICH GCP Guideline, Section 3.1.1第參章\第一節(jié)\責(zé)任Should Safeguard the Rights, Safety, and Well-being of all trial subjects. Special Attention Should be Paid to Trials that May Include Vulnerable Subjects.人體試驗(yàn)委員會(huì)\獨(dú)立倫理委員會(huì)應(yīng)確

29、保受試者的權(quán)利，安全以及福祉受到保護(hù)。對(duì)可能包括易受傷害的受試者之試驗(yàn)應(yīng)特別留意-衛(wèi)生署藥政處公告之「藥品優(yōu)良臨床試驗(yàn)規(guī)範(fàn)(九十一年八月)」,Composition of IRB/IEC,ICH GCP Guideline, Section 3.2第參章\第二節(jié)\第八十五條\組成、功能及運(yùn)作 人體試驗(yàn)委員會(huì)\獨(dú)立倫理委員會(huì)應(yīng)由合理人數(shù)組成，其成員應(yīng)具備審查及評(píng)估試驗(yàn)之科學(xué)、醫(yī)學(xué)層面及倫理之資格與經(jīng)驗(yàn)。 人體試驗(yàn)委員會(huì)\獨(dú)立倫理委員

30、會(huì)應(yīng)保留成員及其資格之名單。,Composition of IRB/IEC (Cont.),建議人體試驗(yàn)委員會(huì)\獨(dú)立倫理委員會(huì)組成人員應(yīng)包含：（一）至少五位成員（二）至少一位專業(yè)為非科學(xué)背景人士（三）至少一位醫(yī)療機(jī)構(gòu)\試驗(yàn)機(jī)構(gòu)外人士人體試驗(yàn)委員會(huì)\獨(dú)立倫理委員會(huì)成員中唯有非試驗(yàn)主持人與試驗(yàn)委託者身分者能夠參與表決或提出試驗(yàn)相關(guān)事宜之意見(jiàn)。,IRB審查須包括:,計(jì)畫(huà)書(shū)是否符合優(yōu)良臨床試驗(yàn)規(guī)範(fàn)？試驗(yàn)學(xué)理依據(jù)是否合理？研究設(shè)計(jì)和統(tǒng)

31、計(jì)是否適當(dāng)？受試者隱私的保護(hù)是否足夠？主持人和研究地點(diǎn)是否合適？是否為當(dāng)?shù)匚幕芙邮埽扛弊饔煤桶踩允欠窨山邮埽?,Phase II Study,Phase II Study,Designed to determine effectiveness and further study the safety of the candidate drug in humans. Depending upon the type of i

32、nvestigational 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 condition the investiga

33、tional 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 Clini

34、cal Trials are:Randomized 隨機(jī)分配Randomly Divided into Groups One group: Receives the Investigational DrugAnother Group: Gets a Placebo Containing no Medication, and Sometimes a Third Group that Receives a Current St

35、andard Treatment to which the New Investigational Drug will be Compared. Double-Blinded 雙盲Neither Patients Nor Researchers Evaluating the Compound Know who is Receiving the Investigational Drug or Placebo.,,Phase III S

36、tudy,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(jī)雙盲Multi-Center, Multi-Nation 多國(guó)多中心Requires 1 t

37、o 4 years of testing, 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 t

38、o Market a New Drug,New Drug Application (NDA): in the U.S.Marketing Authorization Application (MAA) : in the U.K.Applications Need to Present:Document Safety and Efficacy of the Investigational Drug and Contain All t

39、he Information Collected during the Drug Development ProcessConclusion of Successful Preclinical and Clinical TestingSubstantial Evidence that the Drug will have the Effect it is Represented to have when People Use it

40、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,,Do

41、es Testing Continue After A New Drug is Approved?,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-S

42、tage Drug Development Studies of Approved, Marketed Drugs may Continue for Several Months to Several Years.,They are…,Phase IIIb StudyPhase IV StudyPost-Marketing Study上市後監(jiān)測(cè)調(diào)查(Post-Marketing Surveillance Study, PMS st

43、udy)為進(jìn)一步了解病患長(zhǎng)期的治療經(jīng)驗(yàn)，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

