1
HSA WORKSHOP
AN UPDATE ON THE REGULATORY
CONTROLS OF CLINICAL TRIALS AND
CLINICAL RESEARCH MATERIALS
GENERAL CLINICAL TRIAL
REQUIREMENTS
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2
The following slides serve to provide an
overview of the new regulatory requirements.
They should be read in conjunction with the
applicable Regulations.
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3
OUTLINE
1. Overview of Legislative Changes relating to Clinical Trials
and Clinical Research Materials
2. Scope of Clinical Trials Regulated by HSA
3. Risk-based Regulation of TP Trials
4. Sponsor and Investigator Responsibilities
5. Consent Requirements
6. Replacing CTM import approvals with CRM Notifications
7. New Guidance to be Issued
8. Transition to the new CT and CRM Regulations
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CURRENT LEGISLATIVE FRAMEWORK
Medicines Act (1975)
An Act to make provisions with respect to
medicinal products and medical advertisements
and matters connected therewith; and to make
consequential amendments to the Poisons Act.
Medicinal Products:
Medicines
(Clinical Trials)
Regulations
- Pharmaceutical Products
(Chemical and Biologic Drugs)
- Cell, Tissue and Gene Therapy
Products (CTGTP)
- Complementary Health
Products (CHP)
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Health Products Act (2007)
An Act to regulate the manufacture, import, supply,
presentation and advertisement of health products
and of active ingredients used in the manufacture of
health products and provide for matters connected
therewith; and to make related and consequential
amendments to certain other written laws.
Health Products (First Schedule to Act):
-Medical Devices (2007)
-Cosmetic Products (2008)
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REVISED LEGISLATIVE FRAMEWORK
(From 1 Nov 2016)
Medicines Act (1975)
An Act to make provisions with respect to
medicinal products and medical advertisements
and matters connected therewith; and to make
consequential amendments to the Poisons Act.
Medicinal Products:
Medicines
(Clinical Trials)
Regulations
- revised to
align with
HP(CT) Regs
Health Products Act (2007)
An Act to regulate the manufacture, import, supply,
presentation and advertisement of health products
and of active ingredients used in the manufacture of
health products and provide for matters connected
therewith; and to make related and consequential
amendments to certain other written laws.
Health Products (First Schedule to Act):
- Pharmaceutical Products
(Chemical and Biologic Drugs)
-Medical Devices (2007)
- Cell, Tissue and Gene Therapy
Products (CTGTP)
- Therapeutic Products (2016) Health Products
- Complementary Health
Products (CHP)
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-Cosmetic Products (2008)
(Clinical Trials)
Regulations
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REGULATION OF
CLINICAL RESEARCH MATERIALS (CRM)
(From 1 Nov 2016)
Clinical Research Materials refer to Therapeutic Products, Medicinal Products and Medical
Devices intended for the purposes of any clinical research
Medicines Act (1975)
An Act to make provisions with respect to
medicinal products and medical advertisements
and matters connected therewith; and to make
consequential amendments to the Poisons Act.
Medicinal Products:
Medicines
(Medicinal
Products as
CRM) Regs
Health Products Act (2007)
An Act to regulate the manufacture, import, supply,
presentation and advertisement of health products
and of active ingredients used in the manufacture of
health products and provide for matters connected
therewith; and to make related and consequential
amendments to certain other written laws.
Health Products (First Schedule to Act):
HP (Medical Devices)
(Amendment) Regs
- Pharmaceutical Products
(Chemical and Biologic Drugs)
-Medical Devices (2007)
- Cell, Tissue and Gene Therapy
Products (CTGTP)
- Therapeutic Products (2016) Health Products
- Complementary Health
Products (CHP)
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-Cosmetic Products (2008)
(TP as CRM) Regs
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CT REGULATIONS
• Health Products (Clinical Trials) Regulations
- For clinical trials on Therapeutic Products
• Medicines (Clinical Trials) Regulations
- For clinical trials on Medicinal Products (e.g. cell,
tissue and gene therapy products,
complementary health products)
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SCOPE OF TRIALS REGULATED
UNDER CT REGULATIONS
Clinical Trials of therapeutic product(s) or medicinal product(s) intended to a) discover or verify its clinical, pharmacological or pharmacodynamic effects;
b) identify any adverse effect that may arise from its use;
c) study its absorption, distribution, metabolism and excretion; or
d) ascertain its safety or efficacy.
