The Pharma Legal Handbook: Singapore

A brief overview of the situation regarding biosimilars & biologics 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. Are biosimilar medicines considered the same as generic medicines in your country?

Biosimilar medicines are not considered the same as generic medicines. According to the Health Sciences Authority of Singapore (“HSA”), biologics are medicinal products with large complex molecules produced by living cells through highly specific processes. Even a slight change in the manufacturing process can vary the structure of the biologic compound and consequently impact the efficacy, safety and quality of the biologic medicine. Biosimilars are then ‘follow-on’ versions of biologic medicines, which are required to show similarity in physical and chemical characteristics, biological activity, safety and efficacy to the first approved biologic medicine.

On the other hand, generic medicines are small molecule chemical medicines such as paracetamol, for which the manufacturing process can be replicated to produce an identical copy.

Accordingly, different application and processes are required depending on whether the medicine is a biosimilar or a generic drug. Biosimilars are required to be submitted as new drugs under the new drug application (NDA) via NDA-2 or NDA-3. They are not eligible for a generic drug application (GDA) for which only therapeutic products that contain one or more chemical entities and is essentially the same as a current registered product (Singapore Reference Product) in terms of its qualitative and quantitative composition of active ingredients.

 

2. Are all biologic medicines, including biosimilar medicines patentable in your country?

Yes, subject to requirements for patentability under the Patents Act (Cap. 221) of Singapore (“Patents Act”).

 

3. Is there a specific regulatory framework for the marketing authorization of biosimilar medicines in your country? If yes, what is the regulatory framework for the authorization of biosimilar medicines?

The biosimilar medicine is subject to the same regulatory framework as all other therapeutic products in Singapore, i.e. the Health Products Act 2016 and the Health Products (Therapeutic Products) Regulations 2016 (Cap 122D). Companies are required to obtain a dealer’s licence before manufacturing, importing or supplying therapeutic products, and all therapeutic products must be registered with the HSA before they can be supplied in Singapore.

However, the application for a biosimilar product differs from that of other therapeutic products as it can only be registered for as a biosimilar if it is similar to an existing biological product registered in Singapore in terms of physicochemical characteristics, biological activity, safety and efficacy. It is to be submitted as a new drug application (NDA) via the abridged evaluation route, either through NDA-2, for the first strength of a biosimilar product with the same dosage form and route of administration as the Singapore reference biological product, or NDA-3, for subsequent strengths of a biosimilar product that has been registered or submitted as an NDA-2. The administrative requirements are as per those required for an NDA via the abridged evaluation route. There must also have been a comprehensive comparability exercise done with the reference product.

Further, Singapore’s patent linkage system links the marketing approval of drugs to whether there is a relevant patent in force corresponding to the originator’s drug. If there is a relevant patent, applicants have to declare it to the HSA.

 

4. What kind of data package is needed to obtain approval for a biosimilar drug? Is this any different to the requirements for the original Biologics drug?

All therapeutic drugs including both the biosimilar and the original biologics drugs require their application to be approved by the HSA. However, if the original biologics drug contains a new biological entity, an application under NDA-1 is required, while a biosimilar, which contains no new biological entity from its reference product, can apply as either NDA-2 or NDA-3. For an NDA-1 application, it must go through the full evaluation route, which requires

• Administrative documents,
• common technical documents,
• quality documents,
• non-clinical documents and
• clinical documents to be provided.

For an NDA-2 or NDA-3 application, while administrative, common technical and quality documents are required, only an overview of non-clinical documents need to be provided if organized in the ASEAN Common Technical Document (CTD) format, and not at all if organized in the International Council for Harmonisation CTD. However, non-clinical studies should have been performed before initial clinical development, and the studies should be comparative in nature and designed to detect differences in response between the biosimilar product and reference biological products.

As for clinical reports, the requirements depend on the existing knowledge of the reference biological therapeutic product and the claimed therapeutic indication(s). Available product/disease specific guidelines should be followed when appropriate and relevant international guidelines should be referred to in the design of an appropriate clinical study programme for biosimilar products.

 

5. What are the requirements for the choice of the reference comparator product?

The reference comparator product must be a Singapore Reference Biological Product (SRBP). A registered biosimilar product cannot be used as a reference product. A biological product with no suitable SRBP will not qualify for registration as a biosimilar product in Singapore.

Similarity to the Singapore reference biological product (SRBP) needs to be established using a comprehensive comparability exercise based on:

• Quality characteristics
• Biological activity
• Safety
• Efficacy

The same chosen reference product should be used throughout the comparability assessment for quality, safety and efficacy studies during the development of a biosimilar product in order to allow the generation of coherent data and conclusions.

The chosen reference product used should be of the corresponding strength and from the Singapore registered drug product manufacturing source.

The active substance of a similar biological medicinal product must be similar, in molecular and biological terms, to the active substance of the reference medicinal product.

The pharmaceutical form, strength, and route of administration of the similar biological medicinal product should be the same as that of the reference medicinal product.

When the pharmaceutical form, the strength or the route of administration is not the same, additional data in the context of the comparability exercise should be provided.

Any differences between the similar biological medicinal product and the reference medicinal product will have to be justified by appropriate studies on a case-by-case basis

The conditions of use for the biosimilar product must fall within the directions for use including indication(s), dosing regimen(s) and patient group(s) for the Singapore registered reference product.

 

6. Can the comparator product be sourced from another regulatory jurisdiction? If yes, what are the data needed to support this approach?

The chosen reference medicinal product must be a medicinal product registered in Singapore. Data generated from comparability studies with medicinal products registered in other countries may only provide supportive information.

If comparative studies are performed with a reference biological product from a non-Singapore registered manufacturing source, the manufacturer needs to demonstrate that the reference biological product (“RBP”) is comparable to the Singapore reference biological product (“SRBP”) and hence suitable to support the application for marketing authorisation of a biosimilar product by providing an additional bridging study. The type of bridging data needed will typically include data from analytical studies (e.g. structural and functional data) that compare all three products (the proposed biosimilar product, the SRBP and the RBP), and may also include clinical pharmacokinetics (“PK”) and/or pharmacodynamics (“PD”) bridging studies data for all three products. All comparisons should meet the target acceptance criteria for analytical and PK/PD similarity which will be determined on a case-by-case/product-type basis. A final determination regarding the adequacy of the scientific justification and bridging data will be made during the evaluation of the application.

 

7. How are the prices of biosimilar medicines regulated? Is this any different to the requirements for the original Biologics drug?

The prices of therapeutic products (which include biological and biosimilar 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 by way of tender contracts, and this operates in some way to regulate the prices of therapeutic products and medical devices.

 

8. What is the reimbursement policy for biosimilar medicine? Is this any different to the requirements for the original Biologics drug?

There is no specific reimbursement policy for biosimilar medicine or biologics drugs. However, the Ministry of Health provides subsidies for drugs at its public hospitals, specialist outpatient clinics and polyclinics. Patients receive drug subsidies and assistance based on their subsidy and means-test status, and the scheme under which the drug is covered. Various schemes cover different drugs and their active ingredients, including the Standard Drug List (SDL) and the Medication Assistance Fund (MAF).

Further, the national healthcare system in Singapore is funded by a mixed financing system that provides multiple tiers of financing for its citizens’ healthcare expenditure. The four tiers of healthcare funding are direct subsidies from the government, Medisave, Medishield Life and Medifund.

The government also administers a number of other subsidy schemes, such as the Community Health Assist Scheme, the Interim Disability Assistance Programme for the Elderly and the Medication Assistance Fund. These three schemes, respectively, subsidise primary healthcare, provide financial assistance to disabled elderly persons, and subsidise certain drugs.

 

9. Does biosimilar competition impact the reimbursement policy of the originator reference products?

The subsidy scheme in Singapore is based on the active ingredient of the drug. If the active ingredients are those listed in the register under the Ministry of Health, the drug is available for a subsidy regardless of whether it is a biosimilar or the original reference product.

 

10. What is the legal framework for biosimilar medicines prescribing (clinical decision maker) and dispensing (pharmacy level, hospital or retail)? Is this any different to the requirements for the original Biologics drug?

The Health Products (Therapeutic Products) Regulations 2016 (Cap. 122D) (“TPR”) deals with the prescribing and dispensing of therapeutic products, including biosimilars and biologics. There is no difference between the requirements for the two types of drugs.

Prescription

Section 12(a) of the TPR requires a person to be a qualified practitioner or collaborative prescribing practitioner, or a person acting in accordance with the oral or written instructions of a qualified practitioner or collaborative prescribing practitioner to administer prescription-only medicine. Exceptions under section 12(b) of the TPR are listed in the first column of the Third Schedule, which includes persons requiring prescription-only medicines in order to comply with any requirements made by written law with respect to the medical treatment of their employees.

