5 October, 2016
In 2002, the Thai government initiated a universal healthcare scheme to bring equitable healthcare access to the general public. Under the scheme, hospitals receive per capita funding based on 47 million people. At the outset, per capita funding was approximately USD 38 per person. Now, it is USD 83. Although per capita funding has more than doubled, the current figure is still low. This budget constraint has led the Thai government to favor generic companies, as opposed to originator companies.
Definition of Biological Product
The Thai Food and Drug Administration (FDA) defines a “biological product” as “any allergen, antigen, vaccine, hormone, cytokine, enzyme, product derived from stem cells or tissues, human whole blood and plasma derivative, therapeutic serum, immunoglobulin, or monoclonal antibody which is obtained from one of the following procedures:
- Microbial or eukaryotic cells culture;
- Extraction of substances from biological tissues, including human, animal, and plant tissue;
- Recombinant DNA techniques;
- Hybridoma technique; or
- Propagation of microorganisms in embryos or animals.”
The FDA’s definition of a biological product is quite broad, ranging from the well-established structure molecule to cells and tissues. Most biological products have a relatively large molecular weight and are more complex than conventional chemical drugs.
Patent Prosecution and Litigation of Biological Products
Under the Thai Patent Act 1979, as amended in 1992 and 1999, the term of a patent is 20 years from its filing date. Time is therefore a very important factor for follow-on biologic manufacturers, as they are keen to get into the market as soon as possible. Many of the patents on original biological products are expiring in the near future, which will likely lead to the development of a number of biosimilar products across a range of therapies.
Analogous to the patents of innovative chemical medicines, the common types of patents pursued by innovative biologic companies include compounds (biologics); modification of biologics via gene or amino acid modification; modification of biologics by chemical coupling (e.g., pegylated technology); formulation; and pharmacokinetics. These types of innovative biological products may be deemed as non-patentable subject matter under the Thai Patent Act. In addition, Thailand has notoriously protracted periods of patent examination, especially in relation to pioneering biotechnology inventions. Some applications have taken as long as 15 years to grant.
In the United States and the European Union, naturally occurring substances such as cells and genes are patentable if they have been purified or isolated from preexisting material. This is not the case in Thailand. Section 9(1) of the Thai Patent Act precludes patentability of naturally occurring microorganisms and their components, animals, plants, or extracts from animals or plants. If something exists in nature, but needs to be isolated artificially, that same thing—once isolated—is not entitled to patent protection. An example of this would be biological substances isolated from cell or tissue culture and genes. This distinction has become blurred with the advancement of biotechnology research and development.
Most biological products for human and animal therapies are not entirely naturally occurring. They involve human manipulation and are likely to be patentable in the United States and the European Union. In Thailand, however, the courts maintain discretion over whether a biologically derived product—especially one which may be particularly new and groundbreaking—will be considered as manmade or naturally occurring, and how much human manipulation is required for a product to be considered manmade.
This issue has been argued before courts in many jurisdictions, including the United States, but it has yet to be brought before the Thai courts. While the Thai Department of Intellectual Property is most likely to grant patents for biological inventions related to a new formulation or the modification of biological products by a chemical reaction, a patent for a biological product obtained from natural isolation and purification is less certain. In addition, data exclusivity is currently not available in Thailand for any drug product, and innovative biological products are not exempt. The extension of the patent term and data exclusivity are essential terms that are included in free trade agreements, such as the Trans-Pacific Partnership and Thai-European Union agreements. Due to Thailand’s political instability, including the military coup in May 2014, none of these free trade agreements have been concluded.
In Thailand, various pharmaceutical patent litigations have been argued before the Central Intellectual Property and International Trade Court. But there has not yet been a lawsuit involving a patent relating to a biologic pharmaceutical product. With expensive health expenditures and the universal healthcare scheme enjoyed by the public, there are an increasing number of biologics and biosimilar products appearing in the Thai market. Unlike the United States, where the Biologics Price Competition and Innovation Act has already been enacted, there is no linkage in Thailand between the framework for FDA licensing and patent litigation that results from biosimilar applications.
FDA Regulations and Approval Process
The term “biosimilar” has been a topical issue in Thailand since 2013. There is a high prevalence of serious adverse events associated with the increase in follow-on erythropoietin (EPO) products, based on a classical generic regulatory pathway, which have entered the market. In Thailand, the incidence of adverse events of pure red cell aplasia is eight times higher than that found in other countries. This phenomenon has caused the Thai FDA to reevaluate all EPO Marketing Authorization (MA) licenses.
In addition, some biological MA licenses were obtained with insufficient data compared to international norms. For normal registration pathways, biosimilars require a demonstration of bioequivalence with a reference biological product, without the submission of pre-clinical and clinical studies. From a safety standpoint, the FDA has found that relying on bioequivalence alone is not sufficient to demonstrate the similarity of biological-derived products, due to their complexity.
The biosimilar approach, based on a comprehension comparability exercise including both clinical and non-clinical studies, will then have to be followed.
On October 22, 2013, the FDA published a Notification regarding MA drug registration dossiers for biosimilars, requiring applicants of biosimilar products to provide the following information:
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 reference biological product; and
A risk management plan (RMP).
In addition, the FDA has published specific guidelines for preparing registration application dossiers for the following biosimilars:
- Erythropoietin as a biosimilar product;
- Monoclonal antibody as a biosimilar product;
- Interferon Beta as a biosimilar product; and
- Recombinant Follicle Stimulating hormones as a biosimilar product.
Thailand’s registration regime for biosimilars is aligned with the U.S. FDA’s and European Medicines Agency’s biosimilar approval process, as it was adapted from the latter’s biosimilar registration pathway, which was initiated in 2004. Nonetheless, Thailand lags far behind Europe in the area of biosimilars, and it is expected that more regulations on biosimilars will be enacted in the near future.
Outlook of Biosimilars
To address ever-increasing healthcare costs, Thailand is promoting the entry of biosimilars. With a focus on quality, efficacy, and safety, there is now a distinct registration pathway for biosimilar products. The intellectual property protection available for these innovative products remains uncertain because of the novel and innovative nature of biological products as compared to chemical drugs.
In addition to the uncertainty as to whether biologicals fall within the subject matter of patentable technologies, neither data exclusivity nor patent term extensions are currently available under Thai law. With more advancement in this sector, clarity and further legal and regulatory guidance will likely be implemented.
Trends and Developments
There are now an increasing number of biological manufacturing plants in Thailand. Many of these are focused on vaccines. Siam Bioscience Co., Ltd., a biological manufacturing plant, focuses on the production and commercialization of follow-on biologics. Its biosimilar product pipelines include monoclonal antibodies against cancer and hematologic diseases.
Analogous to the trends of global biological products, the biologicals market in Thailand has grown at a fast pace. There is more widespread use of off-patent biologicals, particularly erythropoietin and insulin. It is likely that the future expanded use of biological products in Thailand will come in the form of biosimilars (follow-on biologics) after the patents on originator products expire.
For further information, please contact:
Alan Adcock, Partner, Tilleke & Gibbins
alan.a@tilleke.com
