These FAQs apply to clinical trials involving the use of a medicinal product.
Last updated: 4 October 2011
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[A] REGULATORY REQUIREMENTS FOR CLINICAL TRIALS
[A1] Where can I access the Medicines Act and the Medicines (Clinical Trials) Regulations?
You may access the Medicines Act and the Medicines (Clinical Trials) Regulations from here.
[A2] How can I determine if my research study requires a Clinical Trial Certificate (CTC) from HSA?
Please refer to the Medicines Act for the legislative definition of clinical trial (see section 2 of the Act, Interpretation) and medicinal product (section 3). A CTC is not only required for unregistered medicinal products, but also for clinical trials on locally registered medicinal products.
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[B] CLINICAL TRIAL CERTIFICATE (CTC)
[B1] What are the required documents to be submitted for a CTC application?
Please refer to the regulatory guidance on Application for a Clinical Trial Certificate for further details. Please note that the sponsor applicant must be a locally registered company.
[B2] Are translated informed consent forms required to be submitted to HSA?
No, translated ICFs need not be submitted to HSA. However, it is the sponsor's responsibility to ensure that the translation is correct. Please refer to the industry communication dated Jan 2006 for further details.
[B3] Are clinical trial advertisements required to be submitted to HSA?
No, clinical trial advertisements are not required to be submitted to HSA. Please refer to the regulatory guidance on Guideline for Clinical Trial Advertisement / Recruitment Programme for further details.
[B4] Does HSA require the local product insert to be submitted if the Investigational Product is a locally registered medicinal product?
For industry-initiated studies, a local product insert is not usually required if an Investigator's Brochure of the Investigational Product is submitted. This is more applicable to investigator-initiated studies whereby a copy of the Investigator's Brochure is not available.
[B5] How often should Trial Status Reports be submitted to HSA?
Trial Status Reports should be submitted to HSA on a 6-monthly basis from the CTC approval date, unless otherwise specified on the Clinical Trial Certificate (CTC). They should also be submitted when there are significant changes to the status of the trial e.g. increase in recruitment target, suspension of trial, temporary site closure, termination of trial site, etc.
See also [E2] and [E3].
[B6] Does HSA have any guidance regarding lapse in CTC approval when the clinical trial is still ongoing?
In the event there is a lapse in CTC Approval, the Principal Investigator should suspend the clinical trial, notify the IRB and HSA about the lapse in HSA approval, and seek to renew the HSA approval. The PI should not screen and enroll any new subjects during this period till HSA approval has been renewed. The PI may continue study treatment for ongoing subjects during the lapse period due to safety reasons.
[B7] How can a suspension / termination / completion of a clinical trial be notified to HSA?
The Sponsor can submit a Trial Status Report to HSA via PRISM to notify about the trial suspension / termination / completion and the reason(s) for such a decision.
[B8] Is a valid Clinical Trial Certificate (CTC) required till study completion?
A CTC is required till Last Patient Last Visit is achieved in Singapore.
[B9] What is the timeline to submit a Trial Status Report for extension of the Clinical Trial Certificate (CTC)?
A Trial Status Report should be submitted to HSA within a month before the CTC extension application is submitted.
[B10] What are the requirements for Clinical Study Reports?
The Final Clinical Study Report should be submitted to HSA within 3 months of study completion, unless otherwise agreed by HSA. For more information, you may refer to ICH Guideline E3: Structure and Content of Clinical Study Reports, that elaborates on the note for guidance on structure. For investigator-initiated clinical trials, a publication of the clinical trial may be submitted to HSA in place of a Final Clinical Study Report.
[B11] How long should essential documents be archived for following study suspension / termination / completion?
Please refer to the Medicines (Clinical Trials) Regulations 19 (2)(c), and SGGCP 4.9.6 and 5.5.11 for further guidance on archival of essential documents.
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[C] OTHER REGULATORY REQUIREMENTS AND GUIDANCE FOR CLINICAL TRIALS
[C1a] What are the regulatory requirements on First-in-Human (FIH) trials?
In general the documentation requirement to support FIH applications is not significantly different to that for later phase studies. The drug need not be approved in other countries before FIH can be performed in Singapore. Please note that the sponsor applicant must be a locally registered company.
