iIn Turkey, medicinal products, including biologics and biosimilars, can only be marketed once a marketing authorization has been issued by the General Directorate of Pharmaceuticals and Pharmacy of the Ministry of Health (“MOH”). In order to understand the marketing authorization process in Turkey, it is important to understand how certain terms are defined by the MOH. Important terms include:
1. “Medicinal products” are any natural and/or synthetic active substances or combination of substances (including biological drugs and biosimilar drugs) administered to a human for the purpose of treating and/or preventing disease, making a diagnosis, or correcting or modifying a physiological function.
2. A “substance” is any matter the source of which can or may be human (such as human blood, products obtained from human blood), animal (such as microorganisms, whole animals, parts of organs, animal secretions, toxins, extracts, blood products), vegetable (such as microorganisms, plants, plant parts, vegetable secretions, extracts), or chemical (such as elements, naturally occurring chemical materials, chemical products obtained by chemical change or synthesis).
3. An “active substance” is any pharmacological active substance used in medicinal products.
4. A “registered medicinal product for human use” is a medicinal product, approved by the MOH, which is presented to the market in ready form, in special packaging, with a specific name.
5. A “biological drug” is a product requiring manufacturing and control procedures as well as a combination of physicochemical biological tests to determine the quality of an active substance and is produced or extracted from a biological source. Examples of a “biological drug” include: (a) immunological products; (b) blood products; (c) products obtained through recombinant DNA technology in prokaryotic and eukaryotic cells, the controlled expression of genes coding for biologically active proteins, including transformed mammal cells, hybridoma and monoclonal antibody methods; (d) advanced medical treatment products which concern manufacturing processes involving biological molecules in which the active substance is produced in whole or in part by means of gene transfer and/or genetically modifying cells for the purpose of advanced biological and/or medical treatment; and (e) reagents from which the active substance is not directly derived, namely, products derived from a culture medium, bovine fetus serum, additives, chromatography, etc.
6. A “biosimilar drug” or “biosimilar product” is a medicinal product which demonstrates similarity to a designated or retained biological (medicinal) reference product (“biological reference product”) in terms of quality, safety and efficacy. The active substance of a biosimilar drug or product is similar to a biological reference drug. Generally, a biosimilar drug and a biological reference product are used at the same strength to treat the same disease. Typically, the only difference between a biosimilar drug and a biological reference product is the trade name, appearance and packaging.
7. A “designated or retained biological (medicinal) reference product” or “biological reference product” is a biological drug for which a complete application, including administrative, quality, pre-clinical and clinical data, has been made and approved by a regulatory authority outside of Turkey (such as the FDA or EMA).
Biologics
In Turkey, to obtain approval of a new biological product, an applicant must submit a “full” application to the MOH. A “full” application involves providing sufficient information to demonstrate the quality, safety and efficacy of the new biological product for the indications requested. As will be discussed in more detail below, this information includes complete and detailed information regarding the biological product, pre-clinical studies (including toxicity studies, pharmacokinetic studies (“PK studies”), pharmacodynamic studies (“PD studies”), local tolerance studies, etc.), phase I, II and III clinical studies (in all indications for which approval is sought), as well as a risk management plan. The phase I, II and III clinical trials (for either a biological or a biosimilar) can be conducted in a country other than Turkey provided that the clinical trials have been approved by the regulatory authority of that country (such as the FDA, EMA, etc.).
