The regulatory regime
Control of all medicinal products, devices and substances falls under the purview of the HSA. The HPA governs the regulation of therapeutic products, medical devices and cosmetic products as part of the HSA's continuing efforts to consolidate the regulation of health products into one Act. The MA regulates medicinal products (such as cell, tissue and gene therapy products and complementary health products, including traditional medicines, homeopathic medicines and quasi-medicinal products). The Poisons Act regulates specific substances (excluding use in medicines supplied by medical practitioners), whereas the Sale of Drugs Act regulates the sale of any substance or mixture of substances used as a medicine.i Classification
As mentioned above, the regulatory regime classifies relevant products into the following categories: medicinal products used to treat or prevent disease, to diagnose disease, for contraception, to induce anaesthesia, etc.; medical devices used for the diagnosis, prevention, monitoring, treatment or alleviation of disease not through pharmacological, immunological or metabolic means; cosmetic products used on the external parts of the human body to clean, perfume, change appearance, etc.; therapeutic products used for a therapeutic, preventive, palliative or diagnostic purpose that is constituted by certain specified chemical and biological active ingredients, etc.; complementary health products, including Chinese proprietary medicines and traditional medicines.
Food and supplements of a food nature (including food-based complementary health products) are under the purview of the Agri-Food and Veterinary Authority (AVA) and regulated under the Sale of Food Act (Chapter 283). If there is ambiguity in classifying a product as a food or health product, clarification should be sought from either the HSA or the AVA, depending on whether the product appears to be part of a daily diet, taken as supplement to a diet, or taken for medicinal purposes.
For devices used primarily for aesthetic purposes (e.g., lasers for skin tightening and dermabrasion), the Aesthetics Practice Oversight Committee (APOC) has revised its Guidelines of Aesthetic Practices (the APOC Guidelines), which doctors have to abide by to carry out any of the procedures listed therein. The list of invasive treatments that non-specialists can perform has been reduced under Table 1 of the APOC Guidelines, compared to its predecessors in 2008. Additionally, the list of invasive surgeries, previously under List A, is now reflected in Table 2, with a clear list of specialists who can perform the procedure. List B procedures under the 2008 Guidelines are now disallowed unless performed in the context of a formal and approved clinical trial. Doctors intending to perform procedures or use devices outside Table 1 or 2 have to apply to the APOC to include the procedure or device under Table 1 or 2 before doing so.ii Non-clinical studiesIn vitro human biomedical research
The HBRA, which regulates the conduct of human biomedical research, first came into force on 1 July 2016 (the first phase) and will continue to be enforced in stages. On 1 January 2017, provisions prohibiting the commercial trading of, and the advertising of commercial trading of, human tissue came into force (the second phase). Notably, commercial trading of human tissue was outlawed and offenders may be fined up to S$100,000 or imprisoned for up to 10 years, or both. In the third phase, which commenced on 1 November 2017, provisions on the regulation of human biomedical research took effect. These include the taking of consent, and the constitution of institutional review boards (IRBs) in relevant research institutions as part of the system of 'self-accountability' for reviewing research proposals.
In the next phase (the fourth phase), provisions on the regulation of human tissue research have been targeted to be brought into force in the first half of 2019. These are expected to include regulations pertaining to the duties of tissue banks, restrictions on disclosure of information on tissue donors, among other things. Other provisions of the HBRA relate to codes of practice and ethics, and enforcement powers with respect to activities that contravene the HBRA or any relevant codes of practice or ethics or are contrary to public interest.
Subsidiary legislation regulating human biomedical research includes the Human Biomedical Research Regulations 2017 and the Human Biomedical Research (Restricted Research) Regulations 2017. Read with the HBRA, this legislation cumulatively regulates the conduct of human biomedical research, and subjects certain types of research to stricter controls, such as research involving human eggs or embryos, human-animal combination embryos, and the introduction of human stem cells (pluripotent or not) into animals. Ethically unacceptable human biomedical research, such as the implantation of human-animal embryos into both human beings and animals, is also prohibited under the legislation.
