Biosimilars & Biologics
The low-down on the situation regarding biosimilars & biologics in Turkey. Prepared in association with Moroğlu Arseven, a leading Turkish law firm, this is an extract from The Pharma Legal Handbook: Turkey, available to purchase here for GBP 75.
1. Are biosimilar medicines considered the same as generic medicines in your country?
Generic medicines include identical molecules with the original reference product, and these molecules are small and chemically stable molecules produced through chemical synthesis. However, biosimilar is the name of medicine, which is similar (not identical) with the reference licensed biological medicine.
The active ingredient of a biosimilar is only the similar of the reference medicine. Generics are different than biosimilars because they are considered equivalents and includes the same active ingredient. Biosimilar and reference biological medicines are used to treat the same illness with the same effect.
Since every biologic has a unique manufacturing process, it is impossible to produce the perfect identical of a biologic. A biosimilar’s active ingredient should be highly similar to the active ingredient of the reference biological medicine in terms of molecules and biology. The active ingredients of the biologic and biosimilars are basically similar, yet they have different cell lines and a different manufacturing process.
As generics are chemical-based, and the active ingredients of the original and the generic is the same, they are only different in terms of packaging and trademarks.
2. Are all biologic medicines, including biosimilar medicines patentable in your country?
The patents are regulated under the Industrial Property Rights Law numbered 6769 (“IP Law”).
According to the IP Law, in order to be patentable, an invention must be novel, include an inventive step and be industrially applicable.
According to the Intellectual Property Law, the following are considered non-inventions:
- scientific discoveries and theories;
- mathematical methods;
- schemes, methods and rules for performing mental acts, playing games and doing business;
- computer programs;
- literary, scientific and aesthetic works or creations; and
- presentations of information.
Further, under the Intellectual Property Law, the following inventions are considered non-patentable:
- inventions that are contrary to public order or morality;
- inventions concerning plant or animal varieties or essentially biological processes for the production of plants or animals, excluding the microbiological processes or the products thereof;
- diagnostic methods that are practiced on humans or animals and all such treatment methods, including surgical methods;
- the human body at various stages of its formation and development and the discovery of one of its elements, including the sequence or partial sequence of a gene; and
- the use of human embryos for industrial or commercial purposes, including processes for:
o cloning human beings;
o modifying the germline or genetic identity of human beings; and
o modifying the genetic identity of animals in ways that are likely to cause them suffering without any substantial medical benefit to humans or animals.
However, the IP Law notably lacks an explicit definition of ‘biotechnological inventions’, as outlined by Article 52 of the European Patent Convention (“EPC”) and Rules 27 and 29 of the Implementing Regulations. As a result, each patent is evaluated individually, and as long as they meet the general criterion of novelty, an inventive step and are applicable to the industry, such inventions may also be patented.
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?
In general, the identification of biologics is considered harder than the identification of the chemical derivatives. Three-dimensional structure, the amount of acid-base variations or glycosylation profiles may change drastically due to “minor” changes in the production process. Therefore, for biosimilar products, the approach for the generics are not suitable, and thus further comparability studies for quality, safety and efficiency is required.
TMMDA under MoH has published the “Guideline on Biosimilar Medicinal Products” (“Guideline”) in 2009. There are several issues set forth in the Guideline specifically addressing the marketing authorization process for biosimilars.
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?
In general, there are several data, which is required for all types of pharmaceuticals, for their application for marketing authorization. For biosimilars, the Guideline underlines that the following should be met:
- All requirements for quality, efficiency and safety related data for all types of pharmaceuticals should be met including criteria in the monographs of European Pharmacopoeia, in updated guidelines of Committee for Human Medicinal Products and International Committee for Harmonization
- The pharmaceutical form, power and application form of the biosimilar should be the same with the referenced biologic. In this case, additional data should be submitted in terms of comparative studies.
- Any difference between the biosimilar and the referenced biologic should be evaluated through suitable studies for each case.
- Due to different varieties of biologics, additional data required should be determined considering the special features of the specific biologic. If the referenced biologic addresses more than one indication, the efficiency and safety of the biosimilar should be proven for each indication.
In this context, the following are generally required:
- For quality
o Detailed comparison of the features of the products
- For Pre-clinical Phase:
o Depending on the complexity of the molecule, sub chronic toxicity test,
o Local tolerance testing,
o Pharmacokinetics and pharmacodynamics studies
- For Clinical Phase:
o Phase 1 pharmacokinetics and pharmacodynamics studies
o Phase 3 studies for each indication
o Risk Management Plans
5. What are the requirements for the choice of the reference comparator product?
The choice of the reference comparator product should be a licensed pharmaceutical, whose application has been made to the relevant authority in another country including all data for administrative, quality and clinical data.