Dispensation

Section 11 of the TPR prevents a person from supplying prescription-only medicine by retail sale unless the supply is made at or from a licensed healthcare institution supplying the prescription‑only medicine to a patient of that healthcare institution, and in accordance with the written instructions of a qualified practitioner or collaborative prescribing practitioner practising in that healthcare institution. The person supplying the medicine must be a qualified practitioner or collaborative prescribing practitioner, or a person acting in accordance with the oral or written instructions of a qualified practitioner or collaborative prescribing practitioner, and the supply must be made to a patient under the care of the qualified practitioner or collaborative prescribing practitioner.

Section 2 of the TPR defines a licensed healthcare institution as a healthcare institution that is licensed under the Private Hospitals and Medical Clinics Act (Cap. 248) of Singapore.

A retail pharmacy must obtain a license from the Health Sciences Authority before they can retail therapeutic products classified as prescription-only medicines or pharmacy-only medicines, as prescribed by the Health Products (Licensing of Retail Pharmacies) Regulations 2016 (Cap. 122D).

 

11. Is the system considering physician-led switching and/or pharmacy-level substitution (without involvement of the clinical decision maker)?

As at the date hereof, there is no such publicly available information.

 

12. What are the post – authorisation requirements (including pharmacovigilance, risk management plans, post-approval studies) for biosimilar medicines? Is this any different to the requirements for the original Biologics drug?

Pharmacovigilance

At the time of market approval for a medicinal product, information on the safety of the product is relatively limited, and there are some potential risks which may not have been identified. For biosimilar products, there is also the concern on potential immunogenicity issues. Therefore, post-market monitoring of clinical safety for biosimilar products is necessary as with all medicinal products, with focus on the specific concerns for biosimilar products.

Risk Management Plans (RMP)

RMP documents in support of NDA-1 original biologic product applications and all biosimilar product applications should be provided as part of the application dossier at the point of application submission, and not as part of the post-authorisation measure.

The RMP documents should include the following:

1. Singapore-Specific Annex (SSA);
2. Latest version of the approved EU-RMP and/or US REMS (where available); and
3. Proposed local RMP materials (e.g. draft educational materials, if any).

If the original biologics drug is going through an NDA-2 application, RMP documents may be requested by the HSA on a case-by-case basis, but need not be part of the application dossier. The request for RMPs may be in response to a new safety concern arising from a new route of administration.

Post Approval Studies

Biosimilar products are subjected to a risk-based post-approval batch release programme. The product licence holder would be required to submit batch quality documents prior to import and sale of each batch of biosimilar product for evaluation. The batch release documents are to include the manufacturer’s batch release data and certificate of analysis. The licence holder is also required to update HSA on the stability data of the batch of product selected each year to be part of the stability study program for the drug product. HSA may choose to request additional documents or to carry out independent batch testing of selected batches, if deemed necessary.

Other Post-authorisation Measures

The current post-market vigilance systems for detecting safety issues relating to RBPs are applicable to biosimilars. These may include:

• Reporting of serious adverse events associated with biosimilars to HSA by product registrants or healthcare professionals;
• Timely update by product registrants on significant safety issues and safety-related regulatory actions taken by overseas agencies;
• Submission of benefit-risk evaluation reports relating to the biosimilar by product registrants (when required);
• Conduct of post-marketing safety studies by product registrants (when required).

Risk minimisation activities to mitigate the risks known to be associated with RBPs will generally be adopted for biosimilars. These may include:

• Warnings and precautions in package inserts (e.g. warning statement on the risks associated with switching of products during treatment);
• Provision of educational materials for physicians and/or patients (when required).

 

13. Are there specific policies and requirements in terms of biosimilar medicines labelling in the event of second medical use patents? Is this any different to the requirements for the original Biologics drug?

Section 14(7) of the Patents Act provides that where an invention consists of a substance for use in a method of treatment of the human body by therapy, the fact that the substance forms part of the state of the art does not prevent the invention from being taken to be new if the use of the substance or composition in any such method does not form part of the state of the art.

Since the Patents Act governs second medical use patents, the new biosimilar medicines, when labelling, must not infringe the patent rights of the originator company and their drug.

 

14. Have there been any significant legal/judicial developments in relation to biosimilars in your country? (Including but not limited to IP, procurement, competition, misleading information campaign, access to reference comparator product)

As at the date hereof, there is no such publicly available information.

 

15. Are there proposals for reform or significant change to the legal, regulatory, procurement of biosimilars? If yes, when are they likely to come into force?

As at the date hereof, there is no such publicly available information.

 

Also from this Legal Handbook

The ins and outs of orphan drugs & rare diseases 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 is the definition of Rare Diseases in your country?

As at the date hereof, there is no legal definition of rare diseases in Singapore.

In a press release dated 2 July 2019, the Ministry of Health of Singapore (“MOH”) defined a rare disease as a condition that affects fewer than 1 in 2,000 people.

 

2. Does the designation of ‘Orphan Drug’ exist in your country? (Does it correspond with the definition of Rare Diseases?)

As at the date hereof, there is no publicly available designation of “orphan drug” in Singapore.

 

3. What is the regulatory framework for the authorisation of an Orphan Drug? (Is this regulatory framework based on Rare Disease status or can it alternatively be based on Orphan Drug foreign status?)

Prior to 1 November 2016, orphan drugs were regulated under the Medicines Act (Chapter 176) of Singapore. Specifically, the regulations relating to orphan drugs were contained in the Medicines (Orphan Drugs) (Exemption) Order (“Orphan Drugs Order”).

However, as part of the Health Sciences Authority of Singapore’s (“HSA”) efforts to consolidate the existing regulatory controls under a single legislation, namely, the Health Products Act (CHP of Singapore) (“HPA”), the Orphan Drugs Order was repealed.

The HPA does not contain any specific reference in relation to orphan drugs or rare diseases. However, the HPA would govern orphan drugs in the same manner in which other therapeutic products are governed under the HPA.

 

4. Does your country have provisions for relaxed clinical trial/scientific evidence requirements in respect of Orphan Drugs as compared to other drugs?

As at the date hereof, there are no publicly available provisions for relaxed clinical trial / scientific evidence requirements in respect of orphan drugs as compared to other drugs in Singapore.

 

5. Is there an expedited pathway for Orphan Drugs?

As at the date hereof, there is no publicly available information relating to expedited pathways for orphan drugs, if any.

However, in general, there are four types of evaluation routes for registering a new therapeutic product, namely (i) the full route, (ii) the abridged route, (iii) the verification route and (iv) the verification-CECA route. The full route has the longest turnaround time, followed by the abridged route and the verification route.

The full route applies to any new product that has not been approved by any drug regulatory agency. The abridged route applies to any new or generic product that has been evaluated by at least one drug regulatory agency. The verification route applies to a new or generic product that has been evaluated and approved by one of the HSA’s reference drug regulation agencies. The verification-CECA route applies to any new or generic product manufactured in India that has been evaluated and approved by one of the HSA’s reference drug regulation agencies.

HSA’s reference drug regulatory agencies include Australia’s Therapeutics Goods Administration, the European Medicines Agency, Health Canada, the UK Medicines and Healthcare Products Regulatory Agency and the USA Food and Drug Administration.

The Therapeutic Products Guidance provides that where a product has been designated as an Orphan Drug by at least one reference drug regulatory agency, or has been approved by at least one reference drug regulatory agency via an accelerated approval, approval under exceptional circumstances or equivalent approval process, the applicant should consult the HSA on the eligibility for the verification route. It thus appears that the HSA would determine whether the shorter verification route can be taken to register the Orphan Drug.

 

6. Are foreign marketing authorizations recognized in your jurisdiction for Orphan Drugs? If yes, marketing authorizations from which countries are recognized?

There are no specific foreign marketing organisations recognized in Singapore for orphan drugs.

 

7. Can Orphan Drugs be reimbursed? If so, is there a specific reimbursement procedure for Orphan drugs?

No specific procedures. The market price of a medicinal product is not generally governed by law or regulation in Singapore. However, the MOH administers several drug subsidy schemes (the Standard Drug List (SDL), Medication Assistance Fund, inpatient drug subsidy, etc).

 

8. How are the prices of Orphan Drugs regulated?

As at the date hereof, there is no publicly available information on the regulation of Orphan Drug prices.

The MOH and SingHealth Fund have jointly established the Rare Disease Fund (“RDF”) in 2019. The RDF is a charity fund that combines community donations and government matching contribution to support Singapore citizens with specific rare diseases. This initiative aims to support patients whose treatment costs remain unaffordable even after government subsidies, insurance and financial assistance.