For guidance on non-clinical and clinical requirements, HSA refers to applicable ICH guidelines and relevant guidelines issued by the major agencies (FDA, EMA). The following are examples of such guidance, which the pharmaceutical industry should be familiar with.
- ICH M3(R2) Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (under revision)
- ICH S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (under revision)
- FDA CDER Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers
- EMA Guideline on Strategies to Identify and Mitigate Risks for First-In-Human Clinical Trials with Investigational Medicinal Products (Reference number: EMA/CHMP/SWP/28367/07)
If the investigational product is of a novel therapeutic class or mechanism of action, we would encourage a pre-submission meeting with the sponsor.
[C1b] Are non-clinical safety/toxicology studies required to be conducted in compliance to GLP standards?
Non-clinical studies providing toxicology information to support clinical trials should be conducted in compliance with Good Laboratory Practice (GLP), which is a quality system on the organisation process and conditions under which the non-clinical studies are planned, recorded, archived and reported. The basis to accept studies conducted in compliance to GLP will help assure regulatory agencies that the non-clinical safety data are accurate and reliable for the purpose of risk evaluation. For more information on GLP, please refer to the National GLP Compliance Programme administered by SPRING Singapore.
[C2] Are there any regulatory requirements for clinical trials involving radiopharmaceuticals?
The regulation of radiopharmaceutical clinical trials is similar to that for the conventional medicinal products. HSA generally takes reference to applicable international guidelines from FDA and EMA guidelines for the use of radiopharmaceuticals in clinical trials.
The import, export, possession, use, transport, disposal etc. of radioactive material is subject to control under the Radiation Protection Act, which is regulated by the National Environment Agency (NEA). Please refer to NEA website > Topics: Radiation Protection for more information including the adequacy of the facility.
[C3a] What kind of preclinical data is required for submission of cell and tissue-based therapeutic (CTT) product clinical trials?
(1) Nonclinical proof of concept to provide the scientific basis for conducting clinical trial
- Potential mechanism of action
- Establish pharmacologically effective doses
- Optimize route of administration and dosing regimen
- Rationale for species/model selection
(2) Toxicity studies in relevant animal species to provide useful information about the safety of product
- Identify, characterize, and quantify potential local and systemic toxicities
- Safety data for recommendation of initial dose and dose escalation scheme in humans
[C3b] Are there any additional dossier requirements for submission of cell and tissue-based therapeutic (CTT) product clinical trials?
Yes. The additional dossier requirements for a CTT product clinical trial is the Chemistry, Manufacturing, and Control (CMC) Information including the following:
- consistent control of cell source, reagents, facility, personnel and equipment
- validation of manufacturing process, aseptic processing and test methods
- confirm safety and quality of each lot by product testing
- Quality Overall Summary on Equipment and Facility – this refers to the list of equipments and qualification pertaining to the manufacturing or processing of the CTT product, and a description of the heating, ventilation and air-conditioning system (HVAC)
For regulatory guidance on CTT product clinical trials, HSA refers to applicable guidelines issued by the major agencies (FDA, EMA). The following are examples of such guidance, which trial sponsors should be familiar with:
- FDA Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs)
- FDA Final Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products
- FDA Guidance for Industry: Guidance for Human Somatic Cell Therapy and Gene Therapy
- EMA Guideline on Human Cell-Based Medicinal Products
- EMA Guideline on Potency Testing of Cell Based Immunotherapy Medicinal Products for the Treatment of Cancer
[C4] What are the regulatory requirements for conducting clinical trials on Health Supplements?
Currently, clinical trials on health supplements do not in general require regulatory approval from HSA. However, if the aim of the study is to assess a product's therapeutic benefits or is intended for a medicinal purposes (e.g. treating or preventing a disease), the study may be subject to regulatory approval from HSA.
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[C5] Is HSA approval required for clinical trials on Medical Devices?
Under the current Medicines (Clinical Trials) Regulations, a CTC application is not required for studies assessing the performance of medical device. It is the sponsor's/ principal investigator's responsibility to seek the ethics approval to conduct the trial from the respective IRB(s) before commencement of the trial.