Excluding Observational Trials, i.e.
A clinical trial of one or more registered products, where all of the following conditions
are met in respect of each product:
(a) the product is prescribed in accordance with the terms of the product registration;
(b) decision to prescribe the product is clearly separated from decision to include
patient in the trial; and
(c) assignment of any patient in the trial to a particular treatment is not decided in
advance by a protocol but falls within current practice.
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SCOPE OF TRIALS REGULATED
UNDER CT REGULATIONS
Clinical Trials of
Therapeutic
Products*
(e.g. pharmaceutical
drugs or biologics)
REGULATED
CLINICAL
TRIALS
Clinical Trials of
Medicinal
Products*
(e.g. cell, tissue
and gene therapy
products, or
complementary
health products)
*Excluding observational trials
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Clinical Trial
Authorisation
(CTA)
Clinical Trial
Notification
(CTN)
Clinical Trial
Certificate
(CTC)
Health
Products
(Clinical
Trials)
Regulations
Medicines
(Clinical
Trials)
Regulations
2016
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RISK-BASED REGULATION OF TP TRIALS
• Clinical Trial Authorisation (CTA)
- Clinical Trials of
 Locally Unregistered TPs
 Locally Registered TPs not used in accordance with product
registration*
 Healthy Volunteers (unless approved population is healthy
individuals e.g. vaccine)
*Used for a different indication, patient population, dosing regimen,
dosage form etc from approved label
• Clinical Trial Notification (CTN)
- Clinical Trials (including Placebo-Controlled Trials) of
Locally Registered TPs used in accordance with product
registration
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SCHEMATIC OVERVIEW
Is the product(s) used in the clinical
trial a TP or MP?
Yes
Is the product the subject of
investigation in the trial?
Yes
Is the trial an observational trial
No
Trial is regulated under the
CT Regulations
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No
No
Yes
Trial is not
regulated under the
CT Regulations
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SCHEMATIC OVERVIEW
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SUMMARY OF SUBMISSION ROUTES
Clinical Trial Certificate
(CTC)
30 working days
Regulatory Processing Timelines
(excluding stop-clock time)
Submission Dossier
• Substantial Amendments
• Addition of Trial Site
• Change of PI
Note: 60 working days
for cell and tissue
products
Clinical Trial Authorisation
(CTA)
30 working days
Some phase I studies: 15
working days
• Protocol
• Informed Consent Form
• Investigator’s Brochure
• Principal Investigator’s CV
• GMP Certificate
• COA
• CMC documents, if requested
Approval
Authorisation
Yes
Subject to GCP Inspections
Yes
CTC/CTA/CTN validity period
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CTC
5 working days
• Protocol
• Informed Consent Form
• Approved Product Label
• IRB approval letter
Need to comply with CT
Regulations and GCP
Regulatory Outcome
Clinical Trial Notification
(CTN)
CTA
Duration of trial
Notification
Acceptance of CTN
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REGULATORY ROADMAP FOR TP
TRIALS
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REGULATORY ROADMAP FOR MP
TRIALS
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SPONSOR AND INVESTIGATOR
RESPONSIBILITIES
• Every clinical trial to have a sponsor
• Multi-site investigator-initiated trials (IITs)
More than one sponsor may be allowed if lead sponsor
appointed among the sponsors
• Sponsor must perform its functions in accordance
with GCP
• Investigator must conduct trial in accordance with
GCP
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LEGAL DUTIES OF SPONSORS AND
INVESTIGATORS
Investigators
Sponsors
1.
2.
3.
Obtain CTC/CTA/CTN
Obtain approval for substantial trial amendments1
Notify HSA of trial status, suspension, termination and/or
conclusion, and submit final report within stipulated
timelines
4. Ensure info in IB is concise, objective and kept up to date
5. Ensure trial conducted under supervision of qualified
principal investigator
6. Ensure trial conducted at specified place(s)
7. Carry out functions of the sponsor in accordance with
principles of GCP
8. Put and keep in place arrangements to ensure compliance
with principles of GCP
9. Notify HSA of serious breach2 of GCP/protocol and urgent
safety measures taken to protect subjects against
immediate hazard within stipulated timelines
10. Keep adequate trial-related documents
11. Ensure appropriate investigational health product labelling
12. Report unexpected serious adverse drug reactions
(USADRs) to HSA within stipulated timelines
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1.