 

9. In case of reference price based on a basket of countries, what countries are included?

As at the date hereof, there is no such publicly available information.

 

10. Have there been any significant legal/judicial developments in relation to Orphan Drugs in your country?

As at the date hereof, there is no such publicly available information.

 

11. Are there proposals for reform or significant change to the regulation of Orphan Drugs? If yes, when are they likely to come into force?

As at the date hereof, there is no such publicly available information.

 

Also from this Legal Handbook

Cannabinoid drugs, medicinal cannabis and opioid drugs in Singaporean Pharma – a legal guide. Prepared in association with Drew & Napier LLC, this is an extract from The Pharma Legal Handbook: Singapore, available to purchase here for USD 99.

 

Cannabinoid Drugs

1. Are Cannabinoid Drugs authorized in your country?

In general, Cannabinoid Drugs are not authorised in Singapore. The Misuse of Drugs Act (Chapter 185) of Singapore (“MDA”) prescribes that it shall be an offence to traffic, manufacture, import or export, or possess or consume a “controlled drug”.

The term “controlled drug” is defined in section 2 of the MDA as “any substance or product which is for the time being specified in Part I, II or III of the First Schedule or anything that contains any such substance or product”.

Part 1 of the First Schedule of the MDA specifies cannabis and cannabis resin, cannabinol and cannabinol derivatives as controlled drugs, among others. As regards each of these substances:

1. The term “cannabis” is broadly defined as “any part of a plant of the genus Cannabis, or any part of such plant, by whatever name it is called” (section 2 of the MDA).
2. The term “cannabis resin” is defined as “any substance containing resinous material and in which is found tetrahydrocannabinol and cannabinol in any quantity” (section 2 of the MDA).
3. The term “cannabinol derivatives” refers to tetrahydro derivatives of cannabinol and their carboxylic acid derivatives, and 3-alkyl homologues of cannabinol or its tetrahydro derivatives (Part IV, First Schedule of the MDA).

Assuming that Cannabinoid Drugs contain cannabis, cannabis resin and/or cannabinol derivatives as defined under the MDA, such Cannabinoid Drugs will fall under the definition of a “controlled drug” under the MDA.

 

2. What are the regulatory authorities with jurisdiction over Cannabinoid Drugs?

The MDA confers enforcement powers to the Central Narcotics Bureau of Singapore (“CNB”).

 

3. Is there a specific regulatory framework for the authorization, pricing, and reimbursement of Cannabinoid Drugs?

As at the date hereof, there is no specific regulatory framework for the authorization, pricing, and reimbursement of Cannabinoid Drugs.

 

4. Which are the cannabinoid drugs that have received market approval to date?

As at the date hereof, there is no such publicly available information.

 

5. Who can prescribe Cannabinoid Drugs?

In general, it is an offence under the MDA to traffic in Cannabinoid Drugs. The MDA defines “traffic” as (a) to sell, give, administer, transport, send, deliver or distribute; or (b) offer to do anything mentioned in (a).

 

6. Is there a list of doctors authorized to prescribe Cannabinoid Drugs?

As at the date hereof, there is no such publicly available information.

 

7. What approvals or notifications are required to prescribe Cannabinoid Drugs?

The Misuse of Drugs Regulations provides certain exemptions to the prohibitions set out in the MDA.

In general, the cannabinoid drug is subject to the same regulatory framework as all other therapeutic products in Singapore, i.e. the Health Products Act 2016 and the Health Products (Therapeutic Products) Regulations 2016 (Cap 122D). Companies are required to obtain a dealer’s licence before manufacturing, importing or supplying therapeutic products, and all therapeutic products must be registered with the HSA before they can be supplied in Singapore.

 

8. Which organizations are authorized to sell/distribute Cannabinoid Drugs available?

As at the date hereof, there is no such publicly available information.

 

9. Is there a list of retailers/distributors authorized to sell Cannabinoid Drugs?

As at the date hereof, there is no such publicly available information.

 

10. Are there proposals for reform or significant change to the regulation of Cannabinoid Drugs?

In 2018, the National Research Foundation (NRF) announced the Synthetic Cannabinoid Biology Programme, which is part of a $25-million Synthetic Biology Research and Development (R&D) programme. The R& D program will span five years, and seeks to help boost Singapore’s research into synthetic biology. This refers to the science behind the production of natural products through engineering biological systems.

 

11. When are they likely to come into force?

As at the date hereof, there is no such publicly available information.

 

Medicinal Cannabis

12. Is Medicinal Cannabis authorized in the country?

The MDA prescribes that it shall be an offence to traffic, manufacture, import or export, or possess or consume a “controlled drug”.

Part 1 of the First Schedule of the MDA specifies cannabis as a controlled drug.

 

13. What are the regulatory authorities with jurisdiction over Medicinal Cannabis?

The MDA confers enforcement powers to the CNB.

 

14. What is the regulatory framework for the authorization, pricing, and reimbursement of Medicinal Cannabis?

As at the date hereof, there is no specific regulatory framework for the authorization, pricing, and reimbursement of Medicinal Cannabis.

 

15. How is the production and import of Medicinal Cannabis regulated and by which agencies/authorities?

The production and import of Medical Cannabis is regulated under the MDA, which grants enforcement powers to the CNB.

 

16. What approval or notifications are necessary to produce or import Medicinal Cannabis?

The Misuse of Drugs Regulations provides certain exemptions to the prohibitions set out in the MDA.

In general, the Medicinal Cannabis is subject to the same regulatory framework as all other therapeutic products in Singapore, i.e. the Health Products Act 2016 (“HPA”) and the Health Products (Therapeutic Products) Regulations 2016 (Cap 122D). Companies are required to obtain a dealer’s licence before manufacturing, importing or supplying therapeutic products, and all therapeutic products must be registered with the HSA before they can be supplied in Singapore.

 

17. What is the regulatory framework for the marketing and distribution of Medicinal Cannabis?

In general, it is an offence under the MDA to traffic in Medicinal Cannabis. The MDA defines “traffic” as (a) to sell, give, administer, transport, send, deliver or distribute; or (b) offer to do anything mentioned in (a).

 

18. How can patients obtain Medicinal Cannabis?

Please refer to the response to question 16 above.

 

19. Who can prescribe Medicinal Cannabis?

In general, it is an offence under the MDA to traffic in Medicinal Cannabis. The MDA defines “traffic” as (a) to sell, give, administer, transport, send, deliver or distribute; or (b) offer to do anything mentioned in (a).

 

20. Is there a list of doctors authorized to prescribe Medicinal Cannabis?

As at the date hereof, there is no such publicly available information.

 

21. What approvals or notifications are required to prescribe Medicinal Cannabis?

Please refer to the response in question 16 above.

 

22. Where is Medicinal Cannabis available?

As at the date hereof, there is no such publicly available information.

 

23. Is there a list of retailers authorized to sell Medicinal Cannabis?

As at the date hereof, there is no such publicly available information.

 

24. Are there proposals for reform or significant change to the regulation of Medicinal Cannabis?

As at the date hereof, there is no such publicly available information.

 

Opioid Drugs

25. Are Opioid Drugs authorized in your country?

To the extent such Opioid Drugs fall within the definition of “health products” under the Health Products Act (Chapter 122D) of Singapore (the “HPA”), the HPA prescribes that it shall be an offence to supply any health product unless the health product is a registered under the HPA.

Certain Opioid Drugs may also fall within the definition of a “controlled drug” under the MDA. The MDA prescribes that it shall be an offence to traffic, manufacture, import or export, or possess or consume a “controlled drug”.

 

26. What are the regulatory authorities with jurisdiction over Opioid Drugs?

Assuming that the Opioid Drugs fall within the definition of “health products” under the HPA, the Health Sciences Authority of Singapore (“HSA”) shall have jurisdiction over Opioid Drugs.

 

27. Is there a specific regulatory framework for the authorization, pricing, and reimbursement of Opioid Drugs?

Assuming that the Opioid Drugs fall within the definition of “health products” under the HPA, the HPA regulates the authorisation of Opioid Drugs.

The prices of health products, (including therapeutic products) are generally not regulated by the Singapore government. However, public sector hospitals in Singapore generally purchase medicinal products through centralised Group Procurement Offices by way of tender contracts, and this operates in some way to regulate the prices of health products.

The national healthcare system in Singapore operates on mixed financing systems 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.

 

28. Which are the Opioid drugs that have received market approval to date?

The HSA maintains a register of health products registered under the HPA.

 

29. Who can prescribe Opioid Drugs?

The persons who can dispense drugs and sell medical devices to patients depends on the relevant classification of the drug or device.

