浅谈药物之临床试验课件.ppt

1、淺談藥物之臨床試驗淺談藥物之臨床試驗楊蕙瑛楊蕙瑛,M.S.,RPh.大綱大綱藥物之發展與研究藥物之發展與研究何謂臨床試驗何謂臨床試驗歷史緣由歷史緣由醫學研究的準則醫學研究的準則試驗醫師之責任與義務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 Pharmace

2、utical or Biotechnology Company Nearly$900 Million USD Takes an Average of 10 to 12 Years Out of Every 5,000 New Compounds Identified during the Discovery Process Only 5 are Considered Safe for Testing in Human Volunteers after Preclinical Evaluations.After 3 to 6 Years of Further Clinical Testing i

3、n Patients,Only 1 of these Compounds 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 Safety Purpose:Be designed to ensure that only those pharm

4、aceutical 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 drug on an investigational basis.Patients who participate in clinical research help in the dev

5、elopment of new treatments which 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.O

6、nly after all phases of 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 第一期之臨床試驗第一期之臨床試驗 Phase II 第二期之臨床試驗第二期之臨床試驗 Phase IIIa 第三期之臨床試驗第三期之臨床試驗(NDA/MAA)Phase IIIb/IV 第四期之

7、臨床試驗第四期之臨床試驗 Post-Marketing 藥品上市後之試驗藥品上市後之試驗In General.Clinical 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 Volu

8、nteers?In Preclinical Stage of Drug Development An investigational 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 drug Pharmaceutical Composition(e.g.PK)Safety How the drug w

9、ill be formulated&manufactured How it will be administered to the first human subjectsPre-Clinical Stage Preclinical Technology Laboratory tests document the effect of the investigational drug in living organisms(in vivo)and in cells in the test tube(in vitro)Pharmacology/Toxicology Pharmacological

10、testing determines effects of the candidate drug on the body.Toxicology studies are conducted to identify potential risks to humans.Pre-Clinical Stage(Cont.)Chemistry Manufacturing and Controls(CMC)/Pharmaceutics The results of preclinical testing are used by experts in pharmaceutical methods to det

11、ermine how to best formulate the drug for its intended 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 a

12、ctive ingredient and of the formulated drugPre-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 specifi

13、c tests and documentation that are required 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,and Application for permission to begin administration to healthy volunteers or patient

14、s.Applications Investigational New Drug(IND)-USA Clinical Trial Exception(CTX)-UK Clinical Trial Authorization(CTA)-Australia are examples of requests submitted to appropriate regulatory authorities for permission to conduct investigational research.These researches can include testing of A new dosa

15、ge form,or New use of a drug already approved to be marketed Phase I StudyPhase 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 health

16、y volunteers,take the investigational drug for short periods of time.Testing includes observation and careful documentation of how the drug acts in the body how it is absorbed,distributed,metabolized and excreted Before Start Running.Should Obtain Permission from Appropriate Regulatory Authorities(e

17、.g.FDA of USA;DOH of Taiwan)and An 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

18、in place to protect 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)a

19、nd IRB.Purpose of IRB/IEC ICH GCP Guideline,Section 3.衛生署藥政處頒佈衛生署藥政處頒佈-藥品優良臨床試驗規範藥品優良臨床試驗規範 第參章、人體試驗委員會第參章、人體試驗委員會 獨立委員會獨立委員會 An Independent Committee of Physicians,Community Advocates and Others Ensures a Clinical Trial is Ethical and the Rights of Study Participants are Protected An Important Part

20、 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.Responsibilities of IRB/IEC ICH GCP Guideline,Section 3.1.1第參章第參章 第一節第一節 責任責任 Should Safeguard the Rights,Safety,and Well-being of all

21、trial subjects.Special Attention Should be Paid to Trials that May Include Vulnerable Subjects.人體試驗委員會人體試驗委員會 獨立委員會應確保受試者的獨立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傷害的受試者之試驗應特別留意-衛生署藥政處公告之衛生署藥政處公告之藥品優良臨床試驗規範藥品優良臨床試驗規範(九十一年八月九十一年八月)Composition of IRB/IEC ICH GCP Guideline,Se