The BAC (appointed by the Singapore Cabinet) released its Ethics Guidelines for Human Biomedical Research in June 2015. These Ethics Guidelines do not have statutory force, but operate alongside the more recent HBRA subsidiary legislation to provide guidance and emphasise the fundamental principles of solidarity, respect for persons, justice, proportionality, sustainability, beneficence and research integrity.
For the creation of human embryos under the Human Cloning and Other Prohibited Practices Act (Chapter 131B), the development of a human embryo created other than via fertilisation of a human egg by human sperm, for a period of more than 14 days, is prohibited.
Written approval from the Director of Medical Services must be obtained for all research involving human embryos, human oocytes and human-animal combination gametes or embryos.Animal models
Any research facility that uses animals for scientific purposes must obtain a licence from the AVA. Further, the research facility must comply with the National Advisory Committee for Laboratory Animal Research Guidelines on the Care and Use of Animals for Scientific Purposes, and establish an Institutional Animal Care and Use Committee to oversee and evaluate the animal care and use programmes of an institution.
Singapore adheres to the Organisation for Economic Co-operation and Development (OECD) Mutual Acceptance of Data scheme. Acceptance of this harmonising scheme amounts to an endorsement that Singapore-generated research data complies with the OECD's Principles of Good Laboratory Practice. Such data can be accepted automatically by other OECD countries, facilitating the sharing of research.iii Clinical trialsTherapeutic and medicinal products
The Health Products (Clinical Trials) Regulations 2016 introduced a new assessment regime for clinical trials. A clinical trial of a therapeutic product may either require a clinical trial authorisation (CTA) or a clinical trial notification (CTN), depending on the risk classification of the therapeutic product. A high-risk therapeutic product is a product that is locally unregistered or its use is unapproved, and therefore requires a CTA. Low-risk therapeutic products only require a CTN, as the products have already been reviewed by the HSA for product registration. A CTN can be obtained in a shorter time than a CTA because low-risk therapeutic products undergo a simplified regulatory screening and verification process. For the clinical trial of medicinal products, a Clinical Trial Certificate (CTC) in accordance with the Medicines Act is still necessary.
Under the CTC and CTA/CTN regimes for medicinal products and therapeutic products respectively, a sponsor is mandatory. Insurance must be maintained to provide for compensation in the event of injury or loss.Medical devices
A CTC or a CTA/CTN is not necessary for studies assessing the safety, performance or effectiveness of a medical device. Prior approval by each institution's IRB is, however, still required. The Health Products (Medical Device) Regulations (HP(MD)R) also regulate the use of medical devices in clinical trials.Ethical considerations
The ECEG 2016 stipulates that a doctor must not offer patients remedies that are not generally accepted by the profession, except in the context of a formal and approved clinical trial. The term 'remedy' encompasses a broad range of treatments, including the use of medical devices. Under the ECEG 2016, doctors may offer innovative therapy to patients in desperate or dire situations, and where conventional therapy is unhelpful. Patients' informed consent must be obtained; failing to do so can result in the doctor being struck off the Singapore Register of Medical Practitioners. The ECEG 2016 further mandates that any medical research must be approved by an ethics committee and conform to the Singapore Guidelines for Good Clinical Practice.
Additionally, the HSA's Guideline on Alternative Measures for Investigational Product Management for Investigator-Initiated Clinical Trials helps to overcome difficulties faced in managing investigational products without contravening the principles of the aforementioned Guidelines for Good Clinical Practice.iv Named-patient and compassionate-use procedures
The Health Products (Therapeutic Products) Regulations (HP(TP)R) allow imports of therapeutic products for use on a named-patient exemption basis. Under this exemption, the importer's and wholesaler's licences are not required for the import of an unregistered therapeutic product that is required by a healthcare institution or a pharmacy holding the relevant licences or a qualified practitioner. However, prior approval from the HSA must be sought. For a company acting on behalf of a hospital or clinic to import therapeutic products on this exemption basis, the importer's and wholesaler's licences must still be obtained.
