1. REGULATORY TRIALS – ONCOLOGY EXPERIENCE Anthony TC Chan Comprehensive Cancer Trials Unit Department of Clinical Oncology The Chinese University of Hong Kong

2. BACKGROUND (1) REGULATORY TRIALS Provide clinical evidence of effectiveness for drugs/biological products Well-designed studies focus on specific disease subpopulation Efficacy refers to findings in well-controlled clinical trials Effectiveness refers to regulatory determination made on the basis of efficacy and other data

3. BACKGROUND (2) SINGLE CLINICAL TRIAL OF EFFICACY Any trial may be subjected to systematic biases Chance alone may produce a positive trial result Single center studies may be dependent on site or investigator- specific factors and not be generalizable “Positive” efficacy results may be the product of scientific fraud (e.g. High dose therapy in breast cancer)

4. BACKGROUND (3) CONFIRMATORY TRIAL Preferably trial of different design and independent in execution May be different populations, endpoints, or dosage forms (e.g. concurrent chemo-RT in NPC) Rarely, considered “unethical”, based on findings from multicenter study of excellent design, providing highly reliable and statistically strong evidence of survival benefit

5. QUANTITY OF EVIDENCE REQUIRED FROM REGULATORY TRIALS I.Extrapolation from existing studies II.Single well-controlled study supported by other studies of different endpoints III.Single multicenter study with no other supporting information

6. (I) EXTRAPOLATION FROM EXISTING STUDIES i.Paediatric uses -based on adult data -demonstrate common pathophysiology, drug metabolism and concentration-response relationships ii.Modified-release dosage forms -PK data linking new dosage to previous dosage form, concentration-response relationships iii.Different doses, regimens or dosage forms - PK data, concentration-response relationships may be used to translate trial results

7. (II) SINGLE STUDY OF NEW USE, WITH INDEPENDENT SUBSTANTIATIONS FROM RELATED STUDY DATA i.Different doses, regimens or dosages forms -PK/PD data ii.Studies in other phases of same disease e.g. CPT 11 in Ca Colon iii.Studies in other populations e.g. tamoxifen in male breast cancer iv.Studies in combination vs monotherapy e.g. gemcitibine in lung cancer v.Studies in a closely related disease patterns e.g. pain control studies vi.Studies of different important primary and secondary endpoints e.g. response rate and survival, PFS and OS, QOL and survival

8. (III) SINGLE MULTICENTER STUDY WITH NO OTHER SUPPORTING INFORMATION i.Large multicenter study a.no single site provided unusually large fraction of patients b.no single investigator disappropriately responsible for favorable effect seen. i.e. internal consistency ii.Consistency across study subsets e.g. stratified for prior therapy, disease stage, age, gender iii.Multiple studies in a single study e.g. 2 x 2 disign iv.Multiple endpoints involving different events e.g. response rate and survival v.Statistically very persuasive findings i.e. very low p-value in large trial

9. ACCELERATED NEW ONCOLOGIC DRUG APPROUAL (FDA) > 400 drugs for cancer being tested 1,500 active Investigative New Drug (IND) applications 5-10 New Drug Applications (NDA) “Provide meaningful therapeutic benefit to patients over existing treatments“ (e.g. CML patients intolerant of, or unresponsive to Interferon), preferably with multiple endpoints e.g. haematologic and cytogenetic response. e.g. Glivec (ST1-571) approved in 9 weeks

10. PROCEDURE FOR CLINICAL TRIAL APPLICATION IN HONG KONG Regulatory guideline : Regulation 36B of the Pharmacy and Poisons Regulations “Certificate for Clinical Trial/Medicinal Test, Notes for the Guidance of Applicants” issued by DOH, May 1999 “How to apply for Import and Export License for Pharmaceutical Products and Medicines” issued by Trade Department, August 1995

11. PROCEDURE (I) 1.Sponsor/CRO provides Principal Investigator with essential study documents for submission to Hospital Ethics Committee 2.Principal Investigator submits to Hospital EC the application for clinical trial Sponsor/CRO submits in parallel to Trade Department for Import License for sample package(s) for purposes of Clinical Trial Certificate application 3.EC Approval Letter granted to Principal Investigator Average EC approval time : 1 to 1.5 months Import License for sample package(s) granted to Sponsor/CRO Average Import License approval time : 1 week

12. PROCEDURE (II) 4.Sponsor/CRO submits to Department of Health (DOH) for Clinical Trial Certificate (CTC) In multicentre studies, ONE CTC application is sufficient for all participating centres. In such cases, ONE CTC will be issued with names of all Principal Investigators & Institutions stated. Master/original CTC will be held by Sponsor/CRO Application Fee : HK$2,580.00 5.CTC granted to Principal Investigator Average CTC approval time : 1 to 2 months Validity: 2 years 6.Sponsor/CRO submits to Trade Department for Import License 7.Import license granted to Sponsor/CRO Average Import License approval time : 1 week Validity : 6 months (extension may be granted upon application)

13. Regulatory BodyEssential Documents Hospital EC1. Application Form (institution-specific) 2. Study Protocol 3. Investigators’ Brochure 4. Patient Information Sheet & Informed Consent Form (both English & Traditional Chinese) 5.Principal Investigator’s Curriculum Vitae 6.(Letter of insurance/indemnity not listed as required, but often requested after verbal confirmation of availability)

14. Regulatory BodyEssential Documents Department of 1.Application Form - “Application for Clinical HealthTrial/Medicinal Test Certificate” 2.Study Protocol 3.Investigators’ Brochure 4. Patient Information Sheet & Informed Consent Form (both English & Traditional Chinese) 5.EC Approval Letter 6.Letter from Principal Investigator confirming his involvement in the clinical trial 7.Sample of clinical trial material/study medication (packaged & labelled as will be used in the trial) 8.(Letter of insurance/indemnity not listed as required, but often requested after verbal confirmation of availability)

15. Regulatory BodyEssential Documents Trade DepartmentFor sample package for purpose of CTC application : 1.Application Form - “Import License Form 3” -to specify “Sample Package for Clinical Trial Certificate Application” 2. Copy of Supplier’s Proforma Invoice For import of Clinical Trial Material/Study Medication for entire clinical trial conduct : 1.Application Form - “Import License Form 3” 2.Copy of Clinical Trial Certificate 3. Copy of Supplier’s Proforma Invoice

16. APPLICATION FOR A CLINICAL TRIAL HONG KONG Essential documents Investigator Hospital Ethics Committe EC Approval Letter 1 - 1.5 months Department of Health CTM sample 1 - 2 monthsFee : HK$2,580 Clinical Trial Certificate Trade Department 1 week Import License Total approval time 2 - 4 months EC review by circulation Sponsor/CRO Trade Department Import License 1 week

17. CCTU SOP FOR INTERNAL REGULATORY POLICIES PROTOCOL SYNOPSIS FROM INDUSTRY CCTU Executive Committee approval Indemnity Letter (Industry/HA/RTAO) Full Protocol to EC, CUHK Financial Agreement (Industry/HA/RTAO) Research Project Database and declaration form for research sponsored by external funding INITIATION MEETING with CRA/co-investigators

18. CCTU SAE REPORTING SYSTEM SAE Safety Alert Card / CMS Alert Notes Ward Staff / Radiographers / Other Hospitals’ Medical Staff CCTU IRB DMSC Sponsor

19. Time Cost Risk REGULATORY TRIALS