The regulatory framework for clinical trials involving investigational medical devices is currently under development. The regulation of medical device clinical trials would commence upon the implementation of Health Products (Clinical Trials) Regulations. It is also planned that the regulation of clinical trials involving medical devices would be implemented in phases, in which the initial phase would be notifications of medical device clinical trials to HSA by the sponsors.For more information on the proposed regulatory framework for clinical trials on medical devices, please refer to the presentation slides used at the briefing sessions in August 2011.
Currently, for all medical devices whether they are used in routine practice or in clinical trials, the specific regulatory requirements as per the Health Products (Medical Devices) Regulations 2010 should be followed. The duties and obligations of manufacturers, importers or wholesalers of medical devices that currently applies include:
- Reporting of defects and adverse effects to HSA
- Notification to HSA concerning recall
- Duty to maintain records of supply
- Duty to maintain records of complaints
- Labelling requirements
With effect from 10 August 2010, for import of Class C & D unregistered medical devices for use in clinical trials, you may submit your completed hard-copy CTM (Medical Devices) application form to HSA's Clinical Trials Branch. Upon approval, an import permit number would be indicated on the CTM (Medical Devices) application form. The approval would serve as the regulatory import permit to facilitate the importation of the unregistered medical device for use in clinical trials.
The processing time for CTM (Medical Devices) application is 5 working days upon the receipt of the application. Please refer to the website for application form and application guidance related to CTM (Medical Devices).
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[D] PRINCIPAL INVESTIGATOR
[D1] Who can be a Principal Investigator (PI) of a clinical trial?
Section 2 of the Medicines Act requires the clinical trial to be conducted by a locally registered doctor or dentist. Section 4.1.1 of SGGCP requires the Investigator to be qualified by education, training and experience to conduct the clinical trial.
The PI should be at least an Associate Consultant (AC) or above for clinical trials assessing investigational products in specialised therapeutic areas. This is because clinical trials in such therapeutic areas usually involve complex diagnostic evaluation of the disease condition, or study procedures that require specialized skills. Suitably qualified ACs and above would have sufficient training and experience to conduct such clinical trials properly, as well as handle unforeseen adverse events or difficulties arising from the conduct of the clinical trial. For clinical trials assessing registered medicinal products, the PI may be general practitioner where in clinical practice, s/he would be using the product.
[D2] Can a doctor who has a conditional registration with Singapore Medical Council (SMC) be a Principal Investigator (PI) of a clinical trial?
A PI should have a level of authority to supervise the clinical trial in addition to being able to make independent medical decisions during the trial. The level of supervision should be appropriate to the study site staff, the nature of the trial, and the subject population. If the registration condition requires the doctor to "work under supervision", the doctor would require a statement from the doctor's supervisor indicating support for the doctor's involvement as the PI of the study.
[D3] What should be done when there is a change in Principal Investigator (PI) for a clinical trial?
Approval for change of PI must be sought from the IRB and HSA. Please refer to regulation 10 of the Medicines (Clinical Trials) Regulations and section 5.6.4 of SGGCP.
[D4] What should be done when the Principal Investigator (PI) is on extended leave?
The PI should have sufficient time to properly conduct and supervise the clinical trial. It is recommended that there should be a change of PI in the following situations:
- The PI is also conducting multiple studies concurrently
- Complex clinical trials
- Large number of subjects enrolled
- A subject population that is seriously ill
- Inexperienced site study staff
- For leave extending more than 3 months
[D5] If the Principal Investigator (PI) of a suspended / terminated / completed clinical trial has resigned, is there a need to seek HSA's approval for a change of PI?
HSA approval is not required for change of PI of a terminated / completed clinical trial. However, HSA approval is required for change of PI of a suspended clinical trial where the suspension has been lifted.
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[E1] What are the responsibilities of a Sponsor?
The responsibilities and corresponding liabilities of the sponsor are in accordance with what are specified in the Medicines (Clinical Trials) Regulations, the Singapore Guideline for Good Clinical Practice (SGGCP) and Section 10 of the CTC application form. The sponsor applicant must be a locally registered company.
