Transcript REGULATORY TRIALS – ONCOLOGY EXPERIENCE

REGULATORY TRIALS –
ONCOLOGY EXPERIENCE
Anthony TC Chan
Comprehensive Cancer Trials Unit
Department of Clinical Oncology
The Chinese University of Hong Kong
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
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 investigatorspecific factors and not be generalizable
• “Positive” efficacy results may be the product of scientific fraud (e.g.
High dose therapy in breast cancer)
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
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
(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
(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
(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
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
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
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
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)
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 Investigator’s Curriculum Vitae
6. (Letter of insurance/indemnity not listed as required,
but often requested after verbal confirmation of
availability)
Regulatory Body
Essential Documents
Department of
Health
1. Application Form - “Application for Clinical
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)
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 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
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 review by circulation
EC Approval Letter
CTM sample
Department of Health
1 - 2 months
Fee : HK$2,580
Clinical Trial Certificate
Trade Department
1 week
Import License
Total approval time 2 - 4 months
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
CCTU SAE REPORTING SYSTEM
SAE
Safety Alert Card
/
CMS Alert Notes
Ward Staff / Radiographers / Other Hospitals’ Medical Staff
CCTU
IRB
Sponsor
DMSC
Time
REGULATORY TRIALS
Cost
Risk