Biosimilars and Biologics
Biosimilars and biologics in Thailand – a legal guide. Prepared in association with Tilleke & Gibbins, a leading law firm in Thailand, this is an extract from The Pharma Legal Handbook: Thailand, available to purchase here for GBP 75.
1. Are biosimilar medicines considered the same as generic medicines in your country?
No. At present, a “biosimilar” is not the same as a generic drug. Previously, some biological marketing authorization licenses were obtained by using the same registration pathway of generic medicines (i.e., without the submission of pre-clinical or clinical studies). From a safety standpoint, the FDA has found that relying on bioequivalence studies alone is not sufficient to demonstrate the similarity of biological-derived products, due to their complexity.
2. Are all biologic medicines, including biosimilar medicines, patentable in your country?
Not all biologic medicines are patentable in Thailand. According to Section 9(1) of the Thai Patent Act, patentability of naturally occurring microorganisms and their components, animals, plants, or extracts from animals or plants are precluded.
Many biological products for human and animal therapies are not entirely naturally occurring, and they may involve human manipulation. Such products are likely to be patentable in the United States and the European Union. In Thailand, however, the Patent Office of the Department of Intellectual Property maintains discretion over whether a biologically derived product—especially one that may be particularly new or ground-breaking—will be considered as manmade or naturally occurring, and also over how much human manipulation is required for a product to be considered manmade. Thus, a patent for a biological product obtained from natural isolation and purification is less certain. The Thai Department of Intellectual Property is more likely to grant patents for biological inventions related to a new formulation or the modification of biological products thereof.
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?
Yes. The Drug Act B.E. 2510 (1969), as amended, is the main act regarding marketing authorization for modern drugs, including biosimilars. The Notification of the Food and Drug Administration Re: Biosimilar Registration Guidelines requires applicants of biosimilar products to provide the following information:
- Administrative data i.e., labeling and package inserts, certificate of pharmaceutical product issued by the regulatory authority in the manufacturing country, GMP certificate issued by the regulatory authority in the manufacturing country, GMP clearance approval letter issued by the Thai FDA, declaration of patent or patent application status, market authorization history, etc.
- Information regarding the biological substance, its manufacturing process, and the comparative physicochemical characterization between the biosimilar and the reference biological product (e.g., molecular similarity, structural analyses, etc.);
- Non-clinical and clinical trial data of comparison studies between the biosimilar and a reference biological product; and
- A risk management plan (RMP).
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?
MA licenses for Biosimilars are approved according to the same standards of other pharmaceuticals, wherein the three main aspects mainly considered are quality, safety, and efficacy. A biosimilar dossier must be prepared in a format using either the ASEAN Common Technical Dossier (ACTD) or the electronic CTD (eCTD), according to International Conference on Harmonization, which must further be composed of three main sections (quality, non-clinical, and clinical). In addition, biosimilarity should be established at all levels (quality, safety, and efficacy) in order to demonstrate that the biosimilar and the reference medicinal product have similar profiles.
5. What are the requirements for the choice of the reference comparator product?
According to the Ministry Notification of July 6, 2018, with regard to the documentation of biosimilar registration, the requirements for the reference product are as below:
- The reference biological medicinal product (RBP) must be a medicinal product authorized by the Thai FDA, on the basis of a complete dossier. Alternatively, the reference biological medical product can be one that is listed in the FDA Notification.
- A single reference biological medicinal product should be used as the comparator throughout the comparability program for the quality, safety, and efficacy studies during the development of a biosimilar in order to allow the generation of coherent data and conclusions.
- However, with the aim of facilitating the global development of biosimilars and to avoid unnecessary repetition of clinical trials, it may be possible for an applicant to compare the biosimilar in certain clinical studies and in in vivo non-clinical studies (where needed) with a reference product authorized outside Thailand that is listed in the FDA Notification. In addition, the applicant is responsible for demonstrating that there are no clinically meaningful differences between the reference product authorized outside Thailand and the reference product authorized by the Thai FDA.
- For demonstration of biosimilar comparability at the quality level, the applicant must conduct a side-by-side analysis of the reference product authorized by the Thai FDA and the biosimilar product, with samples taken from a commercial batch and site. However, combined use of a reference product authorized outside Thailand and a reference product authorized by the Thai FDA is acceptable for the development of the Quality Target Product Profile of the biosimilar product.
- If certain clinical and in vivo non-clinical studies of the development program are performed with the reference product authorized outside Thailand, the applicant should provide adequate data to justify the relevance between the three products (i.e., the proposed biosimilar, the Thai FDA authorized reference product, and the reference product authorized outside Thailand). As a scientific matter, the type of bridging data needed will always include data from analytical studies (structural) or clinical pharmacokinetics or pharmacodynamics.
