Clinical Trials: Understanding Drug Development Process

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?

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 onlythose 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 researchhelp 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. 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 • 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.

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

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?

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

37. Conclusion

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 • 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.

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

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 -1948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)

47. Ethical Research Requires Scientific Validity and Careful Thought and Planning to ProtectHuman Subjects

48. ICH GCPGuideline • “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。

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