All about regulation, pricing and reimbursement in Singaporean pharma. Prepared in association with Drew & Napier LLC, this is an extract from The Pharma Legal Handbook: Singapore, available to purchase here for USD 99.
1. What are the regulatory authorities with jurisdiction over drugs, biologicals, and medical devices in your country?
The key regulatory authority with jurisdiction over drugs, biological and medical devices in Singapore is the Health Sciences Authority (HSA). It was established on 1 April 2001 as a statutory board of the Ministry of Health under the Health Sciences Authority Act (Chapter 122C).
2. What is the regulatory framework for the authorization, pricing, and reimbursement of drugs, biologicals, and medical devices?
Therapeutic products (including biological therapeutic products)
Subject to certain prescribed statutory exceptions, all therapeutic products including biological therapeutic products that are imported or sold in Singapore must be registered with the HSA.
The HSA will generally register a therapeutic product if it is satisfied that:
- the overall intended benefits to a user of the therapeutic product outweigh the overall risks associated with the use of the therapeutic product; and
- the therapeutic product is suitable for its intended purpose and that any risk associated with its use is minimised, based on its formulation, manufacturing process controls, specifications and shelf life, as well as its stability under the recommended storage conditions.
The company seeking to market the therapeutic product in Singapore is responsible for obtaining product registration. This must be a locally registered company that will be responsible for the quality, safety and efficacy of the product. Therapeutic products must be marketed in accordance with the Health Products Act and the applicable subsidiary legislation.
For instance, the advertising of therapeutic products is subject to statutory and regulatory requirements and restrictions, such as:
- matters that must be excluded from advertisements of therapeutic products;
- restrictions on promoting therapeutic products for certain specified diseases and conditions;
- the general prohibition against advertising prescription-only medicines; and
- restrictions on the advertising of pharmacy-only medicines.
Biological therapeutic products are generally regulated in the same manner as other therapeutic products.
Dealers such as importers and wholesalers will need to obtain the relevant licence(s) from the HSA in order to import or supply by wholesale therapeutic products in Singapore.
In general, all medical devices (including in vitro medical devices) must be registered with the HSA by a locally registered company, before they can be supplied in the Singapore market. This is subject to certain exceptions, such as for the following types of medical devices:
- custom-made medical devices;
- medical devices which have underwent maintenance or repair;
- medical devices for patients’ use;
- Class A medical devices; and
- medical devices to be used in clinical research.
The HSA classifies medical devices into four risk level classifications, namely:
- Class A, for low risk devices, such as wheelchairs and tongue depressors;
- Class B, for low to moderate risk devices, such as hypodermic needles and suction equipment;
- Class C, for moderate to high risk devices, such as lung ventilators and bone fixation plates; and
- Class D, for high risk devices, such as heart valves and implantable defibrillators.
The risk classification for a medical device is based on several factors, including the duration of medical device contact with the body, the degree of invasiveness, whether the medical device delivers medicinal products or energy to the patient, whether the device is intended to have a biological effect on the patient, and its local versus systemic effects.
Similarly, in vitro medical devices are classified under one of the four different risk level classifications:
- Class A, for devices with low individual risk and low public health risk, such as specimen receptacles;
- Class B, for devices with moderate individual risk and/or low public health risk, such as Vitamin B-12, pregnancy self-testing, anti-nuclear antibody, and urine test strips; and
- Class C, for devices with high individual risk and/or moderate public health risk, such as blood glucose.
The classification of an in vitro medical device is determined based on a set of rules derived from those features that create risk, such as the intended purpose and indications for use as specified by the product owner; the technical, scientific or medical expertise of the intended user; the importance of the information to the diagnosis, taking into consideration the natural history of the disease or disorder including presenting signs and symptoms which may guide a physician; and the impact of the result to the individual and/or public health.