Prescription-only medicines 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 can be supplied by or under the supervision of a pharmacist without a prescription and general sales list medicines can be purchased from any retailer.

 

30. Is there a list of doctors authorized to prescribe Opioid Drugs?

As at the date hereof, there is no such publicly available information.

 

31. What approvals or notifications are required to prescribe Opioid Drugs?

Assuming that the Opioid Drugs fall within the definition of “health products” under the HPA, the HPA regulates the authorisation of Opioid Drugs.

 

32. Which organizations are authorized to sell/distribute Opioid Drugs available?

Please refer to the response in question 29 above.

 

33. Is there a list of retailers/distributors authorized to sell Opioid Drugs?

As at the date hereof, there is no such publicly available information.

 

34. Are there proposals for reform or significant change to the regulation of Opioid Drugs?

As at the date hereof, there is no such publicly available information.

 

35. When are they likely to come into force?

Not applicable.

 

Also from this Legal Handbook

Upcoming regulatory reforms 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. Are there proposals for reform or significant change to the healthcare system?

PROPOSED HEALTHCARE SERVICES BILL

Currently, hospitals and private medical clinics are regulated under the Private Hospitals and Medical Clinics Act (PHMCA), which was first enacted in 1980. Since then, there have been significant changes to the healthcare landscape in Singapore. The Ministry of Health (MOH) has announced plans to replace the PHMCA with a new Healthcare Services Act (HCSA), which will see a move from the current premises-based licensing frame­work to a services-based licensing framework. The HCSA will have a wider regulatory scope than the PHMCA and will include healthcare services, allied health and nursing services, traditional medicine, and complementary and alternative medicine. Other key changes under the HCSA include:

• requiring that the governing body of a healthcare service possess the necessary competence and skills to carry out its role;
• strengthening the governance and oversight of healthcare services by enhancing the role and responsibilities of key personnel;
• introducing a new requirement for Service Review Committees for selected services or programmes that are deemed to be of higher risk, or greater complexity or public interest;
• making Service Ethics Committees mandatory for selected licensees, to ensure that patients are treated in an ethical manner before certain complex and high-risk medical treatment can be conducted;
• empowering the MOH to step in and assist in the operations of failing healthcare services where needed;
• requiring licensees to contribute to the National Electronic Health Record (NEHR), but providing patients with the option to opt-out if they do not wish to have their records accessed on, or uploaded to, the NEHR;
• enhancing the powers of the MOH to gather information for the purposes of patient safety, care and welfare, and public health interest;
• authorising the MOH to publish information concerning non-compliant licensees and unlicensed healthcare providers;
• prohibiting the provision of medical practices and services that have caused harm or may harm patients; and
• implementing measures to minimise public misperception, such as amending existing naming restrictions to allow for greater clarity as to the healthcare services provided.

PROPOSED AMENDMENTS TO THE MEDICAL REGISTRATION ACT

The Ministry of Health (MOH) and the Singapore Medical Council (SMC) have proposed amendments to the Medical Registration Act (Chapter 174) (MRA).

The MRA establishes the regulatory framework governing the practise of medicine and medical practitioners in Singapore. The last major amendments to the MRA were made in 2010.

The proposed amendments to the MRA are aimed at improving the disciplinary proceedings under the MRA for the public as well as medical practitioners, in particular, by: (i) increasing transparency and accountability in the disciplinary and appeals processes; (ii) bringing about better consistency for disciplinary proceedings under the MRA, and aligning them with those of criminal proceedings and other professional boards; and (iii) enhancing efficiency and certainty in respect of timelines.

 

2. When are they likely to come into force?

PROPOSED DRAFT HEALTHCARE SERVICES BILL

The MOH conducted a public consultation seeking feedback on the draft Healthcare Services Bill (Draft HCS Bill) between 5 January 2018 and 15 February 2018. At the time of this writing, the Draft HCS Bill has yet to be tabled in Parliament.

The MOH has indicated that the new Healthcare Services Act (HCSA), when enacted, will be implemented in three phases:

• Phase 1: medical and dental clinics, and clinical laboratories currently licensed under the PHMCA will be licensed under the HCSA.
• Phase 2: hospitals and nursing homes currently licensed under the PHMCA will be licensed under the HCSA.
• Phase 3: new services currently not licensed under the PHMCA (such as telemedicine services, mobile medical services, and sterile pharmaceutical services) will be licensed under the HCSA.

PROPOSED AMENDMENTS TO THE MEDICAL REGISTRATION ACT

The Ministry of Health and the Singapore Medical Council conducted a public consultation seeking comments on the proposed amendments to the Medical Registration Act (Chapter 174) between 28 September 2018 and 26 October 2018. At the time of this writing, there is no clear indication as to when the proposed amendments to the MRA are slated to come into force.

 

Also from this Legal Handbook

What you need to know about patents and trademarks 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 basic requirements to obtain patent and trademark protection?

The relevant applications must be filed with the Intellectual Property Office of Singapore (IPOS) in order to obtain protection for patents in Singapore.

It is not compulsory to register a trade mark in Singapore. An individual, firm or company, who owns a trade mark and uses it in connection with his goods or services, acquires common law rights in that mark by virtue of the use and reputation of the mark. For instance, the proprietor can rely on the tort of passing off at common law to protect his mark against unauthorised use. Trade mark registration can be obtained by filing the relevant applications with the IPOS. Registration of a trade mark under the Trade Marks Act grants the owner a statutory monopoly of the trade mark in Singapore.

 

2. What agencies or bodies regulate patents and trademarks?

The Intellectual Property Office of Singapore (IPOS) administers the patents and trade marks regime in Singapore.

 

3. What products, substances, and processes can be protected by patents or trademarks and what types cannot be protected?

PATENTS

Generally, a patentable invention is one that is new (i.e., the invention does not form part of the state of the art), involves an inventive step (i.e., the invention is not obvious to a person skilled in the art), and is capable of industrial application (i.e., the invention can be made or used in any kind of industry, including agriculture).

However, certain types of inventions cannot be patented. For instance: (i) inventions which, if published or exploited, would generally be expected to encourage offensive, immoral or anti-social behaviour; and (ii) methods of treatment of the human or animal body by surgery, therapy or diagnosis practised on the human or animal body, on the basis that they are not regarded as capable of industrial application.

TRADEMARKS

In order to register a trade mark, it: (i) has to be a sign that is capable of graphical representation; (ii) must be distinctive; (iii) must not conflict with an earlier trade mark; and (iv) must be used in the course of trade, or there must be a bona fide intention that the mark should be so used.

However, certain signs cannot be registered as trademarks. For instance: (i) signs which are contrary to public policy or to morality; and (ii) signs which are of such a nature as to deceive the public (for instance as to the nature, quality or geographical origin of the goods or service).

 

4. How can patents and trademarks be revoked?

PATENTS

Section 80 of the Patents Act (Chapter 221) sets out an exhaustive list of grounds on which the Registrar of Patents may, on the application of any person, order a patent to be revoked:

• the invention is not patentable;
• the patent was granted to a person who was not entitled to be granted that patent;
• the patent specification does not disclose the invention clearly and completely for it to be performed by a person skilled in the art;
• the matter disclosed in the patent specification extends beyond that disclosed in the patent application;
• an amendment or correction has been made to the patent specification or application, and such amendment or correction should not have been allowed;
• the patent was obtained fraudulently, on any misrepresentation, or on any non-disclosure or inaccurate disclosure of prescribed material information; or
• the patent is one of two or more patents for the same invention which have the same priority date, and filed by the same party or the successor in title to that party.

TRADEMARKS

Pursuant to section 22 of the Trade Marks Act, the Registrar of Patents or the Singapore High Court may, on the application of any person, order the registration of a trade mark to be revoked on any of the following grounds:

• the mark has not been put to genuine use in the course of trade in Singapore within five years from the date of completion of the registration procedure, by the proprietor or with his consent, in relation to the goods or services for which it is registered, and there are no proper reasons for non-use;
• such use has been suspended for an uninterrupted period of five years, and there are no proper reasons for non-use;
• the mark has become the common name in the trade for the product or service for which it is registered, as a result of the proprietor’s acts or inactivity; or
• the mark is liable to mislead the public, in particular as to the nature, quality or geographical origin of those goods or services, as a result of the use made of it by the proprietor or with his consent in relation to the goods or services for which it is registered.

