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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 – PowerPoint PPT presentation

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Title: REGULATORY TRIALS


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
  • 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

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
  • 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

9
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

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
  • 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 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)

13
  • 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)

14
  • 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)

15
  • 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

16
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
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)

18
CCTU SAE REPORTING SYSTEM
SAE
Safety Alert Card /
CMS Alert Notes
Ward Staff / Radiographers / Other Hospitals
Medical Staff
CCTU
IRB
Sponsor
DMSC
19
  • Time
  • Cost Risk

REGULATORY TRIALS
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