PRICING AND REIMBURSEMENT
The prices of therapeutic products (including biological therapeutic products) and medical devices are generally not regulated by the Singapore government. However, public sector hospitals in Singapore generally purchase medicinal products through centralised Group Procurement Offices (GPOs) by way of tender contracts, and this operates in some way to regulate the prices of therapeutic products and medical devices.
The national healthcare system in Singapore operates on mixed financing system that provides multiple tiers of financing for its citizens and residents. Apart from direct subsidies for services and drugs at public healthcare institutions, the Singapore government also administers a number of drug subsidy schemes. These include the Medication Assistance Fund (see Chapter 1, Question 10) and the Standard Drug List, to ensure that eligible patients have access to effective medications for medical conditions that are common in Singapore.
3. What are the steps to obtain authorization to develop, test, and market a product?
THERAPEUTIC PRODUCTS (including biological therapeutic products)
Registering a new therapeutic product generally involves the following steps (see the HSA’s Guidance on Therapeutic Product Registration in Singapore):
- pre-submission preparation/consultation;
- application submission;
- application screening;
- application evaluation;
- regulatory decision; and
- post-approval changes.
An application for new product registration can either be in respect of a new drug application (NDA) or a generic drug application (GDA). The GDA is generally available for a therapeutic product that contains one or more chemical entities that is essentially the same as a current registered product, in terms of its qualitative and quantitative composition of active ingredients, pharmaceutical dosage form and clinical indication. Follow-on biologic products, or biosimilar products, are not eligible for a GDA and are required to be submitted via a NDA.
The registration must undergo one of the following evaluation routes:
- Full route: applies to any new product that has not been approved by any drug regulatory agency at the time of submission.
- Abridged route: applies to any new or generic product that has been evaluated by at least one drug regulatory agency.
- Verification route: applies to any new or generic product that has been evaluated and approved by one of the HSA’s reference drug regulatory agencies, including Australia’s Therapeutic Goods Administration, the European Medicines Agency, Health Canada, the UK Medicines and Healthcare Products Regulatory Agency and the US Food and Drug Administration.
- Verification-CECA route: applies to any generic product manufactured in India that has been evaluated and approved by one of the HSA’s reference drug regulatory agencies, including Australia’s Therapeutic Goods Administration, the European Medicines Agency, Health Canada, the UK Medicines and Healthcare Products Regulatory Agency and the US Food and Drug Administration.
Application submission involves: (i) an online submission of the relevant application form through the HSA’s PRISM web portal; and (ii) the submission of the technical dossier.
The application will be screened to ensure that the correct application type has been selected and that the submitted dossier is complete. Where the HSA identifies deficiencies in the dossier, it will send a query stating the same to the applicant and put in place a stop-clock, which ends when the HSA receives a complete and satisfactory response.
Upon acceptance of the application, the HSA will begin its evaluation. Similarly, a stop-clock starts when the HSA issues a query to the applicant and ends when the HSA receives a complete and satisfactory response.
Where necessary, the HSA may involve external evaluators (whose identities will be kept confidential), experts (such as scientists and clinicians from both local and overseas institutions) and advisory committees. The external evaluators and experts will be contractually bound to protect information provided to them.
The HSA will make a regulatory decision following the conclusion of its benefit-risk assessment, based on the data submitted in support of the application.
The regulatory decision issued by the HSA will be one of the following:
- Approval, e., the application satisfies the registration requirements for quality, safety and efficacy. This is a final decision issued by the HSA.
- Approvable, e., the application can be approved subject to adequate response to minor deficiencies. The HSA will inform the applicant of the approval conditions, and the applicant will need to satisfy these conditions within a specified time period.
- Non-approvable, e., the application has major deficiencies. The HSA will inform the applicant of the deficiencies. Should the applicant wish to proceed with the application, it should respond within the specified time period based on the original data set submitted to the HSA.
- Rejection, e., the response provided by the applicant fails to address the major deficiencies specified in the HSA’s non-approvable decision. This is a final decision issued by the HSA.
Further, the HSA may register the product subject to post-approval commitments, in which case the applicant will have to furnish a letter of commitment setting out the undertakings concerned.