[E2] What should the sponsor do if there is a transfer of local sponsorship for an ongoing study? For transfer of local sponsorship for an ongoing study to another locally registered company, the new local sponsor may submit a new CTC application for the study. Upon approval of the new CTC application, the current local sponsor is required to submit a status report to indicate the change of local sponsor. This can be done through the selection of “Premature site closure” status, with reason being given as change of local sponsor. This is necessary to close the loop on the existing CTC application under current local sponsor.
The new CTC application should contain the following:
- All currently-approved study documents as required for a new CTC application
- Letter from the current local sponsor indicating transfer of local sponsorship to the new local sponsor. This letter should be copied to the new local sponsor and the respective trial site PI(s) and IRB(s).
[E3] What should the sponsor do when there is a change in the contact person? The contact person of the local sponsor is the applicant that submits the CTC application. HSA e-mail reminders for submission of trial status report and CTC extension are sent to this contact person. Hence when there is a change in the contact person, it is essential to inform HSA. The change of local sponsor contact person can be effected through the submission of a trial status report. Subsequent regulatory correspondences would thereafter be directed to the new local sponsor contact person.
[E4] What should the sponsor do when there is a change in the address of the company?
The sponsor can inform HSA via e-mail.
[E5] Does the sponsor need to notify HSA about additional sub-investigators?
No, it is not required to notify HSA about additional sub-investigators.
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[F1] Are administrative changes to the protocol and / or informed consent form required to be submitted to HSA?
[F2] Are there any guidelines for reporting Protocol Deviations to HSA?
There are currently no guidelines for reporting protocol deviations to HSA. Sponsors are strongly encouraged to notify HSA of significant protocol deviations affecting any of the following:
- the safety, physical or mental integrity of the subjects of the trial,
- the scientific value of the trial,
- the conduct or management of the trial, or
- the quality or safety of any investigational product used in the trial.
The notification of the Protocol Deviation to HSA should also be accompanied by a Corrective Action and Preventive Action (CAPA) Plan.
[F3] Does HSA approve Protocol Waivers?
The practice of enrolling subjects into a study based on "Protocol Waiver" is discouraged. The protocol's eligibility criteria should be amended to reflect the clinical practice. For industry-sponsored studies, there are implications to the validity of the data presuming that the enrollment of the subject, who has not fulfilled the eligibility criteria has been permitted, is not compromised.
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[G] INFORMED CONSENT FORM (ICF)
[G1] What are the regulatory requirements for an informed consent form?
Please refer to regulations 11-14 of the Medicines (Clinical Trials) Regulations for further details. Additionally, please refer to section 4.8 of SGGCP for further guidance.
[G2] When can substituted consent by a legal representative be obtained?
Substituted consent is required in the event the subject is unable to consent to participate in a clinical trial himself / herself. Please refer to Medicines (Clinical Trials) Regulations 11(1) to 11(3) for further details on substituted consent by a legal representative. In summary, substituted consent is valid only if the subject is a minor, unconscious or incapable of exercising rational judgment.
[G3] Can informed consent be obtained by non-medical study staff?
The Principal Investigator is responsible for obtaining consent, but may delegate this responsibility to his study staff. We would recommend that informed consent be obtained by study staff who are medically trained, so that the subject can have his questions about clinical trial participation adequately addressed. Please refer to SGGCP 4.8.7 for further details.
[G4] Are signatures or date stamps acceptable means of signing and dating the informed consent form?
No, Medicines (Clinical Trials) Regulations 11(4)(a) and SGGCP 4.8.8 require the individual to personally sign and date the informed consent form.
[G5] If a clinical trial involves recruiting subjects who are mentally competent, but unable to sign / date the informed consent form, how can consent be obtained from such a subject?
It would be recommended to develop an informed consent process for such a scenario and submit it to the IRB and HSA for review and approval. Please refer to Medicines (Clinical Trials) Regulation 11(4)(b) for further details.
[G6] How can informed consent be obtained from a subject or his legally acceptable representative (if applicable) who is unable to read the informed consent form?
If the subject is unable to read the informed consent form, an impartial witness would be required to be present during the informed consent process. By signing the informed consent form, the impartial witness attests that the informed consent had been accurately explained to, apparently understood by, and informed consent freely given by the subject or his legally acceptable representative (if applicable). The subject or his legally acceptable representative (if applicable) should sign and personally date the informed consent form, if capable of doing so. Please note that the role of an impartial witness is different from a translator, since the translator does not need to attest to the above-mentioned clauses. Please refer to Medicines (Clinical Trials) Regulations 11(5) and SGGCP 4.8.9 for further details.