The HSA's Guidance on the Requirements for Exemption from Product Registration for Import of an Unregistered Medical Device for Supply on a Named-Patient Basis further allows licensed qualified practitioners to seek approval for the supply of unregistered medical devices in an emergency, or in circumstances in which conventional therapies have failed. These applications are made to the HSA and the HSA's approval is conditional upon, inter alia, the requirement to report adverse events arising from the use of such medical devices.v Pre-market clearanceTherapeutic products
Therapeutic products are divided into two broad categories for registration in Singapore: a new drug application (NDA) and a generic drug application (GDA). Pursuant to the Guidance on Therapeutic Product Registration in Singapore, companies are subject to screening and regulatory evaluation before obtaining a licence for a therapeutic product.
Depending on whether the NDA or GDA has been previously evaluated and approved, as well as the subcategory of the NDA or GDA, the screening and evaluation fees may be abridged.
Applicants seeking approval for an NDA that has been approved by at least one drug regulatory agency at the time of submission may also apply for priority review, which will be granted if the drug is intended for treatment of a serious life-threatening condition and can potentially address local unmet medical needs; or there is currently a local public health concern.Medical devices
The HPA and HP(MD)R require medical devices, other than those exempted in the aforesaid regulations, to be registered with the HSA prior to being placed on the Singapore market. There are four risk classes for the classification of general medical devices.
There were several notable amendments to the HP(MD)R that came into force in 2018. Product registration is no longer required for Class A medical devices (low-risk) that are manufactured, imported or obtained from a validly licensed manufacturer, importer or supplier. An abridged evaluation process for registration has been provided for the other three classes, to allow faster market access. New categories of exceptions for the manufacture of medical devices without a licence have been introduced, namely for clinical labs already licensed under the PHMCA, and where the supply of medical devices is intended for charitable purposes. The category of implantable medical devices has been expanded to include orthopaedic, neurological, breast, intraocular and cardiovascular implants. In another amendment, wellness devices have been expressly excluded from the HP(MD)R.
All medical devices must adhere to the Essential Principles for Safety and Performance for Medical Devices in the First Schedule to the HP(MD)R prior to their placement on the Singapore market. Requirements under all applicable legislation for the supply and use of any medical devices must also be met. Additionally, for medical practitioners, the APOC Guidelines set out the minimum level of competence required for the operation of certain medical devices in aesthetic procedures.
The Association of Southeast Asian Nations (ASEAN) has developed a standardised framework for regulating medical devices – the ASEAN Agreement on Medical Device Directive (AMDD). Under the AMDD, only registered medical devices that conform to its standards are allowed in the Member States' markets. The standardisation of regulation allows for the efficient trading of medical devices among ASEAN states, though it should be noted that the AMDD has yet to be fully implemented as Member States are still aligning the AMDD with their local legislation. Additionally, the ASEAN Product Working Group for Traditional Medicines and Health Supplements was established in 2004 with the aim of harmonising technical requirements, exploring possible mutual recognition arrangements and eliminating technical barriers to trade for traditional medicine and health supplements without compromising the health and safety of the users. Once these harmonisation efforts come to fruition, life sciences companies will enjoy easier access to the entire ASEAN market.Cosmetic products
With the implementation of the ASEAN Cosmetic Directive, manufacturer and import licences are no longer required. Instead, the HSA must be notified before the supply or sale of the cosmetic product. Acknowledgement of a product notification does not constitute an agreement that the product has met all regulatory requirements. The onus is on the company responsible for placing the product on the market to ensure that it meets the requirements of the ASEAN Cosmetic Directive. Only a Singapore-registered company can file a product notification, subject to payment of varying fees based on the risk level of the cosmetic products.Traditional medicines, homeopathic medicines and health supplements
Traditional medicines (e.g., traditional Malay and Indian medicines), homeopathic medicines and health supplements are not subject to pre-marketing approval or licensing for their import, manufacture or sale in Singapore. Dealers and sellers of this category of medicines are responsible for ensuring their safety and quality.Chinese proprietary medicine
Under the Medicines Act, Chinese proprietary medicine dealers must obtain approval from the HSA prior to the import, export, sale or supply of Chinese proprietary medicine.Biosimilar medicinal products
To be registered as a biosimilar medicinal product, the product must fall under the definition of a 'biosimilar product' in the HSA's Guidance on Registration of Biosimilar Products in Singapore. Typically, a biosimilar product is eligible for registration through an abridged evaluation route.vi Regulatory incentives
The Patents Act (Chapter 221) allows for a one-off patent extension of up to five years for pharmaceutical products in a limited exception.