6. Can the comparator product be sourced from another regulatory jurisdiction? If yes, what are the data needed to support this approach?
Yes, a comparator product authorized outside Thailand is acceptable (see answer to question 5 in Regulatory Pricing and Reimbursement Overview).
If certain clinical and in vivo non-clinical studies of the development program are performed with a reference product authorized outside Thailand, the applicant should provide adequate data to justify the relevance between the three products (i.e., the proposed biosimilar, the Thai FDA authorized reference product, and the reference product authorized outside Thailand. As a scientific matter, the type of bridging data needed will always include data from analytical studies (structural) or clinical pharmacokinetics or pharmacodynamics.
7. How are the prices of biosimilar medicines regulated? Is this any different from the requirements for the original Biologics drug?
In general, manufacturers and importers are free to set prices. Prices of pharmaceutical products, including biologics and vaccines, are regulated when they are listed on the National List of Essential Drugs (NLED), which is a list of medications prescribed by doctors in public hospitals and public health services. The prices of the drugs on this list are subject to a maximum allowable price policy. Therefore, normally, the prices of both a reference biologic product and a follow-on biologic product must be less than the maximum allowable price, if the drug has been listed in the NLED.
The Government Procurement and Supplies Management Act was implemented on August 23, 2017, and aims to ensure that the purchased items are considered value for money, maximizing the effectiveness of the procurement process with transparency and accountability. The Act has an impact on the procurement of pharmaceutical products by state organizations, which include universities and university hospitals.
8. What is the reimbursement policy for biosimilar medicine? Is this any different from the requirements for the original Biologic drug?
There are no differences between the reimbursement policy for biosimilars and that for original biological products. Bilosimilars can be reimbursed by the state when the drugs are listed in the NLED.
9. Does biosimilar competition impact the reimbursement policy of the originator reference products?
Yes. Biosimiliars do have an impact on the reimbursement policy of the originator product. Provided that the biosimilar is interchangeable with that of the reference product, the entering of a biosimilar will result in a reduction of the price of the originator reference products.
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?
Under Thai law (including policy statements), the practice of generic substitution or therapeutic substitution is not explicitly described. Nonetheless, in practice, many hospitals in Thailand have established their own policies, wherein hospital pharmacists can consider generic substitutions on a case-by-case basis using their own discretion. In such cases, the cheapest generic drugs are normally chosen for patients. If the prescribing physician has prescribed a specific brand name and has indicated that no substitution is allowed, then the pharmacist will dispense the specific brand product to the patient.
11. Is the system considering physician-led switching and/or pharmacy-level substitution (without involvement of the clinical decision maker)?
Currently, there are no guidelines for the substitution or interchangeability of biosimilars. The choice of prescription is dependent on the individual discretion of the physician prescribing the biological product.
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?
There are no differences in the post-authorisation requirements between original biological products and biosimilars. Both of them must undergo a mandatory Safety Monitoring Program (SMP). During the SMP, the products will be available only in hospitals. In addition, the company must report adverse drug reactions, as per the template provided by the FDA, for at least two years.
The most critical safety concern is immunogenicity. Both originator and biosimilar applicants must provide a Risk Management Plan (RMP). Risk management applies scientifically based methodologies to identify, assess, communicate and minimize risk throughout a drug’s life cycle so as to establish and maintain a favorable benefit/risk profile in patients. The RMP for biosimilars should focus on heightening pharmacovigilance measures, identifying immunogenicity risks, and providing a description of the potential safety issues that may eventuate as a result of differences in the manufacturing processes.
13. Are there specific policies and requirements for labelling biosimilar medicines in the event of second medical use patents? Is this any different from the requirements for the original Biologic drug?
No. There are no specific policies on this matter. Provided that there is a granted patent for the originator product (whether or not there are primary or secondary patents), the biosimilar must ensure that its product does not infringe the patent rights of the originator company. Normally, the originator will file an indication amendment with the FDA for a second medical use. The labelling of the biosimilar should ensure that it does not infringe the rights of the originator company.
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)
Yes. The FDA announced its Notification 2018 Re: Priority Review of Pharmaceutical Products. When a marketing authorization application is submitted for a product of major public health interest, the applicant may request an accelerated or fast-track review. The FDA will then ensure that the marketing authorization decision is made within 200 days. In addition, the Notification of the Ministry of Public Health announced on July 6, 2018, prescribes updated biosimilar registration guidelines as well as specific guidelines for preparing registration application dossiers for specific types of biosimilars.
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?
At present, there is no update of the legal regulatory framework for biosimilar products. However, it is expected that further regulations for biosimilar products will be enacted in the near future.