6. Can the comparator product be sourced from another regulatory jurisdiction? If yes, what are the data needed to support this approach?
Yes. See Question 5 above.
Biosimilars themselves cannot be referenced. Moreover, the reference biologic should get licensed with a full file. The tradename, pharmaceutical form, formulation, production date, and expiry date of the referenced pharmaceutical that shall be used for the comparative study, should be clearly indicated.
The reference standards in the pharmacopoeia, cannot be cited as referenced pharmaceutical. If the referenced pharmaceutical has different strengths, the same strengths should also be chosen for the comparison of the subject biosimilar.
7. How are the prices of biosimilar medicines regulated? Is this any different to the requirements for the original Biologics drug?
In Turkey, the pricing of biosimilars is regulated under the Communiqué on Pricing of Pharmaceutical Products for Human Use (“Communiqué”). According to Article 9/g of the Communiqué, biosimilars’ prices are determined as 100% of its reference price (Reference price means the sale prices to warehouseman. This price is the lowest price of the reference product). If this is not available, the price of a biosimilar is the 100% of the reference price of the referenced original biologic. If the biosimilar of a biologic enters to the market, the reference price of the reference original biologic does not change.
8. What is the reimbursement policy for biosimilar medicine? Is this any different to the requirements for the original Biologics drug?
According to the Communiqué on Health Practices published by the SSI, the financing of treatments and health services which are reimbursed by the SSI is determined under the lists annexed to the Communiqué on SSI’s Health Application. Within these lists, the SSI should evaluate the diagnostics and treatment and confirm that it’s appropriate due to the Communiqué on SSI’s Health Application.
Accordingly, the Commission shall determine the reimbursement to be made by the SSI. There are not specific regulations on the reimbursement of biosimilars, however, there are several biosimilar currently being reimbursed in Turkey.
9. Does biosimilar competition impact the reimbursement policy of the originator reference products?
As explained in Question 7, the reference price of the referenced biologic does not change as a biosimilar enters into the market. Because every biologic product, including the biosimilar is deemed to be a separate product. Neither the reimbursement policy changes with the biosimilar’s market entry. However, considering new market conditions and new competition caused by the launch of the biosimilar and high prices of the biologics, we observe that a voluntary discount can be applied to biologics by the marketing authorization holder to maintain the reimbursement status.
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 not any specific regulation in Turkey for prescribing or dispensing biosimilars. Thus, there are not any differences between biologics and biosimilar in this context.
In general, according to the Regulation on the Classification of Human Medicinal Products, pharmaceuticals are classified only as prescription and nonprescription pharmaceuticals. Both prescription and nonprescription pharmaceuticals are allowed be sold at pharmacies and pharma-organizations only (such as pharmaceutical warehouses) (Article 1, Law on Pharmaceuticals and Medical Preparations). The Turkish legislation prohibits the sale of pharmaceuticals via the Internet or any other electronic medium (Article 24, Law on Pharmacists and Pharmacies).
11. Is the system considering physician-led switching and/or pharmacy-level substitution (without involvement of the clinical decision maker)?
No, there are not any regulation on the interchangeability of the biosimilars with biologics. In general, physicians have discretion to prescribe the biologic or biosimilar versions, where applicable.
The Turkish Law does not regulate interchangeability specifically, the subject is only examined with respect to reimbursement policies. Meaning that pharmacists are entitled to offer patients to switch from a biologic and dispense the biosimilar versions.
In the light of this fact, the reference biologic manufacturer needs to preserve its spot in the reimbursement mechanism and maintain its market share, therefore in order to stay as reimbursed, the referenced biologic companies voluntarily offer further discount around 20%. It is important to underline that such discount does not derive from legal obligations and such decision is only based on marketing strategies. The companies may not choose to offer such discount considering its profitability.
12. What are the post-authorization requirements (including pharmacovigilance, risk management plans, post-approval studies) for biosimilar medicines? Is this any different to the requirements for the original Biologics drug?
No, there are not any specific regulations for biosimilars. However, as stated in the Guideline, Risk Management Plans shall be submitted to the MoH. Moreover, as it is the same for all pharmaceuticals, post-approval safety studies should be conducted, all measures be taken to minimize the risks and the regular risk-benefit reports be prepared.
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?
There are not any specific requirements for labelling biosimilar products in the event of second medical use patents.
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 the patent protection for many biologics expires in 2019 and 2020 in Turkey, there are many preparations in the market to launch upon the expiry date, including the support of the government. Therefore, we expect many lawsuits and other developments in the sector with the launch of new 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?
A draft Guideline on Biosimilar Medical Products was released on 30 May 2017 by the TMMDA. However, there is no indication as to the possible date of entry into force of the draft.