[G7] Who can act as an impartial witness?
SGGCP 1.26 defines an impartial witness as ‘A person, who is independent of the trial, who cannot be unfairly influenced by people involved with the trial, who attends the informed consent process if the subject of the subject's legally acceptable representative cannot read, and who read the informed consent form and any other written information supplied to the subject'.
There is no provision in the Medicines (Clinical Trials) Regulations and SGGCP regarding who can act as the impartial witness. One should consider whether the person who acts as an impartial witness is independent of the clinical trial and is not influenced by people involved in the clinical trial. The possible choices would be either a family member / friend; clinic staff (non-study staff); or a “person from the street”. Whilst it is impractical to get a person from the street, the viable options would either be the family member / friend or the clinic staff (non-study staff). Whilst there may be concerns about family members / friends being under influence, the same could also apply to the clinic staff (non-study staff).
The choice of an impartial witness should be made in the best interest of the subject. HSA has no objections to a family member acting as an impartial witness. If Sponsors have SOPs beyond the regulations and SGGCP for impartial witness, it would be advisable to discuss acceptable options with the site without compromising the regulations and SGGCP.
[G8] How can informed consent be obtained from a non-English speaking subject who is able to read the translated informed consent form by an investigator who is not conversant with the subject's language? Is an impartial witness required in this situation?A translator, who does not have to be independent of the clinical trial, would be required to assist the investigator during the informed consent process. Information on the translator should then be completed in the ICF section on “Translator Information”. If this section is not available, it is recommended that a Note to File be made to describe the informed consent process. An impartial witness is not required in this situation.
[G9] How should informed consent be documented in the subject's medical records?It would be recommended that the person obtaining informed consent from the subject or the subject's legally acceptable representative document the following in the subject's medical records:
- Protocol Reference
- Date of informed consent
- Informed Consent Process (e.g. for use of substituted consent / impartial witness / translator)
- Signed copy provided to subject
For example:
a) Substituted consent for a minor
The informed consent version dated dd/mm/yyyy was explained to Mr ABC on DD/MM/YYYY for participation in Protocol DEF. Mr ABC is the subject's parent / legal guardian. The risks and benefits of the clinical trial were explained and questions answered (if any). He understood the informed consent form and voluntarily agreed to allow his child to participate in the clinical trial. A signed copy of the informed consent form was provided to him.
b) Substituted consent for a subject who is unconscious or incapable of exercising rational judgment
The informed consent version dated dd/mm/yyyy was explained to Mr ABC on DD/MM/YYYY for participation in Protocol DEF. Mr ABC is the subject's spouse / parent / guardian / person having charge / legally acceptable representative. The risks and benefits of the clinical trial were explained and questions answered (if any). He understood the informed consent form and voluntarily agreed to allow the subject to participate in the clinical trial. Dr GHK was the independent doctor who assessed the subject's capacity. A signed copy of the informed consent form was provided to him.
c) Use of Impartial witness
The informed consent version dated dd/mm/yyyy was explained to the subject on DD/MM/YYYY for participation in Protocol DEF. As the subject was unable to read the informed consent form, Mr ABC acted as the impartial witness during the informed consent process. Mr ABC is a family member / friend / clinic staff / lay person. The risks and benefits of the clinical trial were explained and questions answered (if any). Mr ABC confirmed that the subject was accurately explained, understood and voluntarily agreed to participate in the clinical trial.
d) Use of Translator
The informed consent version dated dd/mm/yyyy was explained to the subject on DD/MM/YYYY for participation in Protocol DEF. As the subject preferred to use the translated informed consent form as reference, Mr ABC acted as the translator during the informed consent process. The risks and benefits of the clinical trial were explained and questions answered (if any). The subject understood the informed consent form and voluntarily agreed to participate in the clinical trial. A signed copy of the informed consent form was provided to him.
e) Routine
The informed consent form version dated dd/mm/yyyy was explained to the subject on DD/MM/YYYY for participation in Protocol DEF. The risks and benefits of the clinical trial were explained and questions answered (if any). The subject understood the informed consent form and voluntarily agreed to participate in the clinical trial. A signed copy of the informed consent form was provided to the subject.