2.
3.
4.
5.
6.
7.
8.
Conduct trial in accordance with protocol,
regulatory conditions, the Regulations and
principles of GCP
Conduct trial at specified place(s)
Responsible for medical care/decisions
relating to subject
Consent and provision of information
Keep adequate trial-related documents
Declare financial interest to IRB
Report serious breach of GCP/protocol to
IRB, if required
Report serious adverse events (SAEs) to
sponsor, and IRB if required, within
stipulated timelines
1Substantial
amendments – change of sponsor or principal
investigator, or changes that significantly affect safety,
physical or mental integrity of subjects, scientific value,
conduct or management of trial, or quality or safety of
investigational product
2Serious breach – breach that significantly affects safety,
physical or mental integrity of subjects or scientific value
of trial
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LEGAL DUTIES OF SPONSORS AND
INVESTIGATORS
Additional legal duties for lead and participating site sponsor(s):
Lead Sponsor
1.
2.
3.
4.
Regulatory submissions and notifications to HSA
(e.g. CTC/CTA/CTN applications, amendments,
serious breaches, trial status reports, final trial
reports, etc)
Ongoing safety evaluation of study drug(s)
administered to subject
Prompt notification to all participating site
investigators/institutions of findings that could
adversely affect subject safety or impact conduct
of trial
Notification of unexpected serious adverse drug
reactions, and serious breaches of GCP/protocol,
to HSA
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Participating Site Sponsor(s)
1.
2.
Report immediately to lead sponsor any
SAE at participating site, or any finding that
could adversely affect subject safety or
impact conduct of trial
Provide all relevant information to lead
sponsor that is necessary for the lead
sponsor to perform trial-related regulatory
submissions and notifications to HSA
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REPORTING TIMELINE FOR SERIOUS
BREACH AND URGENT SAFETY MEASURES
Serious Breach
•
Sponsor to notify HSA in writing as soon as possible and in
any event not later than 7 days after becoming aware of
the breach
•
Notify IRB in accordance with its requirements
Urgent Safety Measure
•
Sponsor to notify HSA in writing as soon as possible and in
any event not later than 7 days after the date measure is
taken
•
Notify IRB in accordance with its requirements
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REPORTING TIMELINE FOR TRIAL STATUS
REPORTS
Trial Status Reports
•
Sponsor to submit trial status report to HSA every 6
months starting from CTA authorisation, CTN
acceptance or CTC issuance, until trial conclusion or
termination
•
Immediately or within such other time as required by
HSA.
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REPORTING TIMELINE FOR TRIAL SUSPENSION,
CONCLUSION OR TERMINATION
Trial Suspension or Termination
•
Sponsor to notify HSA (via trial status report) within 15
days after date of suspension or termination.
Trial Conclusion
•
Sponsor to notify HSA (via trial status report) within 30
days of trial conclusion.
•
Sponsor to submit final report of trial within 1 year
after date of trial conclusion.
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CONSENT REQUIREMENTS
General Requirements
•
Fully informed and personal consent
•
In writing, and signed and dated by person giving consent
•
Requires impartial witness if
(a) Person unable to read (e.g. illiterate)
(b) Person unable to physically sign the form (e.g. stroke)
•
Exceptions for personal consent in adults and minors lacking
mental capacity
•
Exceptions for consent in subjects participating in clinical trials
in emergency situations
•
Legal representative must act in best interest of subject
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CONSENT REQUIREMENTS
General Requirements
•
Information regarding the trial must be given by the PI,
another investigator or a person authorised by the PI
•
Consent must be obtained by an investigator who is a qualified
practitioner.
•
If any new information becomes available which may be
relevant to the decision for a subject to continue in the trial,
this information must be provided at earliest feasible
opportunity
•
If adult or minor lacking mental capacity regains capacity,
information regarding the trial must be given and consent
obtained for continued participation at earliest feasible
opportunity.