Some of the information that an applicant must submit to the MOH when seeking approval for a new biological product includes:
1. The name, permanent address, e-mail, telephone and fax number of the applicant;
2. The name, permanent address, telephone and fax number of the manufacturer;
3. The name of the medicinal product;
4. The quantitative and qualitative particulars of the constituents of the medicinal product using common terminology (except for the empirical chemical formula) and its international non-proprietary name (“INN”) as recommended by the World Health Organization (where applicable);
5. A description of the manufacturing method;
6. A description of the therapeutic indications, contraindications, adverse reactions, special precautions for use (including descriptions involving use during pregnancy and lactation, interaction with other drugs and other forms of interactions, symptoms, emergency procedures and antidotes in the event of an overdose, special warnings, effects on the ability to drive and use machines, etc.);
7. The dosage, pharmaceutical form, method and route of administration, shelf life and amount contained in a package;
8. An indication of the disposal method for waste products (after consideration of the storage conditions of the medicinal product, its administration to patients and the potential risks presented by the medicinal product to the environment);
9. A description of the control methods used by the manufacturer (including quantitative and qualitative analysis of the constituents and finished products, sterility tests, pyrogen substances, tests for measuring the presence of heavy metals, stability tests, biological and toxicity tests, controls conducted during the intermediate phase of manufacturing, etc.);
10. Results of physicochemical or microbiological tests;
11. Toxicological, pharmacological tests and clinical studies (namely, phase I, II and III);
12. For new medicinal products that are to be imported (rather than manufactured in Turkey), a summary of the product characteristics drafted by the originating company and an indication of the term of validity (there are 3 different terms of “validity”, specifically, (a) the “proposed” shelf life of the product; (b) the shelf life of the product after the packaging has been opened; and (c) the shelf life of the product after dilution), package insert and a mock-up of the proposed packaging;
13. For new medicinal products that are to be imported, a document drafted by the originating company, along with a Turkish translation thereof, indicating that the real or legal person importing the product is the sole authorized representative for the manufacture, registration and sale of the product in question or a co-marketing representative, where applicable;
14. For new medicinal products for which the manufacturing of the product is licensed to a third party, a document drafted by the originating company along with a Turkish translation thereof, indicating that the real or legal person manufacturing the product is the sole authorized representative for the manufacture, registration and sale of the product in question or a co-marketing manufacturer, where applicable;
15. A good manufacturing practice (“GMP”) document approved by the MOH or a competent authority of a relevant country (such as the FDA, EMA, etc.), indicating that the manufacturer will manufacture the product in accordance with GMP rules;
16. In the event that the applicant is not the manufacturer of the new biological product, a notarized toll manufacturing agreement signed with the manufacturer (the agreement must contain the conditions specified in the Regulation on Manufacturing Sites of Medicinal Products for Human Use as published in the Official Gazette dated 23/10/2003, no. 25268);
17. A list of other countries where an application for the biological product has been submitted for approval by a competent authority (such as the FDA, EMA, etc.) and a certified copy of a Pharmaceutical Product Certificate issued by such authority in any other country or countries where the product has been approved and introduced into the market;
18. Description of the potential risks to be imposed on the environment by the new biological product upon consideration of the provision of the Regulation on Radiation Safety, enforced by the Decision dated 24/07/1985, no. 85/9727 of the Council of Ministers, the Regulation on the Safe Transportation of Radioactive Substances, published in the Official Gazette dated 10/09/1997, no. 23106, the Regulation on Radiation Safety published in the official Gazette dated 24/03/20002, no. 23999, and the Regulation on the Waste Formed in the Use of Radioactive Substances, published in the Official Gazette dated 02/09/2004, no. 25571;
19. A summary of the product characteristics as specified in the legislation pertaining to the packaging and labeling and a package insert prepared accordingly, mock-ups of the immediate outer-packaging including the size and design to be used in the market, the original summary of the product characteristics approved by competent authorities in other countries for products imported or manufactured under a license, including the product insert and package mock-ups; and
20. A list of the countries in which a biological product has been rejected, recalled or suspended by a competent authority or in which the applicant has withdrawn the product, including specific and detailed information regarding the rejection, recall, suspension or withdrawal and the steps taken by the applicant to rectify the problem.
Biosimilars
In Turkey, to obtain approval of a “biosimilar product”, an applicant must submit an “abridged” application to the MOH. The “abridged” application must demonstrate that there are no significant differences in terms of the quality, safety or efficacy between the biosimilar product and a biological reference product. In addition, a sponsor of a biosimilar product must comply with the requirements of Annex I of the Turkish Regulation for Approval of Human Medicinal Products, the technical requirements of the European Pharmacopeia monographs and any additional general requirements related to biosimilar products described in the guidelines of the Committee for Human Medicinal Products (“CHMP”) and the International Committee for Harmonisation (“ICH”).