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[H] INVESTIGATIONAL PRODUCTS (IP)
[H1] What are the regulatory requirements for labelling of Investigational Products?
The current labelling requirements can be found in regulation 18 of the Medicines (Clinical Trials) Regulations and section 4.6.3 of SGGCP.
[H2] What should be done if the IP Labelling requirement for ‘Date of manufacture' or ‘Name and address of manufacturer' cannot be complied with?
The Sponsor should submit a request for waiver to HSA justifying the rationale for being unable to comply with the IP labelling requirements eg. the date of manufacture or name of manufacturer can potentially unblind the studies This should preferably be done prior to study initiation. In addition, if the waiver is provided, it is the sponsor's responsibility to ensure that there is traceability to the source of manufacture and the IP can be identified in cases of product recalls or similar situations.
[H3] What should be done if the entire IP label cannot be affixed onto the primary packaging due to size constraints?
The IP labelling requirements should be on the IP, preferably on both the inner and outer container. If the primary container does not contain the all the labelling elements, it should contain at least the following minimum requirements i.e the designation, reference number or identification mark of each product, the production batch no. or reference no., the name or identification mark of the subject and the expiry / retest date. It is important that the product can be identified from the point of storage to the point of subject administration in order to ensure identification and protection to the subject, traceability and to facilitate the proper use of the product.
[H4] What language(s) are required to be on the label of investigational product(s)?
The language on the labels should be in English.
[H5] What additional information is required for the labelling of marketed/ commercially sourced comparator(s) or concomitant product(s) in a clinical trial?
All investigational health products (i.e. referring to investigational product and comparator product), regardless of where they are sourced, should be labelled in accordance to the labelling requirements outlined in the Medicines Act (Clinical Trial) Regulation and Singapore Guidelines for Good Clinical Practice. Hence, if the marketed/commercially sourced product is used as either the study drug or the comparator drug in a clinical trial, it should be labelled in accordance with the aforementioned regulation and guidelines. Background therapy drugs (referred to as concomitant product) need not be relabelled for clinical trials.
[H6] What are the regulatory requirements for importing a medicinal product for clinical trial use?
Please refer to the regulatory guidance on Import of Clinical Trial Test Materials for further details.
[H7] If the IP is a locally registered medicinal product sourced from the hospital pharmacy, does the site need to maintain IP Inventory and Accountability Logs?
Yes, it is the Investigator's responsibility to maintain IP Inventory and Accountability Logs as per SGGCP 4.6.3.
If the hospital pharmacy utilizes an electronic inventory system to maintain the general inventory, a separate IP Inventory Log for the clinical trial may not be required if it is a validated system and an IP Accountability Log is maintained for the clinical trial clearly indicating the batch number and expiry date of the IP used for each subject.
[H8] Is temperature monitoring required to monitor the storage of the IP?
Yes, temperature is required to provide assurance that the IP has been stored as per Sponsor requirements as per SGGCP 4.6.4 and 5.14.5. The Sponsor should provide written instructions for handling and storage of IP as per SGGCP 5.14.3. The temperature monitoring devices should be calibrated as per SGGCP 2.13. Further, there should be traceability between various temperature monitoring devices, temperature logs and calibration and maintenance certificates as per SGGCP 2.13.
[H9] What are the required procedures if the site is involved in re-packaging of the IP?
The Sponsor should ensure that written procedures for handling and storage of IP are provided to the site in accordance with SGGCP 5.14.3. Whilst there is no specific guidance in SGGCP for re-packaging of IP, there is some guidance in PIC/S Annex 13 (Para 23 and 24) appended below:
“23. During packaging of investigational medicinal products, it may be necessary to handle different products on the same packaging line at the same time. The risk of product mix up must be minimised by using appropriate procedures and/or, specialised equipment as appropriate and relevant staff training.
24. Packaging and labelling of investigational medicinal products are likely to be more complex and more liable to errors (which are also harder to detect) than for marketed products, particularly when “blinded” products with similar appearance are used. Precautions against mis-labelling such as label reconciliation, line clearance, in-process control checks by appropriately trained staff should accordingly be intensified.”
