Presentation is loading. Please wait.

Presentation is loading. Please wait.

淺談藥物之臨床試驗 楊蕙瑛, M.S., RPh..

Similar presentations


Presentation on theme: "淺談藥物之臨床試驗 楊蕙瑛, M.S., RPh.."— Presentation transcript:

1 淺談藥物之臨床試驗 楊蕙瑛, M.S., RPh.

2 大綱 藥物之發展與研究 何謂臨床試驗 歷史緣由 醫學研究的倫理準則 試驗醫師之責任與義務

3 Quiz How long will it take? Probability? Profit? vs. Cost?
Luck vs. Effort? Pattern expired Local vs. global

4 Statistics New Drugs Begin in the Laboratory , Discovering and Bringing One New Drug to the public Typically Costs a Pharmaceutical 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 in Patients, Only 1 of these Compounds is Ultimately Approved as a Marketed Drug for Treatment.

5 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 pharmaceutical products that are both safe and effective are brought to market.

6 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 which help people to live longer and feel better.

7 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 research are complete can the Food and Drug Administration approve drugs for use by the general public.

8 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

9 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.

10 In Preclinical Stage of Drug Development
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 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 will be formulated & manufactured How it will be administered to the first human subjects

11 Pre-Clinical Stage Preclinical Technology Pharmacology/Toxicology
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 testing determines effects of the candidate drug on the body. Toxicology studies are conducted to identify potential risks to humans.

12 Pre-Clinical Stage (Cont.)
Chemistry Manufacturing and Controls (CMC)/Pharmaceutics The results of preclinical testing are used by experts in pharmaceutical methods to determine 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 drug's active ingredient and of the formulated drug

13 Pre-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 required to proceed to the next stages of development. The European Agency for the Evaluation of Medicinal Products (EMEA)

14 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 patients.

15 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 dosage form, or New use of a drug already approved to be marketed

16 Phase I Study

17 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 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 證實

18 Before Start Running…….
Should Obtain Permission from Appropriate Regulatory Authorities (e.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.

19 Why? Many laws and safeguards are 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) and IRB.

20 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 Protected An 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.

21 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 Paid 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)」

22 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。

23 Composition 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。

24 IRB審查須包括: 計畫書是否符合優良臨床試驗規範? 試驗學理依據是否合理? 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?

25 Phase II Study

26 Phase II Study Designed to determine effectiveness 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 condition 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.

27 Phase II Study (Cont.) Most Phase II Clinical Trials are:
Randomized 隨機分配 Randomly Divided into Groups One group: Receives the Investigational 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 Neither Patients Nor Researchers Evaluating the Compound Know who is Receiving the Investigational Drug or Placebo.

28 Phase III Study

29 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, 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.

30 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 Present: 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 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

31 Does Testing Continue After A New Drug is Approved?
非類固醇發炎抑制劑比較容易導致胃部與腎臟的副作用,像阿斯匹靈就屬此類,所以藥界發展出副作用比較少的第二代非類固醇發炎抑制劑,學術上稱為COX-2抑制劑。 最近美國默沙東藥廠所產屬於COX-2抑制劑的Vioxx下架不再上市,導致藥廠股票大跌,聽說這個事故的發生是這樣的: 默沙東藥廠嘗試讓Vioxx多加一個新的適應症:預防腸息肉再發。所以藥廠開始進行一項人體試驗,讓腸息肉患者連續使用18個月的Vioxx。雖然此藥看來好像有效,但研究結果同時發現18個月後這些試驗者心臟血管疾病發生率增加, 一直被當作 Cox-2 選擇性抑制劑而廣泛地受到使用的新藥 Vioxx,因為在臨床上有心血管的負面影響,因此研發商 Merck 公司在 2004 年 9 月正式宣布將 Vioxx 全面下架。 製藥產業也開始進行製品及規範的重新評估。

32 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.

33 They are… Phase IIIb Study Phase IV Study Post-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。   

34 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.

35 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)

36 Post-Marketing Study 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 Drug Development Testing, the Purpose is to Ensure the Safety and Effectiveness of Marketed Drugs NSAIDs vs. COX-2 inhibitor

37 Conclusion I II III IV Safety/ Tolerability Safety/ Efficiency
Min./Max. Dose Expanding Efficiency/Safety Long-Term Safety Surveillance 6~ 9 mth. 6 M ~ 3 yr. 1~4 yr. Over 1yr. 20~100 人 數百人 數百至數千人 數十至數千人不等

38 Guidelines in Research Ethnics
醫學研究的倫理準則

39 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 :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.

40 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 contract the disease. 1906:Dr. Richard Strong, Harvard professor of tropical medicine--experimented with cholera on prisoners in the Philippines killing thirteen.

41 Nuremberg War Crimes - 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 acts 紐倫堡審判: 第二次世界大戰- 德國紐倫堡 醫生審判 醫生認為審判的命運, 2003年德國醫生誰也參加了納粹計劃euthanize的人認為“不配生活” (精神病患者,智障或身體殘疾)或誰進行實驗集中營囚犯沒有他們同意。醫生審判歷時140天。有85名證人作證,幾乎1500年的文件進行了介紹。 16的醫生收取被判定有罪。七名被處決。

42 Principles of Research Ethics --Nuremberg Code 1947
Informed 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 Injury

43 Nuremberg Code (紐倫堡宣言)
1948年公佈 Voluntary Participation/自願參與 Informed Consent/知情同意 Benefits Overweight Risks/ Risks should not exceed benefits 利益超過風險

44 醫學研究的倫理準則 (Codes of Research Ethnics)
Nuremberg Code for Human Experimentation 紐倫堡宣言 年發表 Declaration of Helsinki 赫爾辛基宣言 1964年發表 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

45 赫爾辛基宣言之精神 自主:受試者是在被充分告知相關訊息後,自由決定要參加的。
有益: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,並不會犧牲其權益,仍會受到已證明有效的最佳照顧 附註:中文有台北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

46 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 Physical and Mental Impact on the Subject Informed Consent * (1996, 2000, 2002 and 2004) 遵守

47 Ethical Research Requires Scientific Validity and Careful Thought and Planning to Protect Human Subjects 正當性 合法性

48 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 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, in the Federal register)

49 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)所修訂的。 藥品優良臨床試驗準則

50 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

51 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。

52 Good Clinical Practice (GCP)
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 the Declaration of Helsinki

53 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

54 Principles of ICH GCP (cont.)
Use Qualified Support Staff Obtain Informed Consent Record Information Appropriately Protect Confidentiality Handle Investigational Products Appropriately Implement Quality Systems

55 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

56 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

57 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。

58 但………自97年5月18日起~~~~

59 FDA debarment list

60 責任?義務?

61 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

62 GCP Conduct Standards IRB & Regulatory Approval
Compliance with Protocol Informed Consent Confidentiality of Data Medical Management of Adverse Events Product Accountability Qualification & Training

63 GCP Recording Standards
CRF Completion Data Handling Security Maintenance Audit Requirements by Sponsor/FDA/DOH/IRBs Investigational Product Accountability Management of Study Files/Essential Documents

64 GCP Reporting Standards
To Sponsor/IRB/Regulatory Authorities Adverse Events/Serious Adverse Events Interim Reviews Progress Reports Final Reports Monitoring /Audit Reports

65 References http://www.fda.gov http://www.acrpnet.org

66 Thanks for Your Attention


Download ppt "淺談藥物之臨床試驗 楊蕙瑛, M.S., RPh.."

Similar presentations


Ads by Google