 

5. Are foreign patents and trademarks recognized and under what circumstances?

PATENTS

A person intending to register a patent in Singapore who has a corresponding application filed earlier in a Paris Convention country or a World Trade Organisation member country (other than Singapore) may claim priority over that patent from the first-filed application, if the Singapore application is filed within 12 months from the date of the first filing. There are limited circumstances under which an applicant may be able to apply to restore a declaration of priority of an earlier relevant application even though they had failed to file a subsequent patent application within 12 months from the date of the earlier application, e.g. where the failure to file within the 12-month period was unintentional, or occurred in spite of due care required by the circumstances having been taken.

TRADEMARKS

A person intending to register a trade mark in Singapore who has a corresponding application filed earlier in a Paris Convention country or a World Trade Organisation member country (other than Singapore) may claim priority from the first-filed application, if the Singapore application is filed within 6 months from the date of the first filing. When a priority is claimed, the filing date in Singapore dates back to the date of the first filing.

 

6. Are there any non-patent/trademark barriers to competition to protect medicines or devices?

THERAPEUTIC PRODUCTS

Where an applicant has provided to the HSA information relating to the safety or efficacy of a therapeutic product in support of an application for product registration, and the HSA has registered that therapeutic product, the HSA may not, for 5 years after the date of that earlier registration, register a similar therapeutic product on the application of another person on the basis of the earlier registration, unless the registrant of the earlier registration has so consented.

In respect of innovative therapeutic product applications, there is additional protection for confidential supporting information, subject to certain exceptions. An innovative therapeutic product application is an application to register a therapeutic product that refers to a substance that is an ingredient in the manufacture or preparation of the therapeutic product to which the application relates, and that has not, before that application is received by the HSA, been referred to as an ingredient in the manufacture or preparation of any other therapeutic product in any previous application.

MEDICAL DEVICES

There is no equivalent protection in respect of medical devices.

 

7. Are there restrictions on the types of medicines or devices that can be granted patent and trademark protection?

See  Question 3 above.

 

8. Must a patent or trademark license agreement with a foreign licensor be approved or accepted by any government or regulatory body?

It is not mandatory to record a trade mark or patent license with the IPOS, or for the terms of the license agreement to be approved or accepted by the IPOS.

There are, however, benefits to registering transactions, instruments or events affecting the rights in respect of patents or registered trademarks, such as licence agreements and assignment agreements, upon their execution. Where a dispute relating to such rights arises, the registration would serve as prima facie evidence of the parties’ rights. Further, the entry of a transaction, instrument or event in the IPOS’s register(s) affects the right of the proprietor or licensee to claim certain remedies for infringement.

 

Also from this Legal Handbook

Key legal info on product liability 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 types of liability are recognized in your jurisdiction?

In Singapore, product liability in relation to medicines can arise under an action in tort, contract and/or breach of relevant statutory provisions.

 

2. How do these types of liabilities apply to the manufacturers of medicines and devices?

An action in tort can arise where the manufacturer has breached its duty of care, such as its duty to ensure adequate quality control measures for medicines or medical devices, or to exercise reasonable care in the marketing and advertisement of such products.

An action for a breach of contract can arise from a breach of express or implied contractual terms, most commonly of an implied term that goods supplied are of satisfactory quality, as supported by section 14 of the Sale of Goods Act (Chapter 393).

Criminal liability can also arise under the Health Products Act. For instance, a person who manufactures, procures or arranges for the manufacture of a medicine or medical device that is adulterated, counterfeit or unwholesome may be liable for an offence for which such person may be subject to fines and/or imprisonment upon conviction.

 

3. Does potential liability extend to the manufacturer only or could claims extend to corporate executives, employees, and representatives?

Potential criminal liability under the Health Products Act can extend to the company’s officers such as its directors, where it is proved that the offence was committed with the consent or connivance of such officer(s), or is attributable to any neglect on the part of such officer(s).

 

4. How can a liability claim be brought?

To establish the tort of negligence, it must be shown that:

• there was a duty of care owed by the person committing the tort to the consumer;
• the person committing the tort did not meet a reasonable standard of care, as determined by the court; and
• the injury to the consumer is causally linked to the person committing the tortious act and the injury was reasonably foreseeable, as determined by the court.

To establish a breach of contract, certain elements will have to be proved, such as the existence of a contract and a breach of its terms.

Liability for statutory offences differs, depending on the conditions in the relevant statute.

 

5. What defenses are available?

For actions in tort, some possible defences include that the elements of the tort of negligence are not made out, for instance, that the duty of care was not owed, or the standard of care was not breached, or that there is contributory negligence or a voluntary assumption of risk. For breach of contract cases, possible defences include certain vitiating factors such as frustration, mistake, misrepresentation, illegality and unfairness. In respect of offences under the Health Products Act, statutory defences may be available.

 

Also from this Legal Handbook

Want to know more about traditional medicines and OTC products in Singapore? Read on! 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 requirements for traditional, herbal, complementary, or alternative medicines and devices?

Chinese proprietary medicines, traditional (Indian and Malay) medicines, homeopathic medicines and medicated oils and balms are regulated under the Medicines Act (Chapter 176), the Medicines (Advertisement and Sale) Act (Chapter 177), the Sale of Drugs Act (Chapter 282) and the Poisons Act (Chapter 234) and their subsidiary legislation, which fall under the regulatory purview of the Health Sciences Authority (HSA).

Persons who sell, supply or export Chinese proprietary medicines, or who procure Chinese proprietary medicines for sale, supply or export, are exempted from licensing requirements. However, persons that intend to import, distribute as a wholesaler or manufacture Chinese proprietary medicines in Singapore must respectively obtain an import licence, a wholesale dealer’s licence and a manufacturer’s licence.

Traditional medicines, homoeopathic medicines and medicated oils and balms are not presently subject to licensing for their manufacture, import and sale in Singapore. However, dealers of such products such as manufacturers, importers, wholesale dealers and sellers are responsible for the safety and quality of the products which they deal with.

 

2. Can these traditional, herbal, complementary, or alternative products be advertised directly to the public?

Generally, yes. However, Chinese proprietary medicines, traditional (Indian and Malay) medicines, homeopathic medicines and medicated oils and balms are subject to advertisement controls, and an advertising permit and approvals may be required from the HSA prior to advertising such products if the advertisement contains any medicinal or therapeutic claims.

 

3. What health, advertising, and marketing claims may be made for traditional, herbal, complementary, or alternative products?

General health claims may be used in the advertisement of traditional medicinal materials, based on traditional or long-standing use, as documented in approved traditional medicine literature. However, such products cannot be advertised with any direct or indirect reference to any of the 19 prohibited diseases and conditions specified in the Schedule to the Medicines Act, namely, blindness, cancer, cataract, drug addiction, deafness, diabetes, epilepsy or fits, hypertension, insanity, kidney diseases, leprosy, menstrual disorders, paralysis, tuberculosis, sexual function, infertility, impotency, frigidity as well as conception and pregnancy. In addition, no efficacy claims are allowed for serious medical diseases, disorders and conditions, including osteoporosis, insomnia, hepatitis, thyroid disorders, heart or cardiovascular diseases, genetic disorders, infectious diseases and sexually transmitted diseases.

 

4. What are the regulatory requirements for over-the-counter (non-prescription) medications?

Over the counter medications, or general sales list (GSL) medicines, are regulated as “therapeutic products” under the Health Products Act and its subsidiary legislation. Such products will generally need to be registered with the HSA before they are supplied in the Singapore market.

 

5. Are there any limitations on locations or channels through which OTC products may be sold?

OTC medicines can generally be purchased from any retailer.

It is also possible to purchase OTC medicines from automatic vending machines, provided that the following statutory requirements are met:

• the person’s name and contact information are prominently displayed on the automatic vending machine;
• the automatic vending machine is sufficiently equipped and secure to ensure appropriate storage conditions for the medicine;
• the medicine is labelled and packaged in accordance with the conditions attached by the HSA to the registration of the medicine under the Health Products Act;
• the package size of the medicine is the same as the package size specified for the registration of the medicine, and the total amount of the medicine in each package does not exceed a total dosage of 3 months per individual.

 

6. What health, advertising, and marketing claims may be made for OTC products?

Advertising and marketing claims made in relation to OTC medicines must comply with the applicable legislative requirements including those under the Health Products (Advertisement of Therapeutic Products) Regulations 2016. Such claims should provide factual information about the OTC medicine, and any advertisements must be aligned with the intended uses or indications of the OTC medicine as registered with the HSA. Any text, emphasis, certification, award or unique feature or prominence of an advertised OTC medicine must be substantiated by facts or robust objective evidence from credible sources, such as articles published in scientific or medical journals. Information must be presented in a balanced, objective and accurate manner and must be referenced by reflecting the appropriate citations (where relevant). Any scientific terminologies used should be in a manner that is readily understood by the targeted audience.