22、ction 3.2第參章第參章 第二節第二節 第八十五條第八十五條 組成、功能及組成、功能及運作運作 人體試驗委員會人體試驗委員會 獨立委員會應由獨立委員會應由合合人數組成人數組成，其成員應具備審查及評估試驗之，其成員應具備審查及評估試驗之科學、醫學層面及之資格與經驗。科學、醫學層面及之資格與經驗。人體試驗委員會人體試驗委員會 獨立委員會應獨立委員會應保留保留成成員及其資格之員及其資格之名單名單。Composition of IRB/IEC(Cont.)建議人體試驗委員會建議人體試驗委員會 獨立委員會組成獨立委員會組成人員應包含：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

23、（三）至少一位醫療機構試驗機構外人士人體試驗委員會人體試驗委員會 獨立委員會成員中獨立委員會成員中唯唯有非有非試驗主持人與試驗委託者身分者試驗主持人與試驗委託者身分者能夠參能夠參與表決或提出與表決或提出試驗相關事宜之試驗相關事宜之意見意見。IRB審查須包括:計畫書是否符合優良臨床試驗規範？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 StudyPhase II Study Designed to determine effectiveness and further study

24、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 condition the investigational drug

25、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 隨機分配隨機分配 Randomly Divided into Groups One group:Receives the Investigat

26、ional Drug Another 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 雙盲雙盲 Neither Patients Nor Researchers Evaluating the Compound Know who is Receiving the Invest

27、igational Drug or Placebo.Phase III StudyPhase 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,depending upon the type of d

28、rug 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):in the U.K.Applications Need to Pr

29、esent:Document Safety and Efficacy of the Investigational Drug and Contain All the Information Collected during the Drug Development Process Conclusion of Successful Preclinical and Clinical Testing Substantial Evidence that the Drug will have the Effect it is Represented to have when People Use it

30、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?Yes After the FDA(or other Regulatory A

31、gency 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 Study Phase IV Study Post-Marketing Study 上市後監測調查(

32、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 Approval May Supplement or Complete Earlier Trials by Providing Additional Safety Data,or May Test the Approved Drug for Additional Conditions for which it may Prove Useful.Phase IV Study To Exp

33、and 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 Groups or Different Patient Types.Some Studies F

34、ocus 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 DrugsPost-Marketing StudyConclusionIIIIIIIVSafety/TolerabilitySafety/Efficiency Min./Max.DoseExpandingEfficiency/SafetyLong

35、-Term SafetySurveillance6 9 mth.6 M 3 yr.14 yr.Over 1yr.20100 人人數百人數百人數百至數千數百至數千人人數十至數千數十至數千人不等人不等Guidelines in Research Ethnics醫學研究的準則醫學研究的準則Pre-Nuremberg Research Scandals 1796:Edward Jenner(discovered smallpox vaccine)-injected healthy eight-year-old James Phillips first with cowpox then three mo

36、nths later with smallpox 1845-1849:J.Marion Sims,father of gynecology”-performed multiple experimental 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-in

37、jected 22 Spanish 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 cholera on prisoners in the Philippines killing thirteen.Nuremberg War Crim

38、es-Nov 20,1945 Nazi doctors trials for medical experiments Conducted among civilians and Allied forces under the custody of the German Reich Without subject consent Committed murders,brutalities,cruelties,tortures,atrocities and other inhuman actsPrinciples of Research Ethics-Nuremberg Code 1947 Inf

39、ormed Consent Requirement of Prior Animal Experiment Anticipated Scientific Findings to Result from the Experiment Only Qualified Scientist Avoidance of Physical and Mental Suffering No Death or Disabling InjuryNuremberg Code(堡宣言)1948年公佈 Voluntary Participation/自願參與 Informed Consent/知情同意 Benefits Ov

40、erweight Risks/Risks should not exceed benefits利超過風險利超過風險醫學研究的準則 (Codes of Research Ethnics)Nuremberg Code for Human Experimentation 堡宣言堡宣言-1948年發表 Declaration of Helsinki 赫爾辛基宣言赫爾辛基宣言 1964年發表年發表 The Nuremberg Code had little or no influence on the actual conduct of research.The medical and research