44、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 Sam

45、e Condition.Post-Marketing Surveillance (PMS),To Test a Marketed Drug in New Age Groups or Different Patient Types. Some Studies Focus on Previously Unknown Side Effects or Related Risk Factors. As with All Stages of

46、Drug Development Testing, the Purpose is to Ensure the Safety and Effectiveness of Marketed Drugs,Post-Marketing Study,Conclusion,,Guidelines in Research Ethnics醫(yī)學(xué)研究的倫理準(zhǔn)則,Pre-Nuremberg Research Scandals,1796: Edward Jen

47、ner (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 experim

48、ental surgeries on enslaved African 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 S

49、panish immigrant workers in Cuba with the agent for yellow fever paying them $100 if they survive and $200 if they contract the disease. 1906:Dr. Richard Strong, Harvard professor of tropical medicine--experimented with

50、 cholera on prisoners in the Philippines killing thirteen.,Nuremberg War Crimes- Nov 20, 1945,Nazi doctors’trials for medical experimentsConducted among civilians and Allied forces under the custody of the Germa

51、n ReichWithout subject consentCommitted murders, brutalities, cruelties, tortures, atrocities and other inhuman acts,Principles of Research Ethics --Nuremberg Code 1947,Informed ConsentRequirement of Prior Animal Ex

52、perimentAnticipated Scientific Findings to Result from the ExperimentOnly Qualified ScientistAvoidance of Physical and Mental Suffering No Death or Disabling Injury,Nuremberg Code (紐倫堡宣言),1948年公佈Voluntary Partic

53、ipation/自願(yuàn)參與Informed Consent/知情同意Benefits Overweight Risks/Risks should not exceed benefits利益超過(guò)風(fēng)險(xiǎn),醫(yī)學(xué)研究的倫理準(zhǔn)則 (Codes of Research Ethnics),Nuremberg Code for Human Experimentation 紐倫堡宣言 - 1948年發(fā)表Declaration of Hel

54、sinki 赫爾辛基宣言1964年發(fā)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 a

55、ctivities carried out by medical doctors,赫爾辛基宣言之精神,自主：受試者是在被充分告知相關(guān)訊息後，自由決定要參加的。有益：參加試驗(yàn)的風(fēng)險(xiǎn)相對(duì)於可能有的好處，是可以接受的。受試驗(yàn)者參加試驗(yàn)後，並不會(huì)犧牲其權(quán)益，仍會(huì)受到已證明有效的最佳照顧附註：中文有臺(tái)北榮總江晨恩醫(yī)師翻譯，成大醫(yī)學(xué)院創(chuàng)院院長(zhǎng)黃崑巖教授修訂版,Declaration of Helsinki * Principles,Rese

56、arch must Conform to Scientific Principles Protocol and Independent Ethics Committees Supervision and Conduct of Trial by Suitably Qualified Persons Objectives and Possible Benefits Balanced against Risk to Subject

57、s 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

58、Protect Human Subjects,ICH 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 count

59、ries & WHO)The World Medical Association（WMA）世界醫(yī)學(xué)協(xié)會(huì)The Good Clinical Practice (GCP) guideline is Topic E6Adopted:17 January, 1997 in the EU (guideline, as CPMP / ICH /135/95)1 April, 1997 in Japan (law)9 May,

60、1997 in the USA (guideline, in the Federal register),藥品優(yōu)良臨床試驗(yàn)規(guī)範(fàn),本規(guī)範(fàn)係依據(jù)八十五年十一月二十日衛(wèi)生署藥政處公告之「藥品優(yōu)良臨床試驗(yàn)規(guī)範(fàn)(九十一年八月)」，並參考國(guó)際醫(yī)藥法規(guī)協(xié)合會(huì)之ICH E6 Guidance for Industry（E6 Good Clinical Practice: Consolidated Guidance）所修訂的。,藥品優(yōu)良臨床試驗(yàn)規(guī)範(fàn) (G