 

7. Can OTC products be marketed or advertised directly to the public?

Generally, yes, provided that the restrictions set out under Health Products Act and its subsidiary legislation such as the Health Products (Advertisement of Therapeutic Products) Regulations 2016 are complied with. For instance, advertisements of OTC medicines must not discourage the reader from seeking medical or professional advice or encourage inappropriate or excessive use of the medicine. Any sales promotions of OTC medicines to the public must not offer a prize as an inducement to purchase the therapeutic product, offer any other health product or medicinal product with the OTC medicine or offer of any sample of the OTC medicine.

 

8. What is the mechanism by which a prescription-only product can be converted to an OTC product?

In general, a medicine may be reclassified from a prescription-only medicine to a pharmacy-only medicine, or from a pharmacy-only medicine to a GSL medicine, if it has been deemed sufficiently safe for use with reduced or without medical supervision.

There are two mechanisms by which prescription-only medicines can be reclassified:

• firstly, the product registrant may submit an MAV-2 application to the HSA for reclassification of an already registered therapeutic product; and
• secondly, by legislative mechanisms, following a review by the HSA that a prescription-only medicine can be used in a safe and effective manner under the supervision of a pharmacist, subject to certain conditions or restrictions such as indication, strength, maximum daily dose, maximum supply quantity, and age restriction.

 

9. What are the requirements for the importation of either traditional medicines or OTC products?

Subject to certain limited exceptions, an importer’s licence under the Health Products Act is required for the import of OTC medicines into Singapore, whereas an import licence under the Medicines Act is required for the import of traditional medicines into Singapore. For OTC medicines, additionally, the product will generally need to be registered with the HSA.

 

Also from this Legal Handbook

Everything you need to know about the marketing, manufacturing, packaging, labeling and advertising of pharmaceuticals in Singapore. 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 is the authorization process for the marketing of new drugs, biologics, medical devices, over-the-counter medications, and other medicinal products?

THERAPEUTIC PRODUCTS

For therapeutic products, marketing approval may be obtained by making an application to the Health Sciences Authority (HSA) for product registration.

The applicant (or product registrant) must be a locally registered entity in Singapore, which is responsible for the quality, safety and efficacy of the product.

The production registration process involves, broadly, the following steps:

• pre-submission preparation, which involves:
  • considering the type of application (new drug application (NDA) or a generic drug application (GDA));
  • considering which one of the four evaluation routes is appropriate (full, abridged, verification or verification-CECA route); and
  • arranging for a pre-submission consultation with the HSA for advice (if required);
• application submission through the HSA’s online portal, PRISM;
• application screening by the HSA to ensure the correctness of the application type and of the dossier submitted, following which the application may be accepted if there are no deficiencies, or when all deficiencies have been adequately addressed and the HSA is satisfied that the dossier is complete for evaluation;
• application evaluation by the HSA; and
• regulatory decision by the HSA. The HSA may register a product subject to post-approval commitments.

There are four types of evaluation routes for registering a new therapeutic product:

• full route: for a new therapeutic product that has not been approved by any drug regulatory agency at the time of submission of the application to the HSA;
• abridged route: for a therapeutic product that has been evaluated and approved by at least one foreign drug regulatory agency, and which meet certain other criteria;
• verification route: for a therapeutic product with similar indication(s), dosing regimen(s), patient group(s), and/or direction(s) for use, that has been approved by at least one (for GDAs) or two (for NDAs) of the HSA’s reference drug regulatory agencies and which meet certain other criteria; and
• verification-CECA route: for a generic product manufactured in India which has been evaluated and approved by HSA’s reference drug regulatory agencies via certain specified routes.

MEDICAL DEVICES

For medical devices, similarly, marketing approval may be obtained by making an application to the HSA for product registration.

The appropriate product registration route and evaluation route depends on the risk classification of the medical device, whether the medical device has received reference agency approvals (if any) and the prior safe marketing history of the medical device (if applicable).

The HSA adopts the following risk classification for medical devices:

• 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.

There are certain statutory exemptions where product registration is not required. For instance, all Class A medical devices, except those that are supplied in a sterile state, are exempted from the registration requirements.

All applications for medical device registration must be submitted via the HSA’s online portal, MEDICS.

Generally, the registration of a medical device which has not obtained prior approval from any of the HSA’s reference agencies at the point of application will need to be done via the full evaluation route, which generally involves a longer and more complex registration process. Medical devices which have obtained the approval from the HSA’s reference regulatory agencies may qualify for the abridged, expedited or immediate evaluation routes where they meet the criteria specified by the HSA for such evaluation routes.

For applications under the full or abridged routes, after submission of the application, the application will be verified for eligibility and completeness before it is accepted for evaluation. Following the HSA’s evaluation of the submitted dossier, it will make a regulatory decision. Applications which satisfy the registration requirements will be registered and listed on the Singapore Medical Device Register. For applications under the immediate route, the medical device will be registered immediately and will generally be listed on the Singapore Medical Device Register within the hour.

 

2. What is the authorization process for the marketing of generic versions of these products?

The overall authorisation process for marketing of generic drugs is generally similar to that for non-generic drugs (see Question 1 above). A generic drug application (GDA) may be submitted for a therapeutic product that is essentially the same as a product currently registered in Singapore (known as the Singapore reference product) in terms of its qualitative and quantitative composition of active ingredients, pharmaceutical dosage form and clinical indication. It should be noted that biosimilar products are not eligible for a GDA and product registrations for biosimilars must be submitted via an NDA.

 

3. What are the typical fees for marketing approval?

The relevant application fee payable for product registration depends on the application type, and the level of screening and evaluation required.

More information on the applicable fees can be found on the HSA’s website, http://www.hsa.gov.sg/content/hsa/en.html.

 

4. What is the period of authorization and the renewal process?

Generally, once a therapeutic product or a medical device has been registered, the registration will remain in force for so long as the product registrant pays to the HSA the relevant annual retention fee within the prescribed time.

The HSA may cancel the registration if it has reasonable grounds to believe that:

• the registration has been obtained by fraud or misrepresentation;
• the registrant of the product has contravened or is contravening any applicable statutory requirements, and/or condition(s) attached to the registration;
• the formulation, composition, design specification, quality, safety or presentation of the product has changed such as to render it unsuitable to continue to be registered;
• the product no longer complies with a prescribed requirement; or
• it is in the public interest to do so.

 

5. What are the requirements, if any, for post-approval pharmacovigilance?

For therapeutic products, the product registrant is required to comply with the obligations set out in Part VIII of the Health Products Act and Part 6 of the Health Products (Therapeutic Products) Regulations 2016, which include:

• maintaining records of every receipt and supply of the product to another person, and records of defects in and adverse effects arising from the use of the product, and producing these records for inspection by the HSA if required;
• reporting defects and adverse effects of the product to the HSA within specified timeframes;
• notifying the HSA at least 24 hours before recalling the product;
• obtaining prior approval from the HSA before making any change to the particulars of the registered product or any change which may affect the quality, safety or efficacy of the product;
• informing the HSA within 15 days of receiving information that adversely affects the validity of any data relating to the quality, safety or efficacy of the product; and
• submitting periodic benefit-risk evaluation reports or implementing a risk management plan as and when required by the HSA.

For medical devices, the product registrant is required to comply with the obligations set out in Part VIII of the Health Products Act and Part VIII of the Health Products (Medical Devices) Regulations 2010, which include:

• ensuring and maintaining objective evidence to establish that the medical device complies with the safety and performance requirements for the medical device as set out on the HSA’s website;
• maintaining records of every complaint received by it pertaining to the medical device, and producing such records for inspection by the HSA if required;
• informing the HSA of defects or adverse effects arising from the use of the medical device within the prescribed time limits;
• informing the HSA within 15 days of receiving information that adversely affects the validity of any data relating to the quality, safety or efficacy of the medical device; and
• notifying the HSA at least 24 hours before recalling the medical device;
• notifying the HSA of any intended field safety corrective action it intends to take in relation to a medical device, before carrying out such field safety corrective action; and
• obtaining prior approval from the HSA before making any change to the particulars of the registered medical device or any change which may affect the quality, safety or efficacy of the medical device.

 

6. Are foreign marketing authorizations recognized?

Depending on the scope and type of the marketing authorisation granted by the foreign regulator, and which and how many regulatory agencies have given their approval, a therapeutic product or medical device may be subject to a lower level of screening and evaluation by the HSA (e.g. may qualify for the abridged evaluation route, or verification evaluation route).

 

7. Are parallel imports of medicines or devices allowed?

Generally, parallel imports of therapeutic products and medical devices are allowed, provided that the importers of therapeutic products or medical devices hold the requisite product registrations and licences (e.g. import licence) for the products imported (where applicable).

