Regulatory trials oncology experience
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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. BACKGROUND (1) REGULATORY TRIALS. Provide clinical evidence of effectiveness for drugs/biological products

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REGULATORY TRIALS – ONCOLOGY EXPERIENCE

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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

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

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)


Background 3 confirmatory trial

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

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) 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

(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


Iii single multicenter study with no other supporting information

(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


Accelerated new oncologic drug approual fda

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

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


Regulatory trials oncology experience

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


Regulatory trials oncology experience

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

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)


Regulatory trials oncology experience

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)


Regulatory trials oncology experience

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)


Regulatory trials oncology experience

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


Application for a clinical trial hong kong

Essential documents

Sponsor/CRO

APPLICATION FOR A CLINICAL TRIAL HONG KONG

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

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


Regulatory trials oncology experience

CCTU SAE REPORTING SYSTEM

SAE

Safety Alert Card / CMS Alert Notes

Ward Staff / Radiographers / Other Hospitals’ Medical Staff

CCTU

IRB

Sponsor

DMSC


Time cost risk

Time

Cost Risk

REGULATORY TRIALS


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