Biosimilars & Biologics
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
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.
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.
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?
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:
- Singapore-Specific Annex (SSA);
- Latest version of the approved EU-RMP and/or US REMS (where available); and
- 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.