Under Regulation 23 of the Health Products (Therapeutic Products) Regulations 2016, when the HSA is determining whether to approve a therapeutic product registration application, it will consider:

• whether a patent under the Patents Act (Chapter 221) is in force in respect of the product;
• whether the applicant is the patent proprietor or has obtained the consent of the patent proprietor.
• whether the patent is invalid or will not be infringed by doing the act for which the licence is sought.

The patent proprietor (if it is not the applicant) can oppose the licence application, by applying for an order or a declaration by a court or the Registrar of Patents.

 

8. What are the restrictions on marketing practices such as gifts, sponsorships, consultancy agreements, travel and entertainment, or other incentives for healthcare organizations and individual medical practitioners?

The Health Products Act and its subsidiary legislation set out restrictions governing the advertising, marketing and sale of products. Statutory offences under the Health Products Act and its subsidiary legislation include the advertisement of therapeutic products which encourage, or are likely to encourage, inappropriate or excessive use of the therapeutic product, or which offer a prize as an inducement to purchase the therapeutic product.

Additionally, healthcare professionals are required to comply with statutorily imposed obligations under various legislation such as the Medical Registration Act (Chapter 174) and also the ethical codes and guidelines applicable to their profession (e.g. the Singapore Medical Council Ethical Code and Ethical Guidelines).

Members of the Singapore Association of Pharmaceutical Industries (SAPI) and the Singapore Manufacturing Federation Medical Technology Industry Group (SMF MTIG) respectively must also comply with the SAPI Code of Marketing Practices and the SMF MTIG Revised Code of Ethical Conduct for Interactions with Healthcare Professionals.

The industry codes contain set out principles and guidelines regarding the relationship between individual doctors and the pharmaceutical/medical device industry, including in relation to:

• acceptance of gifts, promotional items and educational materials by doctors; and
• invitations from pharmaceutical/medical device companies for doctors to travel overseas to attend medical conferences and associated sponsorships or grants.

More generally, it is also an offence under the Prevention of Corruption Act (Chapter 241) for a person to corruptly solicit or receive, or agree to receive for himself or for another person (or corruptly give, promise or offer to a person, for the benefit of that person or another person), any gratification as an inducement to or reward for a person doing or not to do anything in respect of any matter or transaction, actual or proposed. This also applies to acts of Singapore citizens outside Singapore.

 

9. How is the manufacturing of medicines and devices regulated and by which agencies?

The manufacturing of therapeutic products and medical devices are regulated under the Health Products Act and its subsidiary legislation, including the Health Products (Therapeutic Products) Regulations 2016 and the Health Products (Medical Devices) Regulations 2010. The HSA has regulatory oversight over these regulations.

Generally, manufacturers of therapeutic products and medical devices will need to obtain a manufacturer’s licence from the HSA. The manufacture of the products/devices will need to be carried out in accordance with the conditions of the licence, statutory requirements and other regulatory requirements as may be imposed by the HSA. The manufacture of the product/device can only be carried out at the premises or facility which has been authorised by the HSA for the manufacture of the product/device.

 

10. Are local manufacturing requirements compatible with Good Manufacturing Practices (GMPs) as defined by the US Food & Drug Administration (US FDA) and/or the European Medicines Agency (EMA)?

Yes, the HSA adopts the standards set out in the Pharmaceutical Inspection Convention/Co-operation Scheme (PIC/S) Guide to Good Manufacturing Practice (GMP) for Medicinal Products. The U.S. Food and Drug Administration is a member of the PIC/S and has adopted the PIC/S GMP standard. Generally, the HSA would only grant a Manufacturer’s Licence when the manufacturing facilities has been assessed, audited and found to comply with the PIC/S GMP for Medical Products.

 

11. What is the inspection regime for manufacturing facilities?

Local manufacturers will be subject to the following audit process when applying for a manufacturer’s licence:

• pre-audit, which involves preparation and submission of a Site Master File, which is description of the manufacturing site or plant, and its level of GMP compliance, to the HSA;
• site audit, where the HSA’s audit team will identify any non-conformities; and
• post-audit, which involves the HSA sending a report to the manufacturer to obtain his response to any non-conformities observed during the audit and the time frames required to correct the non-conformities.

The frequency of GMP audits for holders of a manufacturer’s licence is determined by the HSA based on a risk-assessment approach, which includes risk classification of the manufacturer, degree of compliance to the GMP and other quality and regulatory concerns (if any).

Overseas manufacturers who intend to register their therapeutic products in Singapore will be subject to a GMP conformity assessment by the HSA. This involves an on-site audit by the HSA’s GMP auditors to assess whether the manufacturing site, facilities, and the quality system of the operations comply to the PIC/S GMP standard. If an overseas manufacturer has previously been audited and found to conform to the GMP standards by a PIC/S member authority or any of the HSA’s benchmark GMP inspection authorities, and have submitted appropriate GMP evidence to the HSA (e.g. a valid GMP Certificate), such manufacturer may not need to be audited by the HSA.

 

12. Are manufacturing facilities open for inspection by foreign inspectors or third-party inspectors as authorized by the FDA/EMA?

On-site inspections of local manufacturing facilities by foreign authorities or regulators are not specifically regulated under the Health Products Act.

 

13. What are the requirements for storage, packaging, and handling of medicines and devices and their constituent components?

The requirements with regard to the storage, packaging and handling of therapeutic products and medical devices are generally set out in the PIC/S GMP standard and the HSA’s Guidance Notices on Good Distribution Practice (GDP). Dealers such as manufacturers, importers and wholesalers are required to hold the appropriate dealers’ licence(s) in order to engage in the local manufacture, import and wholesale supply of therapeutic products and medical devices in Singapore. As part of the licensing regime, manufacturers are required to conform to the PIC/S GMP standard whereas importers and wholesalers are required to conform to the HSA’s GDP standard.

 

14. What information must be included in medicine and device labeling?

In general, the following information must be included on the label of every therapeutic product:

• the proprietary name and the appropriate non-proprietary name of the therapeutic product;
• the appropriate quantitative particulars of any active ingredient of the therapeutic product;
• an appropriate control number, such as a serial number, batch number or lot number;
• the expiry date of the therapeutic product;
• where the therapeutic product is registered, the registration number assigned to the registered therapeutic product by the HSA; and
• where the therapeutic product contains any of those substances specified in the Fourth or Fifth Schedules to the Health Products Act, an appropriate statement or cautionary warning that the therapeutic product contains such substance.

Additional requirements may apply depending on the type of packaging used for the therapeutic product, e.g. on the outer carton box and on the blister strips. For instance, the outer carton box may need to contain information such as the manufacturing date, expiry date, dosage form, route of administration, storage condition, name and address (or logo) of the product owner or product registrant, name and address of the manufacturer, and pack size (unit or volume).

For medical devices, generally, the following information must accompany the medical device when it is supplied:

• 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.

Additionally, specific labelling requirements may apply to certain types of medical devices, e.g. medical devices that are supplied in a sterile state, medical devices that are intended for single-use only, refurbished medical devices, and medical devices incorporating or administering medicinal or biological substances.

 

15. What additional information may be included in labeling and packaging?

For both therapeutic products and medical devices, the product label must be in English. If non-English text is included in the labelling, the non-English text must be complete, accurate and unbiased and it must also be consistent with the English text.

 

16. What items may not be included in labeling and packaging?

The following may not be included in the labelling or on the packaging of therapeutic products and medical devices:

• trade descriptions which are false or misleading;
• trade descriptions which explicitly or implicitly suggest that the supply or use of the therapeutic product or medical device (as the case may be) is promoted or endorsed by the HSA, the Ministry of Health or the Health Promotion Board.

 

17. What are the restrictions and requirements for the marketing and advertising of medicines and devices?

In general, therapeutic products and medical devices must not be advertised in a false or misleading way. Registered therapeutic products or registered medical devices must not be advertised in such a way as to represent the registered product or device as being usable for any purpose other than that for which it has been registered.

Advertisements of therapeutic products must comply with the applicable legislative requirements including those under the Health Products (Advertisement of Therapeutic Products) Regulations 2016. Amongst others, these regulations restrict the advertisement of prescription-only medicines and prohibit certain specified types of sales promotions to the public, for instance:

• the offer of a prize as an inducement to purchase the therapeutic product;
• the offer of any other health product or medicinal product with a therapeutic product; and
• the offer of any sample of a therapeutic product.

Advertisements of medical devices must comply with the applicable legislative requirements including those under the Health Products (Medical Devices) Regulations 2010 and the HSA’s Guidance on Medical Devices Advertisements and Sales Promotion of Medical Devices. Amongst others, the regulations restrict the advertisement of certain “professional use only” medical devices to only qualified practitioners.

