Biosimilars and Biologics
The key facts about biosimilars and biologics in Japan. Prepared in association with Nishimura & Asahi, a leading law firm in Japan, this is an extract from The Pharma Legal Handbook: Japan, available to purchase here for GBP 75.
1. Are biosimilar medicines considered the same as generic medicines in your country?
A biosimilar medicine is differentiated from a generic medicine in the point that final biosimilar products possibly differ from the original product, depending on the manufacturing process. This is because the production of biosimilars is much more complicated due to the complex molecular structure and unique manufacturing process of biopharmaceuticals; on the other hand, producing generic medicines is not difficult because ordinary pharmaceuticals have simple and stable low-molecular compounds. This means an authorization for biosimilars does not constitute evidence of pharmaceutical equivalence, bioequivalence or clinical equivalence to the original (preceding) biopharmaceuticals.
2. Are all biologic medicines, including biosimilar medicines, patentable in your country?
Yes, as long as the biologic medicine meets the requirements of the Patent Act, its patentability is assured. However, in Japan, the patentability of biotechnological products is not specifically provided for in the act and other laws.
In this regard, Japan has not yet established a statutory system which coordinates the relationship between market approval for generic medicine and the patent status of its branded original, called a patent linkage system such as referred to in the Drug Price Competition and Patent Term Restoration Act of 1984 (known as the Hatch Waxman Act); nevertheless, a similar system has been put into practice at the governmental notification level.1 Under this coordination system, companies cannot obtain marketing approval for a generic medicine prior to the expiration of the patent term on the branded equivalent.
Please note, however, it is uncertain whether the word “generic medicine” in the notification includes biosimilar medicines. This suggests that it is possible that biosimilar medicines will not be treated in the same way as generic medicine, resulting in a situation where biosimilar medicines cannot acquire linkage protection. Therefore, the situation surrounding the patentability of biotechnological products is significantly different from other countries which have particular biopharmaceutical-protection systems, such as the Biologics Price Competition and Innovation Act in the United States.
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?
No. Please refer to Q2 with regard to the relationship between market appro-val for a biosimilar medicine and the patent status of its branded original.
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?
Under the Act on Securing Quality, Efficacy, and Safety of Products Including Pharmaceuticals and Medical Devices, which provides the need for market approval, there is no difference between the approval requirements for biosimilar drugs and the ones for other drugs. However, in many cases, it is difficult to prove the identity of the active ingredients between the original Biologics drug and its biosimilars, so it is thought that the same approval approach for generic products cannot be applied to biosimilars.
Given this situation, MHLW specifically issued a notification and guideline for market approvals for biosimilars.2 According to this documentation, the essential data required to obtain approval for a biosimilar drug are (1) data detailing the origin or history of discovery and usage status in foreign countries; (2) data detailing the manufacturing method, standards, test methods, etc.; (3) data detailing stability; (4) data detailing pharmacological action; (5) data detailing toxicity; and (6) data detailing the results of clinical studies. In addition to these data, depending on the nature of the biosimilar product, other data may be required.
5. What are the requirements for the choice of the reference comparator product?
According to MHLW’s guideline, the reference product to which a biosimilar should be compared is the biologic drug that was already authorized on the basis of a complete data package in Japan. Another biosimilar can never be used as a reference product for the whole duration of the biosimilar development period (including the quality development period, non-clinical development period, and clinical development period).
6. Can the comparator product be sourced from another regulatory jurisdiction? If yes, what are the data needed to support this approach?
No. As mentioned at Q5, under MHLW’s guideline, the reference comparator product must be a drug which was already authorized in Japan.
7. How are the prices of biosimilar medicines regulated? Is this any different from the requirements for the original Biologics drug?
In Japan, drugs are typically expected to be used under the auspices of the national health insurance system. The Japanese government determines the price of medicines by using a model prescribed under the national health insurance pricing system.
The price of a new biosimilar medicine is generally determined by multiplying the standard price (which is calculated based on the price of the most similar drug to the biosimilar medicine) by 70%. However, for internal medicines, when the brand number of the same kind of biosimilar product (limited to those with similar efficacy and effect to the new biosimilar product) exceeds 10, the new biosimilar medicine’s price is determined by multiplying the standard price (as calculated the same above) by 60%. Exceptionally, based on the results of clinical trials, it may be possible to add a 10% premium at most to the price of new biosimilar medicine.3
8. What is the reimbursement policy for biosimilar medicine? Is this any different from the requirements for the original Biologic drug?
Biosimilar medicines are reimbursed as well as other drugs under the National Health Insurance system. There is no special reimbursement procedure for biosimilar medicines.
In this regard, the Japanese government has promoted the development and use of biosimilars, and introduced special treatment regarding self-injection of biosimilars by patients, under which a certain price is added to self-injection instruction management charges when biosimilars are prescribed with the patient’s consent. Please note that this treatment is one kind of reimbursement (medical fee) revision under the National Health Insurance system, notwithstanding the medicine price decision itself based on the Act on Securing Quality, Efficacy, and Safety of Products Including Pharmaceuticals and Medical Devices. This treatment has been enforced since April 1, 2020.
9. Does biosimilar competition impact the reimbursement policy of the originator reference products?
Yes. The Japanese government has promoted biosimilars, which means there is possibly a strong competitive effect on the existing biopharmaceuticals market. This is mainly due to the fact that they are less expensive (as mentioned at Q7) and in light of the reimbursement policies (as mentioned at Q8). The Japanese government is planning other strategies to accelerate the introduction of biosimilars into medical practice in Japan, so it is necessary to continue monitoring its movement.
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?
There is no particular legal framework for prescribing biosimilars.
11. Is the system considering physician-led switching and/or pharmacy-level substitution (without involvement of the clinical decision maker)?
Switching patients from biologics to the biosimilar versions is fundamentally permitted for doctors. There is no evident rule banning pharmacists from changing biologics to biosimilars, but it is not recommended that pharmacists do so in medical practice.
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?
Manufacturers must set up methods for post-marketing safety control for pharmaceuticals (referring to collecting and reviewing matters related to quality, efficacy and safety, and other information necessary for the appropriate use thereof, and necessary measures based on the results), and such methods have to comply with the standards specified by order of MHLW. This rule also applies to biosimilar medicines, but if their efficacy and safety are assured by the original biologics drugs, they are exempt from such rule, including post-marketing safety control research.
However, a guideline by MHLW (referred at Q4) suggests that manufacturers should research the safety profile of biosimilar medicines. Regarding this post-marketing safety control research, the guideline also requires that manufacturers anticipate risks that could not be sufficiently evaluated by the equivalence / homogeneity evaluation in the development stage, formulate an appropriately designed post-marketing surveillance plan based on that risk, and submit it to the authority when applying for approval. In addition, the guideline provides that the results of such post-marketing surveillance plan should be delivered to the authority by the appropriate time after approval of the biosimilars.
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 and requirements regarding the labelling of biosimilar drugs in the case of a second medical use patent.
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. In recent years, the Japanese government has promoted biosimilars in some way. Please refer to Q7 and Q9.
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?
Yes. In recent years, the Japanese government has promoted biosimilars in some way. Please refer to Q7 and Q9.
- The the Minister of Health, Labour and Welfare (“MHLW”) as the Japanese authority issued a notification detailing this matter: https://www.mhlw.go.jp/web/t_doc?dataId=00tb5511&dataType=1&pageNo=1
Please refer to the detailed calculation method; online: https://www.mhlw.go.jp/content/000497468.pdf