Following product registration, product registrants are responsible for ensuring the product’s quality, efficacy and safety throughout its life cycle, and must notify the HSA of any changes to the same.
The risk classification of a medical device (see Chapter 1, Question 2) will affect its registration requirements and the evaluation route that applies to such registration. The relevant product evaluation route will also depend on whether the medical device has received reference agency approvals (if any) and the prior safe marketing history of the medical device (if applicable).
- Class A medical devices are generally exempt from product registration requirements.
- Class B, C and D medical devices may have a complex registration process, especially if the abridged, expedited, or immediate route is not available for the device. Any medical device which has not obtained prior approval from any of the HSA’s reference agencies at the point of application is subject to a full evaluation.
- Class B medical devices may qualify for immediate registration if the device has obtained prior approval from any two of the HSA’s independent reference agencies for an intended use identical to that being submitted for registration in Singapore and has been marketed for at least three years in two of the independent reference regulatory agencies’ jurisdictions without quality, performance, efficacy or safety concerns.
- Class C standalone medical mobile applications which are medical devices may qualify for immediate registration if it has obtained prior approval from at least one of the HSA’s independent reference agencies at the point of application and has been marketed for at least three years in the independent reference regulatory agency’s jurisdiction without quality, performance, efficacy or safety concerns.
The medical device registration applications must be made as online submissions through the HSA’s MEDICS web portal. All information and documents submitted in support of the registration of Class B, C and D medical devices must be compiled in the ASEAN Common Submission Dossier Template format.
The processing of the application differs depending on the product evaluation route. For instance, Class B medical devices that qualify for immediate registration can be registered immediately and listed on the Singapore Medical Device Register within an hour.
4. What are the approximate fees for each authorization?
The product registration fees for therapeutic products and medical devices vary, depending on the type or risk classification of the product and the evaluation route.
For therapeutic products, the product registration fees comprise a screening fee of between S$500 and S$2,750, and an evaluation fee of between S$3,850 and S$82,500, depending on whether the application is an NDA or GDA, and the evaluation route used.
For medical devices, the application fee is S$500, and the evaluation fees (depending on the evaluation route) range from S$900 to S$75,000. Additional fees apply where the application is submitted for a full evaluation under the priority review scheme.
5. For how long are marketing authorizations/registrations valid? How are marketing authorizations/registrations renewed?
For both therapeutic products and medical devices, registration is generally valid for one year, and may be renewed upon paying an annual retention fee, unless the registration is suspended by the HSA, or cancelled by the HSA or the product registrant.
6.A. How does the authorization process differ between brand-name products and generic products? Are there differences for local manufacturers versus foreign-owned manufacturers?
A generic product is a therapeutic product that has the same qualitative and quantitative composition in active substances and is of the same pharmaceutical form and dosage as a currently registered product in Singapore. Such product must demonstrate bioequivalence to the Singapore reference product via appropriate bioequivalence studies.
A generic drug application (GDA) can apply for the registration of generic products (see Question 3 above). The fees for a GDA are generally lower compared to that for a new drug application (NDA), and the evaluation processing time is generally also shorter.
The application for therapeutic product or medical device registration can only be submitted by a locally registered entity.
Overseas manufacturers that intend to register their therapeutic products in Singapore are subject to a Good Manufacturing Practice (GMP) Conformity Assessment by the HSA. Overseas manufacturers must comply with Pharmaceutical Inspection Co-operation Scheme (PIC/S) GMP standard and can submit a valid GMP certificate or other evidence of GMP compliance from a PIC/S member authority. If such evidence is found to be acceptable, an audit by the HSA would not be necessary. Otherwise, the HSA will conduct an on-site GMP compliance audit of the applicant manufacturer.
7. How are combination products (drug + drug, drug + biologic, drug + device, biologic + device, drug + biologic + device) regulated?
Biological therapeutic products are subject to the same regulations as other therapeutic products. These regulations would similarly apply to combination products consisting of multiple biological and/or other therapeutic products.