 

18. Where can medicines and devices be sold or delivered? Can medicines and devices be sold or delivered via post?

In Singapore, therapeutic products are classified as prescription-only medicines, pharmacy-only medicines, and general sales list (GSL) medicines. Prescription-only medicines can generally only be supplied by a qualified doctor or dentist, from licensed retail pharmacies or at or from licensed healthcare institutions to their own patients. Pharmacy-only medicines can be supplied by or under the supervision of a pharmacist without a prescription, from licensed retail pharmacies or at or from licensed healthcare institutions to their own patients. GSL medicines can be purchased from any retailer, over-the-counter or by means of an automatic vending machine, provided that the relevant statutory requirements are met.

Medical devices may only be supplied in accordance with the prescribed requirements, which may depend on the risk classification of the medical device and the licence conditions applicable to it. For instance, “professional use only” medical devices may only be supplied by way of administration or application by a qualified doctor or dentist or by a person who is acting under the supervision of a qualified doctor or dentist.

 

19. What are the restrictions and requirements for electronic marketing and advertising via email, by Internet, social media, and other channels?

The advertising and marketing restrictions under the Health Products Act and its subsidiary legislation apply to all forms of advertisements relating to therapeutic products and medical devices, including the following:

• publication in a newspaper, magazine, journal or other periodical;
• display of posters or notices;
• circulars, handbills, brochures, pamphlets, books or other documents;
• letters addressed to individuals or bodies corporate or unincorporate;
• photographs or cinematograph films;
• sound broadcasting, television, the Internet or other media;
• public demonstration of the use of the product or device;
• offer of trials of the product or device to members of the public; and
• sales promotions or campaigns, exhibitions, competitions or any activities meant to introduce, publicise or raise the profile or public awareness or visibility of any product or device for the purpose of promoting the sale or use of the product or device.

All advertisements in Singapore will generally also need to comply with the Singapore Code of Advertising Practice (SCAP). The Advertising Standards Authority of Singapore, a self-regulatory body which enforces the SCAP, acknowledges that it may be difficult to ensure compliance with the SCAP for advertisements received through the Internet and mail-order brochures from overseas. The Appendices of the SCAP contain further guidance in this area, in particular Appendix D on interactive advertisements concerning commercial communications over the Internet and Appendix E on direct marketing of goods sold directly to consumers outside of retail establishments.

 

20. May medicines and devices be advertised or sold directly to consumers?

Prescription-only medicines can generally only be supplied by a qualified doctor or dentist, from licensed retail pharmacies or at or from licensed healthcare institutions to their own patients. Advertisements of prescription-only medicines to the general public are generally prohibited. Pharmacy-only medicines can be supplied by or under the supervision of a pharmacist without a prescription, from licensed retail pharmacies or at or from licensed healthcare institutions to their own patients. GSL medicines can be purchased from any retailer, over-the-counter or by means of an automatic vending machine provided that the relevant statutory requirements are met. Advertisements of pharmacy-only and GSL medicines to the general public are permitted, provided that the relevant regulatory requirements are met. For instance, advertisements of pharmacy-only medicines will generally need to contain or be accompanied by the appropriate advisory or warning statement required by the HSA.

Medical devices may only be supplied and advertised in accordance with the prescribed requirements, which may depend on the risk classification of the medical device and the licence conditions applicable to it. For instance, “professional use only” medical devices may only be supplied by way of administration or application by a qualified doctor or dentist or by a person who is acting under the supervision of a qualified doctor or dentist. Advertisements of such “professional use only” medical devices can be distributed only to, or contained only in a publication intended for circulation mainly among, qualified practitioners.

 

21. How is compliance monitored?

The HSA’s Vigilance and Compliance Branch actively monitors advertisements of therapeutic products and medical devices, amongst others, as part of its routine compliance review and investigations. In this regard, the HSA is empowered to require any advertiser or a manufacturer, importer, supplier or registrant of a medical device to furnish it with copies of any advertisements which have been advertised or are about to be advertised within a specified timeframe.

Where any advertisement is found to be in contravention of the applicable regulatory requirements, the HSA may order corrective measures to be taken, such as requiring the advertiser to:

• stop the advertisement with immediate effect;
• take reasonable measures to remove the offending advertisements that have been published or distributed; and/or
• publish a corrective advertisement in such manner and containing such information as may be specified by the HSA.

 

22. What are the potential penalties for noncompliance?

In relation to non-compliant advertisements, the HSA may order that corrective measures be taken by the person who has advertised or caused the non-compliant advertisement to be advertised. The failure to comply with such order by the HSA may constitute an offence, for which the person may be liable on conviction to a fine of up to S$20,000, imprisonment for a term of up to 12 months, or both.

 

Also from this Legal Handbook

The key facts about conducting preclinical and clinical trials in Singapore. 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. Are clinical trials required to be conducted locally as a condition (stated or implicit) for marketing approval?

No, there is no such express statutory requirement under Singapore legislation.

 

2. How are clinical trials funded?

Clinical trials may be funded by pharmaceutical companies, hospitals, medical technology companies, biotechnology companies and government agencies, among others.

 

3. What are the requirements for preclinical and clinical trial protocols? Who must approve the protocols?

Regulatory approval from the HSA as well as ethics approval from the relevant Institutional Review Board (IRB) are required prior to the conduct of any clinical trial in Singapore.

The clinical trial protocol must be clear and detailed, and describe the objectives, design, methodology, statistical considerations and organisation of a clinical trial. Protocols are also expected to comply with section 6 of the ICH E6 Good Clinical Practice Guidelines, which specify the content to be included in respect of:

• general information;
• background information;
• trial objectives and purpose;
• trial design;
• selection and withdrawal of subjects;
• treatment of subjects;
• assessment of efficacy;
• assessment of safety;
• statistics;
• direct access to source data/documents;
• quality control and quality assurance;
• ethics;
• data handling and record keeping;
• financing and insurance;
• publication policy; and
• supplements

Substantial amendments to the protocol, such as a change to the sponsor or principal investigator of a clinical trial, must be submitted to the HSA for approval or acceptance of notification, whichever applicable.

 

4. What are the requirements for consent by participants in clinical trials?

Generally, prior consent must be obtained in respect of all subjects participating in a clinical trial. This is subject to certain exceptions. Under certain circumstances, consent is to be obtained from a person other than the subject himself, for instance, where the subject is a minor who lacks capacity or sufficient understanding and intelligence to give consent, consent must be obtained from his legal representative.

Full and reasonable explanation on certain prescribed matters must be given to the subject (or the person giving consent on his behalf), including but not limited to the following:

• the purpose of the trial;
• the treatments or procedures to be administered in the trial and the probability for random assignment of each treatment or procedure;
• the procedures to be followed in the trial, including all invasive procedures;
• the reasonably foreseeable risks or inconveniences to the subject and, where applicable, to any embryo, foetus or nursing infant;
• the reasonably expected benefits, including whether there is any intended clinical benefit to the subject;
• any alternative procedures or treatments available to the subject, and their potential benefits and risks; and
• any compensation and treatment available to the subject in the event of injury arising from participation in the trial.

Consent must be in writing and must be signed and dated by the person giving the consent.

Where the person is unable to sign or date the written form, the consent must be signed and dated in the form and manner approved by the relevant IRB and be obtained in the presence of an impartial witness. Should the person giving consent be unable to read, the written form must be read and explained to him in the presence of an impartial witness.

Legal representatives or family members giving consent on behalf of the subject must act in his best interests in accordance with the Mental Capacity Act (Chapter 177A). Relevant factors would include the subject’s past and present wishes and feelings, beliefs and values and other factors he would likely consider if he were able to do so.

 

5. May participants in clinical trials be compensated?

Yes, clinical trial subjects may be compensated for participating in the trial, provided that such compensation is approved by the IRB and neither presents problems of coercion nor undue influence on the trial subjects.

 

6. How are participants in clinical trials protected and indemnified against any harm that arises as a result of participation in the trial?

Clinical trial insurance is typically provided to research participants. Clinical trials conducted by the public healthcare institutions in Singapore with ethics approval are declared for insurance under the National Clinical Trial Insurance, which was initiated in 2015 by the Ministry of Health Holdings, and which harmonises the policy terms and coverage across all public healthcare institutions.

 

Also from this Legal Handbook

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?

AUTHORISATION

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.

 

Medical devices

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.

Pre-submission Preparation

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

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.

Application Screening

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.

Application Evaluation

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.

Regulatory Decision

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.

Post-Approval Changes

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.

MEDICAL DEVICES

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).

For instance:

• 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.