61、CP),第壹章、名辭解釋 第貳章、基本方針 第參章、人體試驗(yàn)委員會(huì)\獨(dú)立倫理委員會(huì) 第肆章、試驗(yàn)主持人 第伍章、試驗(yàn)委託者 第陸章、臨床試驗(yàn)計(jì)畫(huà)書(shū) 第柒章、主持人手冊(cè) 第捌章、執(zhí)行臨床試驗(yàn)的必要文件,緒論,其為臨床試驗(yàn)設(shè)計(jì)、執(zhí)行、記錄與報(bào)告之倫理與科學(xué)品質(zhì)的國(guó)際標(biāo)準(zhǔn)。遵守此標(biāo)準(zhǔn)可確保受試者的權(quán)利、安全與福祉，使臨床試驗(yàn)執(zhí)行與赫爾辛基宣言的原則相符，並可保證臨床試驗(yàn)數(shù)據(jù)的可信度。凡供查驗(yàn)登記用之藥品臨床試驗(yàn)均應(yīng)符合本規(guī)範(fàn)

62、；凡供學(xué)術(shù)研究用之藥品臨床試驗(yàn)及其他有關(guān)人類安全與福祉之臨床研究亦應(yīng)參考本規(guī)範(fàn)。,Good Clinical Practice (GCP),An International Ethical and Scientific Quality Standard for Designing, Conducting, Recording, and Reporting Trials that Involve the Participation of

63、Human Subjects Public assurance that the Rights, Safety, and Well-being of trial subjects are protected well-Results in Credible Data Consistent with the Declaration of Helsinki,Principles of ICH GCP,Conduct Trials ac

64、cording 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.),U

65、se Qualified Support Staff Obtain Informed Consent Record Information Appropriately Protect Confidentiality Handle Investigational Products Appropriately Implement Quality Systems,何謂 Qualified 的 Physicians 呢？,I

66、CH GCP Guideline, Section 4.1藥品優(yōu)良臨床試驗(yàn)規(guī)範(fàn)\第四章\第一節(jié) \第一○二條:試驗(yàn)主持人的資格與認(rèn)定,藥品優(yōu)良臨床試驗(yàn)規(guī)範(fàn) (GCP),第壹章、名辭解釋 第貳章、基本方針 第參章、人體試驗(yàn)委員會(huì)\獨(dú)立倫理委員會(huì) 第肆章、試驗(yàn)主持人 第伍章、試驗(yàn)委託者 第陸章、臨床試驗(yàn)計(jì)畫(huà)書(shū) 第柒章、主持人手冊(cè) 第捌章、執(zhí)行臨床試驗(yàn)的必要文件,試驗(yàn)主持人的資格與認(rèn)定,試驗(yàn)主持人合格與否應(yīng)藉由教育、訓(xùn)練課

67、程、和具備適當(dāng)執(zhí)行臨床試驗(yàn)的經(jīng)驗(yàn)來(lái)判定。除了需符合所有衛(wèi)生主管機(jī)關(guān)規(guī)定的資格和能力，並且需提供試驗(yàn)委託者、人體試驗(yàn)委員會(huì)\獨(dú)立倫理委員會(huì)和衛(wèi)生主管機(jī)關(guān)最新的學(xué)經(jīng)歷資料或其他相關(guān)文件，以證明其符合試驗(yàn)主持人的資格。,但………自97年5月18日起~~~~,責(zé)任?義務(wù)?,共十三節(jié),一、試驗(yàn)主持人的資格與認(rèn)定二、足夠的資源三、受試者的醫(yī)療四、與人體試驗(yàn)委員會(huì)\獨(dú)立倫理委員會(huì)的聯(lián)繫五、遵從試驗(yàn)計(jì)畫(huà)書(shū)六、研究用藥品七、隨機(jī)分配過(guò)程及盲性

68、解碼八、受試者的受試者同意書(shū)九、紀(jì)錄和報(bào)告十、進(jìn)度報(bào)告十一、安全性通報(bào)十二、試驗(yàn)提早中止或撤銷十三、試驗(yàn)主持人\機(jī)構(gòu)之總結(jié)報(bào)告,GCP Conduct Standards,IRB & Regulatory Approval Compliance with Protocol Informed Consent Confidentiality of Data Medical Management of Advers