Hence, it would be recommended that Standard Operating Procedures (SOPs) are developed for IP re-packaging. The IP re-packaging process should have line clearance (SGGCP 5.13.3), IP label re-conciliation, performed and witnessed by delegated study staff, and documented accordingly.
[H10] How should the re-labelling be carried out if the expiration date of the IP has been extended?
It is the sponsor's responsibility to ensure that the IP is stable over the period of use and stored as specified by the manufacturer as per SGGCP 5.14.5. Supporting documents for such an extension of shelf-life should be available in the study files. It is not necessary for the local sponsor to submit retesting and relabeling information of the investigational product to HSA. Site staff involved in the study should be informed of the new re-test date or shelf life of the investigational product(s).
Hence the changes can be implemented provided the guidance in sections 5.14.5, 8.2.15, 8.2.16, 8.3.8, and 8.3.9 of the SGGCP is fulfilled. These records should be kept at both the sponsor and investigator files and available at all times for inspection (as per Medicines (Clinical Trials) Regulations 19).
Whilst there is no specific guidance in GCP for re-labelling of IP, there is some guidance in PIC/S GMP Guide Annex 13, Para 33, appended below:
"33. If it becomes necessary to change the use-by date, an additional label should be affixed to the investigational medicinal product. This additional label should state the new use-by date and repeat the batch number. It may be superimposed on the old use-by date, but for quality control reasons, not on the original batch number. This operation should be performed at an appropriately authorised manufacturing site. However, when justified, it may be performed at the investigational site by or under the supervision of the clinical trial site pharmacist, or other health care professional in accordance with national regulations. Where this is not possible, it may be performed by the clinical trial monitor(s) who should be appropriately trained. The operation should be performed in accordance with GMP principles, specific and standard operating procedures and under contract, if applicable, and should be checked by a second person. This additional labelling should be properly documented in both the trial documentation and in the batch records."
[H11] Is the import of medicinal product into Singapore for pre-clinical studies (e.g. cell lines for in vitro or in vivo studies) subjected to regulatory control in Singapore?
This will not require an import permit from HSA. However, if you are dealing with radiolabelled substances, you may wish to enquire with Centre for Radiation Protection and Nuclear Science, National Environment Agency, to ascertain if there are regulatory requirements to be met with regard to radiolabelled substances.
Gazetted poisons should be imported by a Form A License Holder. However, even if the product is not a gazetted poison, the principles of Good Distribution Practice should still apply.[H12] What are the regulatory controls for conducting clinical trials on controlled drugs?
Compliance with the Medicines (Clinical Trials) Regulations and the Misuse of Drugs Act must be observed with conducting clinical trials on controlled drugs.
[H13] How can Investigational Products be destroyed in Singapore?
It is not necessary to obtain prior approval from (or notify) HSA for destruction of Investigational Products. As per sections 4.6 and 5.14 of SGGCP, it is the Sponsor's and Principal Investigator's responsibilities to ensure proper documentation are maintained for receipt, storage, dispensing, accountability and return and / or destruction.
If the Investigational Products are to be destroyed locally, it is important to comply with NEA guidelines for disposal of drugs (particularly for cytotoxic or biohazardous items). General information on toxic wastes control, including pharmaceutical waste disposal management is outlined at NEA website > Topics: Toxic Waste > Control of Biohazardous Waste. Please contact them for further information.
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[I1] Is an export licence required for sending biological samples to overseas for testing?
An export licence is not required from HSA for shipping of biological samples to overseas for testing.
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[J1] What are the regulatory requirements for safety reporting in clinical trials?
Please refer to regulation 17 of the Medicines (Clinical Trials) Regulations. Serious Adverse Events that are subjected to expedited safety reporting (i.e. related and unexpected) must be reported to HSA by the sponsor.
[J2] When should the sponsor start to submit expedited safety reports to HSA?
They should be submitted from the point when the protocol is submitted to HSA for approval. The safety information should cover the period of time from the last Investigator's Brochure update and preferably in a summarized version e.g. line listings or periodic reports. This is to ensure any new safety information which might affect the risk-benefit ration of the study drug is taken into consideration during the review process. Moreover, this is supplementary to the information available in the Investigator's Brochure.
