REGULATORY TRIALS

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REGULATORY TRIALS ONCOLOGY EXPERIENCE

• Anthony TC Chan
• Comprehensive Cancer Trials Unit
• Department of Clinical Oncology
• The Chinese University of Hong Kong

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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

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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)

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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

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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

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(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

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(II) SINGLE STUDY OF NEW USE, WITH INDEPENDENT
SUBSTANTIATIONS FROM RELATED STUDY DATA

• Different doses, regimens or dosages forms
• - PK/PD data
• Studies in other phases of same disease e.g. CPT
  11 in Ca Colon
• Studies in other populations e.g. tamoxifen in
  male breast cancer
• Studies in combination vs monotherapy e.g.
  gemcitibine in lung cancer
• Studies in a closely related disease patterns
  e.g. pain control studies
• Studies of different important primary and
  secondary endpoints e.g. response rate and
  survival, PFS and OS, QOL and survival

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(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
• Multiple studies in a single study e.g. 2 x 2
  disign
• Multiple endpoints involving different events
  e.g. response rate and survival
• Statistically very persuasive findings i.e. very
  low p-value in large trial

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ACCELERATED NEW ONCOLOGIC DRUG APPROUAL (FDA)

• gt 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

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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

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• 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
• 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

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• 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 HK2,580.00
• CTC granted to Principal Investigator
• Average CTC approval time 1 to 2 months
• Validity 2 years
• Sponsor/CRO submits to Trade Department for
  Import License
• Import license granted to Sponsor/CRO
• Average Import License approval time 1 week
• Validity 6 months (extension may be granted
  upon application)

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• Regulatory Body Essential Documents
• Hospital EC 1. Application Form
  (institution-specific)
• 2. Study Protocol
• 3. Investigators Brochure
• 4. Patient Information Sheet Informed Consent
  Form (both English Traditional Chinese)
• 5. Principal Investigators Curriculum Vitae
• 6. (Letter of insurance/indemnity not listed as
  required, but often requested after verbal
  confirmation of availability)

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• Regulatory Body Essential Documents
• Department of 1. Application Form - Application
  for Clinical
• Health Trial/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)

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• Regulatory Body Essential Documents
• Trade Department For 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 Suppliers 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 Suppliers Proforma Invoice

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APPLICATION FOR A CLINICAL TRIAL HONG KONG
Essential documents
Sponsor/CRO
Investigator
Trade Department
Hospital Ethics Committe
1 week
Import License
1 - 1.5 months
EC Approval Letter
EC review by circulation
CTM sample
Department of Health
1 - 2 months
Fee HK2,580
Clinical Trial Certificate
Trade Department
1 week
Import License
Total approval time 2 - 4 months
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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)

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CCTU SAE REPORTING SYSTEM
SAE
Safety Alert Card /
CMS Alert Notes
Ward Staff / Radiographers / Other Hospitals
Medical Staff
CCTU
IRB
Sponsor
DMSC
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• Time
• Cost Risk

REGULATORY TRIALS