Where a combination product comprises a medical device as well as a medicinal product, whether it will be regulated as a medical device or a therapeutic product is determined based on its primary mode of action (PMOA), i.e., the mode of action that makes the greatest contribution to the overall intended therapeutic purpose of the combination product.
The combination product will be regulated as a medical device under the Health Products Act where it does not achieve its PMOA in or on the human body by pharmacological, immunological or metabolic means. Examples of such products include drug eluting stents and dermal filler incorporating analgesic.
Medical devices incorporating registrable medicinal products are Class D medical devices. The Medical Devices Branch and the Therapeutic Products Branch of the HSA will jointly evaluate the product registration applications for such devices. Medical devices incorporating non-registrable medicinal products will be classified according to the risk class applicable to the medical devices.
8. How is compliance with regulation monitored and evaluated? Is the regulatory regime comparable with the U.S. Food and Drug Administration or the European Medicines Agency expectations and requirements?
The HSA has broad powers of investigation and enforcement under Part X of the Health Products Act, including the right to enter, inspect and search premises, as well as take samples for testing, examination or analysis without payment.
A person who furnishes to the HSA false or misleading information in a product registration application shall be guilty of an offence and shall be liable on conviction to a fine not exceeding $20,000 or to imprisonment for a term not exceeding 12 months or to both.
The US Food and Drug Administration and the European Medicines Agency are reference agencies of the HSA. Prior approval for a therapeutic product or medical device by the HSA’s reference drug regulatory agencies does not oblige the HSA to approve the application for product registration in Singapore, but such prior approval may allow an applicant to submit its application via a more simplified evaluation route for the Singapore registration.
9. What is the potential range of penalties for noncompliance?
Penalties for non-compliance with the regulatory requirements under the Health Products Act, which includes requirements on the manufacture, import, supply and advertisement of therapeutic products and medical devices in Singapore and the licensing of dealers of such products, include fines and/or imprisonment.
For instance, the failure to keep proper records relating to the manufacture, import, supply, use or administration of a therapeutic product (where applicable) is an offence which can attract a fine of up to S$10,000 and/or imprisonment for a term of up to 6 months. The supply of an unregistered therapeutic product or medical device is an offence which can attract a fine of up to S$50,000 and/or to imprisonment for a term of up to two years. A person who manufactures a counterfeit therapeutic product can be liable upon conviction to a fine of up to S$100,000 and/or imprisonment for a term of up to 3 years.
10. Is there a national healthcare system? If so, how is it administered and funded?
Yes. Singapore’s national healthcare system is funded by a mixed financing system, comprising multiple tiers of financing for Singaporeans’ healthcare expenditure.
There are broadly four tiers of healthcare funding, namely:
- Direct subsidies from the Singapore government for all Singaporeans, of up to eighty per cent (80%) of the total bill in acute public hospital wards;
- Medisave, which is a compulsory individual medical savings account scheme under which every working Singaporean as well as his employer must contribute a portion of his monthly wages into the account to save for his future medical needs;
- Insurance plans such as MediShield Life, which is a basic, low-cost medical insurance scheme for all Singaporeans and permanent residents, which helps to pay for large hospital bills and specified costly outpatient treatments, including dialysis and chemotherapy; and
- MediFund, which is a medical endowment fund established by the Singapore government to further aid needy Singaporean patients who are unable to pay for their remaining medical bills even after using other means of payment (including the abovementioned tiers of financing).
In addition, the Singapore government also administers several other subsidy schemes, such as:
- Community Health Assist Scheme: Common outpatient medical treatment and basic dental services are provided at subsidised rates to needy elderly or disabled patients by general practitioners and dental clinics that have agreed to partner with the MOH.
- Interim Disability Assistance Programme for the Elderly: Financial help is provided to certain disabled elderly Singapore citizens.
- Medication Assistance Fund: Subsidies are provided for certain drugs at public hospitals, specialist outpatient clinics and polyclinics.