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INVESTIGATIONAL PRODUCT LABELLING
Principles of Labelling:
1. Ensure protection of subject and traceability
2. Enable identification of product and trial
3. Facilitate proper use and storage of product
4. Ensure reliability and robustness of data generated in clinical trial
Labelling Particulars (for unregistered investigational / auxiliary TP):
1. Name, address, telephone no. of main contact (e.g. sponsor, CRO or investigator)
2. Name of substance and its strength (for blinded trials, name of substance
/comparator or placebo)
3. Pharmaceutical form, route of administration, quantity of dosage units
4. Batch/code number
5. Trial reference code/number
6. Trial subject identification number or treatment number and, where relevant,
the visit number
7. Directions for use (reference may be made to leaflet or other explanatory
document)
8. “For clinical trial use” or similar wording
9. Storage conditions
10. Period of use (expiry date or re-test date)
Investigational TP = TP/placebo used
as test or reference
Auxiliary TP = TP used for trial but not
Copyright
© HSA, All rights
as
investigational
TP reserved
Reference:
PIC/S Annex 13
Manufacture of
Investigational
Products (Labelling)
Exceptions:
1. Certain particulars can be omitted if provided by other
means (e.g. centralised electronic randomisation system)
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CLINICAL TRIAL REGISTER
•
HSA may publish particulars of clinical trial (marked with ^ in
form) in a publicly available clinical trial register.
•
The new CT Register to be implemented in 2017/2018.
Current Data Set in CT
Register (PRISM)
• Protocol Title/ No.
• Phase
• Therapeutic Area
• Intervention [Name of Study
Drug]
• Sponsor
• Trial Site
• Principal Investigator
• Trial Status
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NEW Data Set in CT Register
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CLINICAL RESEARCH MATERIALS (CRM)
Clinical Research Materials (CRM)
Registered or
unregistered
therapeutic
product (TP)
Licensed or
unlicensed
medicinal
product (MP)
Placebo
Medical Device
(MD)
Manufactured, imported or supplied for the purpose of being used
in any clinical research in accordance with a research protocol
Regulated Clinical Trials
Clinical Trials requiring a
CTA/CTN/CTC
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Clinical Research not regulated by HSA
• Observational clinical trials of TP and MP;
• Clinical research for which TP or MP is not the subject
of investigation
• Medical device clinical trials; or
• Food and nutrition studies involving the use of MD
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•
CRM NOTIFICATION
~ Facilitates access to CRM
Activity
Licence
CRM Notification
Manufacturer’s Licence
Not required
CRM Notification
required prior to supply
of CRM by local
manufacturer
Importer’s Licence
Not required
CRM Notification
required prior to import
of CRM
Wholesale of CRM
Wholesaler’s Licence
Not required
-
Supply of CRM
Product Registration
Not required
-
Manufacture of CRM
Import of CRM
- Dealers of CRM subject to prescribed duties and obligations.
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NEW GUIDANCE TO BE ISSUED
New Guidance
1
Guidance on Determination of Whether a Clinical Trial Requires a
Clinical Trial Authorisation (CTA), Clinical Trial Notification (CTN) or
Clinical Trial Certificate (CTC)
2
Guidance on Regulatory Requirements for New Applications and
Subsequent Submissions
3
Guidance on Safeguards and Consent Requirements in Vulnerable
Subjects
4
Guidance on Determining Whether an Amendment to a Clinical Trial
is a Substantial Amendment
5
Guidance on Labelling of Therapeutic Products and Medicinal
Products Used in Clinical Trials
6
Guidance on Clinical Research Materials
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TRANSITION TO THE NEW CT AND CRM
REGULATIONS
Description
Transition
Ongoing clinical trials of TPs
Considered as an authorised trial (CTA) after 1 Nov 2016
CTC -> CTA
CTM import permit
Can continue to be used to import CRM after 1 Nov 2016
(without need for separate CRM notification) as long as it
remains valid.
TP and MP Labelling
1 year grace period to comply with labelling
requirements
Observational Trials
Exclusion of observational trials will apply only to trials
initiated after 1 Nov 2016.
Ongoing observational trials (for which CTC(s) issued) will
be considered an authorised trial (CTA) after 1 Nov 2016.
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THANK YOU!
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