41、 community realized that the Code did not provide adequate guidance for most of the research activities carried out by medical doctors赫爾辛基宣言赫爾辛基宣言之 自主自主：受試者是在被充分告知被充分告知相關訊息後，自由決定自由決定要參加的。有有：參加試驗的風險相對於可能有的好處，是可以接受的。受試驗者參加試驗後，並不會犧牲其權，仍會受到已證明有效的最佳有效的最佳照顧照顧附註：附註：中文有台榮總江晨恩醫師台榮總江晨恩醫師翻譯，成大醫學院創院院長黃崑巖教授成大醫學院

42、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 Persons Objectives and Possible Benefits Balanced against Risk to Subjects Privacy Respected and Minimal Phy

43、sical 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 SubjectsICH GCP Guideline“International Conference on Harmonization of Technical Requirements for Registration of Pharmace

44、uticals 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 E6 Adopted: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

45、,in the Federal register)藥品優良臨床試驗規範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本規範係依據八十五年十一月二十日衛生署衛生署藥政處藥政處公告之公告之藥品優良臨床試驗規範藥品優良臨床試驗規範(九九十一年八月十一年八月)，並參考國際醫藥法規協合，並參考國際醫藥法規協合會之會之ICH E6 Guidance for Industry（E6 Good Clinical Practice:Consolidated Guidance）所修訂的。）所修訂的。藥品優良臨床試驗規範藥品優良臨床試驗規範(GCP)第壹章、名辭解釋第壹章、名辭解釋 第貳章、基本方針第貳章、

46、基本方針 第參章、人體試驗委員會第參章、人體試驗委員會 獨立委員會獨立委員會 第肆章、試驗主持人第肆章、試驗主持人 第伍章、試驗委託者第伍章、試驗委託者 第陸章、臨床試驗計畫書第陸章、臨床試驗計畫書 第柒章、主持人手冊第柒章、主持人手冊 第捌章、執行臨床試驗的必要文件第捌章、執行臨床試驗的必要文件 緒論緒論 其為臨床試驗設計、執行、記錄與報告之其為臨床試驗設計、執行、記錄與報告之與與科學科學品質的國際標準。品質的國際標準。遵守此標準可確保遵守此標準可確保受試者的權利受試者的權利、安全與福安全與福祉祉，使臨床試驗執行與赫爾辛基宣言的原則，使臨床試驗執行與赫爾辛基宣言的原則相符，並可保證相符，並可

47、保證臨床試驗數據的可信度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其他有關人類安全與福祉之臨床研究亦應參考本規範。考本規範。Good Clinical Practice(GCP)An International Ethical and Scientific Quality Standard for Designing,Conducting,Recording,and Reporting Trials that Involve th

48、e 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 the Declaration of Helsinki Principles of ICH GCP Conduct Trials according to GCP Weigh Risks vs.Benefits Protect the Subjects Have A

49、dequate Information to Justify Trial Write a Sound Protocol Receive IRB/IEC Approval Use Qualified Physicians Principles of ICH GCP(cont.)Use Qualified Support Staff Obtain Informed Consent Record Information Appropriately Protect Confidentiality Handle Investigational Products Appropriately Impleme

50、nt Quality Systems 何謂何謂 Qualified 的 Physicians 呢？ICH GCP Guideline,Section 4.1 藥品優良臨床試驗規範藥品優良臨床試驗規範第四章第四章 第一節第一節 第一第一二條二條:試驗主持人的資格與認定試驗主持人的資格與認定 藥品優良臨床試驗規範藥品優良臨床試驗規範(GCP)第壹章、名辭解釋第壹章、名辭解釋 第貳章、基本方針第貳章、基本方針 第參章、人體試驗委員會第參章、人體試驗委員會 獨立委員會獨立委員會 第肆章、試驗主持人第肆章、試驗主持人 第伍章、試驗委託者第伍章、試驗委託者 第陸章、臨床試驗計畫書第陸章、臨床試驗計畫書 第