The HP(TP)R and MA provide for a data exclusivity regime over a five-year period. The data provided by the company to the HSA is protected by the HSA, which is obliged to take reasonable steps to ensure that the data submitted remains confidential and is not used when evaluating the grant of any other application.
Under the Inland Revenue Authority of Singapore's Productivity and Innovation Credit Scheme (the PIC Scheme), businesses may receive a tax deduction of up to 400 per cent or allowances of up to S$400,000 (the cap) of their expenditure per year in research and development (R&D) from the years of assessment 2011 to 2018. R&D expenditure exceeding the cap will enjoy a tax deduction of 150 per cent if the R&D is done in Singapore. Any other R&D expenditure, including expenditure of R&D carried out overseas, will enjoy a tax deduction of 100 per cent. Accordingly, businesses engaged in R&D of new drugs may enjoy substantial tax benefits under the PIC Scheme.vii Post-approval controlsTherapeutic products
The product licence holder must put in place a system to ensure responsibility and liability for its products on the market and be able to take appropriate action, if necessary. For therapeutic products, the duty to maintain records and report defects and adverse effects is now required by legislation. Every manufacturer, importer, supplier or registrant of a therapeutic product must report the defect to the HSA as soon as it is identified.
Under the HPA and MA, the HSA has the power to suspend, revoke or vary licences. A licence may be revoked at the request of the licence holder, or if the HSA is satisfied that there is an infringement of a patent, or if there was fraud or misrepresentation in the application process.Medical devices
Registrants of medical devices are required to notify the HSA of any changes to particulars provided in relation to the registration of the medical devices, or changes that may affect the safety, quality or efficacy of a registered medical device. In addition, registrants must report any defects or adverse effects that occur in connection with the medical device.
The HSA may also suspend or cancel the registration of a health product (including medical devices) if there is suspicion of fraud or misrepresentation in the first instance or safety concerns in the use of the health product.Cosmetic products
The manufacturer, importer, supplier or registrant of a health product or any cosmetic product has a duty to inform the HSA in the event of any defect or adverse effect arising from the use of the health product. Further, persons or companies supplying a product to the market must retain a product information file, which includes key information about the product's composition and safety assessments.
As with other health products, the HSA has the power to suspend, cancel or reclassify the registration of cosmetic products, as set out above.viii Manufacturing controls
A valid licence from the HSA is required for the manufacturing of health products and medicinal products under the HPA and MA respectively. For therapeutic products, under the HP(TP)R, a manufacturer's licence will only be granted when the manufacturing facilities have been audited and found to comply with the Pharmaceutical Inspection Convention or Cooperation Scheme Guide to Good Manufacturing Practice for Medicinal Products. For medical devices, an ISO 13485 certificate for finished medical device manufacturing is required to obtain a manufacturer's licence. Additionally, a manufacturer of medical devices must comply with the requirements set out in the First Schedule to the Health Products (Medical Devices) Regulations 2010.
Cosmetic products manufactured in Singapore must comply with Appendix VI of the ASEAN Cosmetic Documents entitled 'ASEAN Guidelines for Cosmetic Good Manufacturing Practice'.ix Advertising and promotion
It is an offence under the HPA and MA to issue false or misleading advertisements relating to therapeutic products or medicinal products.
Unlike medicinal products, prior approval from the HSA is not required for advertisements relating to therapeutic products. Advertisement of therapeutic products is governed by the HPA and the Health Products (Advertisement of Therapeutic Products) Regulations (HP(ATP)R). The onus is on the advertiser to ensure compliance with rules under the HP(ATP)R, with the HSA undertaking a monitoring role to ensure due compliance. Advertisements for both medicinal products and therapeutic products must not claim to prevent, alleviate or cure certain diseases or conditions specified in the First Schedule to the MA and the Second Schedule to the HP(ATP)R respectively.
Advertisements and promotions of medical devices also do not require prior approval from the HSA, but such advertisements must not be false or misleading, and must be capable of verification by objective evidence, pursuant to the HP(MD)R.
With regard to cosmetic products, advertisements cannot include claims that they have therapeutic benefits or can be used for therapeutic purposes, nor can they create an erroneous impression regarding the formulation, composition, quality or safety of the product.