To demonstrate the “quality” of the biosimilar product, the “abridged” application must include complete and detailed information regarding the biosimilar product, including head-to-head comparability studies with the biological reference product. For example, a biosimilar applicant must provide (1) data demonstrating that the active substance of the biosimilar product exhibits molecular and biological similarity to the active substance of the biological reference product; (2) biological activity, immunochemical properties and physicochemical studies; (3) purity and impurity studies, including an impurity profile; (4) stability data; (5) in vitro dissolution studies; and (6) data demonstrating that the pharmaceutical form, strength and route of administration of the biosimilar product and the biological reference product are the same (if they are not the same, then additional data will need to be presented to show comparability).
In addition, in order to demonstrate safety and efficacy of the biosimilar product, an “abridged” application will need to provide data from pre-clinical and clinical studies. Specifically, with respect to data from pre-clinical studies, an applicant must provide in vivo data showing the comparability of the biosimilar product and the biological reference product with respect to: (1) at least one repeat dose toxicity study (up to 4 weeks); (2) local tolerance; and (3) PK and PD studies.
Finally, a biosimilar applicant will need to present comparability data from clinical studies. Specifically, a biosimilar applicant will need to present data from phase I PK and PD studies (the PK and PD studies can be combined provided that the PK/PD relationship is characterized) as well as phase III studies (for each indication for which approval is sought). No phase II clinical trials are required. The clinical trial data submitted can be data from clinical trials conducted outside of Turkey provided that the clinical studies were done with the approval from a competent authority (such as the FDA, EMA, etc.) and are comparative with the biological reference product. In addition, a risk management plan will also be required.
Data Exclusivity
In Turkey, a biosimilar product cannot be marketed at any point during the period of data exclusivity for a biological reference product. However, according to the Guidelines on Biosimilar Medicinal Products in Turkey, biosimilar products are exempt from the data exclusivity period if “additional”studies, which are not required to be submitted for the biological product, are submitted to the MOH for approval. Interestingly, the regulations are silent as to the type of “additional” studies that would be accepted by the MOH.
In many countries, the periods of patent exclusivity and regulatory data exclusivity are completely independent and separate from each another. However, in Turkey, this is not the case. In Turkey, the period of data exclusivity is tied to the term of any issued Turkish patent having claims that encompass the active substance of the biological reference product. Specifically, the data exclusivity period for a biological reference product is 6 years from the date of first registration of the product in the European Customs Union (which comprises the member states of the European Union (such as Great Britain, Germany, France, Italy, etc.) as well as some other non-European Union countries (such as Turkey)). However, this 6 year data exclusivity period is limited to the term of any issued Turkish patent having claims that encompass the active substance of the biological reference product. Specific examples of how the data exclusivity period is calculated are provided below.
Example 1: A biological reference product receives marketing approval in Germany in August 2013, which is the date of first marketing approval (date of registration) for the product in any European Customs Union (“ECU”) country. Marketing approval for the product is granted by the MOH in Turkey in December 2013. A patent covering the biological reference product (a humanized antibody) expires in February 2020 in Turkey. Under this scenario, data exclusivity would be available for the biological reference product in Turkey until August 2019.
Example 2: A biological reference product receives marketing approval in the Netherlands in August 2011, which is the date of first marketing approval (date of registration) for the product in any ECU country. Marketing approval for the product is granted by the MOH in Turkey in August 2013. A patent covering the biological reference product (a humanized antibody) expired in March 2012 in Turkey. Under this scenario, no data exclusivity would be available for the biological reference product in Turkey.
Example 3: A biological reference product receives marketing approval in Great Britain in August 2013, which is the date of first marketing approval (date of registration) for the product in any ECU country. Marketing approval for the product is granted by the MOH in Turkey in December 2013. A patent covering the biological reference product (a humanized antibody) expires in October 2016 in Turkey. Under this scenario, data exclusivity would be available for the biological reference product in Turkey until October 2016.
Biosimilars in Turkey
To date, two biosimilars have been approved by the MOH in Turkey. The first is “Leucostim” (the licensee of which is Dem İlaç, a Turkish pharmaceutical company, and the manufacturer is DONG-A PHARM. CO., LTD., a South Korean pharmaceutical company) which contains the active substance filgrastim. The second is “Epobel” (the licensee is Nobel İlaç, a Turkish pharmaceutical company, and the manufacturer is STADA Arzneimittel AG, a German pharmaceutical company) which contains the active substance epoetin zeta.
Canan Ozturker and Aydin Deris from Deris Patents & Trademarks Agency A.S. also contributed to this article.