[J3] When should the sponsor cease the submission of expedited safety reports?
Safety reporting to HSA may stop when Last Patient Last Visit (LPLV) is achieved in Singapore and HSA has been informed of the status, unless indicated otherwise in the study protocol. Please note that we consider clinical trials to be completed upon achieving LPLV status.
[J4] In the event of trial termination, does HSA have any requirements on when to cease submission of safety reports?
Safety reporting to HSA may stop when the Last Patient Last Visit is achieved in Singapore and HSA has been informed of the status, unless indicated otherwise in the study protocol.
[J5] Does the sponsor need to submit safety reports from local Named Patient Programme or for compassionate use?
Where there is a CTC issued for compassionate programme, the safety reports should be submitted to the Clinical Trials Branch. However, for Named Patient Programme where an import permit is issued by the Pharmaceutical & Biologics Branch (PBB) of HSA, and a CTC was not issued, the safety reports should be submitted to the Vigilance Branch of HSA.
[J6] Does the sponsor need to submit line listings, DSURs, annual or periodic safety reports to HSA?
There are currently no requirements for submission of such documents. These documents may be submitted to HSA at the sponsor's discretion. However, HSA may request for these reports to be submitted when deemed necessary.
[J7] Do expedited safety reports related to concomitant drugs require reporting to HSA?
Only local reports arising from ongoing trial protocols are required to be submitted.
[J8] If the causality is stated to be related to the study procedure, is there a need to report this event?
In general, reports that are not drug-related need not be reported to HSA, unless the event impacts on the safety and welfare of subjects, and for which preventive actions can be taken at local trial sites to prevent similar occurrences.
[J9] Are there any instances whereby serious and expected reactions are to be reported?
Expected reactions can be reported when the information may materially influence
the benefit-risk assessment of a medicinal product, or
the overall conduct of a clinical trial
An increase in the rate of occurrence of a serious and expected ADR, which is judged to be clinically important, would fit these criteria.
[J10] When does the reporting timeline for safety reports start?
The reporting timeline starts upon first receipt by the sponsor, regardless of their physical location.
[J11] Can the sponsor do a batch submission for expedited safety reports?
The reports should not be batched, but submitted in a real-time process, as the event is made known to the sponsor.
[J12] Who should assume responsibility when the sponsor company does not have a local party performing safety reporting submissions?
All clinical trials conducted in Singapore require a local sponsor. The local sponsor assumes responsibility for ensuring that safety reporting in clinical trials is in accordance with local regulatory requirements. Although the function of safety reporting submissions may be contractually delegated to a contract research organisation, the local sponsor assumes overall responsibility for ensuring that safety reporting submissions are performed in accordance with local regulatory requirements.
[J13] How can one gain access to ESR module in PRISM?
The CRIS administrator of your company must assign either drafter or submitter rights for the ESR module to you. Please note that if drafter role was assigned, the CRIS administrator will need to map the necessary protocols to the drafter/submitter for access. Please refer to our guidelines for mapping of ESR function.
[J14] In cases where safety reporting is done by the pharmacovigilance department of the sponsor company located overseas, can the reporting be done via ESR?
The overseas staff may gain access to ESR module by applying a HSA PIN. Please note that only drafter rights can be assigned to a HSA PIN holder and the submission must still be done by a Singpass holder. Information on how to apply for HSA PIN is available here.
[J15] If the local sponsor outsources the safety reporting to a CRO, how may the CRO use the online ESR module?
There are two options available:
- The local sponsor may provide drafter rights for ESR module to the CRO, who could then draft ESR applications and the local sponsor will automatically be informed through the system to proceed with the submission.
- The CRO may submit the safety reports in CIOMS format via email or fax.
The sponsor is encouraged to consider the first option as this will enable the safety reports to be captured in the PRISM system. It also allows immediate display acknowledgement of submissions of reports and provides a searchable electronic audit trial. Please note that submitter rights should not be provided to the CRO as this will allow the CRO to have access to all CTC applications filed under the sponsor company unless this has been contractually agreed by the companies.
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