The ECEG 2016 also prohibits doctors from associating themselves with 'parties that do not provide legitimate medical or medical support services in a way which could mislead the public into believing that any of the services are medically endorsed'. Doctors are only allowed to promote food, vitamins, tonics and health and nutrition supplements if there is sufficient scientific basis or if they are generally accepted by the medical profession.x Distributors and wholesalers
Any person (except for licensed manufacturers) must apply for the relevant wholesaler's licence for the resale of registered therapeutic products or medical devices or wholesale dealer's licence for medicinal products. A licensee for a therapeutic product must appoint a responsible person to ensure compliance with the HSA's good distribution practice (GDP). The licence for medicinal products will only be granted if the company has been audited and found to comply with the HSA's GDP.
With regard to medical devices, a wholesaler must possess either a GDP for medical devices certificate or ISO 13485 certificate with the scope for storage and distribution. A licensed local manufacturer does not require a wholesaler's licence to supply, by wholesale, any medical devices it manufactures.
In respect of cosmetic devices, the company responsible for supplying the cosmetic product in the market must notify the HSA before doing so.xi Classification of products
The classification of therapeutic products is carried out by the Therapeutic Products Branch, a department of the HSA. Therapeutic products are classified under three forensic classes: prescription-only medicines, pharmacy-only medicines and general sales list medicines.
Therapeutic products may be reclassified if the product has been deemed sufficiently safe for use with reduced, or without, medical supervision. The reclassification may be effected by an application by the party who registered the therapeutic product or through legislative mechanisms.
Introduced in 2018, the collaborative prescribing service will allow collaborative prescribing practitioners (e.g., accredited pharmacists and nurses) to prescribe and dispense pharmacy-only and prescription-only medicines without having a medical practitioner sign them off. This will save both time and costs for patients and also ease the patient load on the already stretched healthcare system.xii Imports and exports
Under the HPA, a person must now obtain an importer's licence to import therapeutic products or medical devices, and a wholesaler's licence to export them. Importers and exporters of therapeutic products must also appoint a person to be responsible for ensuring compliance with the HSA's GDP standards. This requirement of a responsible person does not extend to importers and exporters of medical devices, although they must possess either a GDP for medical devices certificate or ISO 13485 certificate with the scope for storage and distribution. Companies applying for an importer's or wholesaler's licence for therapeutic products for patients' use or restricted activities between 1 November 2016 and 31 October 2019 are eligible for a fee waiver to facilitate the adoption of this new regulatory regime.
Imports and exports of medicinal products remain under the purview of the MA, and importers of such products require either a product licence or an import licence, while exporters require a product licence.xiii Controlled substances
As a party to both the 1961 United Nations Single Convention on Narcotic Drugs and 1971 United Nations Convention on Psychotropic Drugs, Singapore conforms to the international control measures provided in both conventions. The Misuse of Drugs Act makes it an offence to import, export or traffic controlled drugs, or to import, export or supply controlled equipment, materials or substances if one knows or has reason to believe that they are to be used in or for the manufacture of a controlled drug.
To import or export controlled drugs and psychotropic substances or medicinal products with psychotropic substances, an applicant must obtain an import or export licence from the HSA, and the purpose of the import or export will be assessed before the licence is processed and issued.xiv Enforcement
The HSA has the right of entry into premises for the purpose of ascertaining whether there is, or has been, any contravention of the MA. Any duly authorised person has the power to inspect, take samples and seize goods and documents to ascertain whether any contravention of the MA has taken place.
Under the HPA, an enforcement officer may, at any time and without warrant, enter, inspect and search a premise if there is reason to suspect a contravention of the HPA. The enforcement officer may also seize items, require a person to furnish information or documents in his or her knowledge, or arrest, without warrant, a person who is believed to have committed an offence under the HPA.
With regard to private hospitals and medical clinics, the MOH's Director of Medical Services or any authorised enforcement officer may, at any time and without warrant, enter, inspect and search any premises if there is reasonable cause to suspect a contravention of the Private Hospitals and Medical Clinics Act (Chapter 248), or to assess the quality and appropriateness of the services provided, and the practices carried out in those establishments, including clinical laboratories.