11. How does the government (or public) healthcare system function with private sector healthcare?
Singapore adopts a mixed delivery healthcare model, with primary healthcare services, acute hospital services and step-down care services being offered by healthcare providers in both the public and private sectors. Briefly, the distribution of services provided by the public and private sectors is as follows:
- Primary care sector: Private sector providers account for around 80% of the market.
- Acute care sector: Public sector providers account for around 80% of the market.
- Step-down care sector: Voluntary welfare organisations, most of which are funded by the government for services provided, account for a majority of the market.
12. Are prices of drugs and devices regulated and, if so, how?
The prices of therapeutic products (including biological therapeutic products) and medical devices are generally not regulated by the Singapore government, though prices in the public sector may be indirectly regulated through the purchasing of drugs and devices through centralised Group Procurement Offices (GPOs) by way of tender contracts.
13. How are drugs and devices used by patients paid for? What roles do public and private payers play?
The national healthcare system in Singapore operates on mixed financing system that provides multiple tiers of financing for its citizens and residents (see Question 10 above). Government subsidies are available for certain drugs at public sector healthcare institutions, for instance, drugs under the Standard Drug List. Private insurers may provide reimbursement for the cost of drugs and medical devices, depending on the specific terms of the relevant policies.
14. Who dispenses drugs and devices to patients and how are those dispensers compensated?
The persons who can dispense drugs and sell medical devices to patients depends on the relevant classification of the drug or device.
For therapeutic products:
- prescription-only medicines (POMs) can only be supplied by a doctor or dentist, or by a pharmacist at a retail pharmacy according to a prescription by a doctor or a dentist;
- pharmacy-only medicines (P-Medicines) can be supplied by or under the supervision of a pharmacist without a prescription; and
- general sales list (GSL) medicines can be purchased from any retailer;
For medical devices:
- “professional use only” medical devices can only be supplied to a licensed wholesaler of medical devices or a qualified medical or dental practitioner; and
- “trained user only” medical devices can only be supplied to a person who has been provided with training on the safe and efficacious use of the medical device as the manufacturer of the medical device determines is necessary.
The Singapore Government provides subsidies for certain drugs, such as those on the Standard Drug List, dispensed through the public sector hospitals.
15. What are the professional and legal responsibilities of those who dispense drugs and devices? What role do they play in providing patient care, information, and safety?
Under regulation 17 of the Health Products (Therapeutic Products) Regulations 2016, a qualified practitioner or collaborative prescribing practitioner (or a person acting under the supervision of the same) or a qualified pharmacist (or a person acting under the supervision of the same) may dispense a therapeutic product only if the package or container of the therapeutic product is labelled with all of the following information in English:
- the name of the person to whom the therapeutic product is to be administered;
- the name, address and any identification number or logo of the licensed healthcare institution or licensed retail pharmacy where the therapeutic product is supplied or dispensed;
- the date that the therapeutic product is dispensed;
- the directions for use of the therapeutic product;
- the name of the therapeutic product, being either the proprietary name or the appropriate non-proprietary name; and
- where the appropriate non-proprietary name is included on the label, the appropriate quantitative particulars of any active ingredient of the therapeutic product.
Under regulation 15 of the Health Products (Medical Devices) Regulations 2010, any person supplying a medical device must ensure that it is accompanied with the following information:
- the trade or brand name of the medical device;
- where the medical device is supplied for use in any investigational testing, the statement “For Clinical Trial Use” or any other statement in English that conveys the same meaning;
- where the medical device is contained in a package and the contents of the package are not readily apparent, an indication of what the package contains, expressed in terms appropriate to the medical device, such as the size, net weight, length, volume or number of units;
- the expiry date of the medical device, if the medical device has one, as determined by the product owner of the medical device on the basis of the component of the medical device that has the shortest projected useful life;
- the product owner’s name or trading name, address, telephone number and electronic mail address; and
- an appropriate control number, such as a batch code, lot number or serial number.
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