The new Regulation on Licensing of the Human Medicinal Products (“Regulation”) prepared by Turkish Medicines and Medical Devices Agency (“Agency”) has entered into force following its publication in the official Gazette numbered 31686 and dated December 11, 2021. The purpose of the Regulation is reflecting processes already existing in the Agency’s practice which were not regulated under the Regulation on Licensing of the Human Medicinal Products dated 2005 (“previous Regulation”) and aligning the legislation with the European Union (“EU”) Directive numbered 2001/83/EC. In this context, the outstanding new provisions have been mentioned below.
Reference and Equivalent Human Medicinal Product
With the amendments made to the article regulating definitions; already existing concepts like human medicinal product and active ingredient have been elaborated and definitions that were not regulated under the previous Regulation such as biosimilars products, hybrid application and licensor company, have been regulated.
One of the most remarkable amendments made to the article regulating definitions is that the original and generic human medicinal product terms have been replaced with reference and equivalent human medicinal product. We are of the opinion that the reason for this amendment is terminological compliance with the existing pricing and reimbursement legislation in Turkey.
Types of Abridged Marketing Authorization Application
The requirements regarding the marketing authorization (“MA”) application and the MA holder are expected to comply pursuant to the Regulation have been regulated in more detailed and clear manner and the decisions given as a result of the MA application have been classified as acceptance, rejection on procedural grounds and rejection on the merits. Additionally, provisions on prioritization processes of the MA application have been included.
As part of compliance with the EU legislation, abridged MA applications have been divided into 7 application types as follows: informed consent application, well-established medicinal use application, allergen product application, equivalent medicinal product application, hybrid application, biosimilar product application and fixed dose combination application.
Within the framework of that article, allergen product application has been added to the types of the abridged applications. Also, regarding the biosimilar medicinal products application; the Regulation refers to the Guideline on Biosimilar Products (“Guideline”) recently published by the Agency, thus a legislative relation between the Guideline and the Regulation has been established.
Besides, it has been regulated that the application made with data obtained from partially reference product data and partially from the studies of the new product is going to be named as hybrid application. A more substantiated criteria has been identified for well-established medicinal use application by stating that an application can be filed if the product is determined to be used for at least 10 years and has a well-established and well-known use with acceptable efficacy and safety.
Availability of Medicines on the Market
In order to preclude the problems on market availability of medicines, comprehensive amendments have been made in the Regulation, especially on articles regulating suspension and withdrawal of the MA and the liability of the MA holder.
According to the provisions of the previous Regulation on suspension of MA, not placing a medicinal product into the market within 3 years after issuance of MA or not providing a medicinal product which has been already launched to the market for an uninterrupted one-year term would be a reason for suspension of MA. The Regulation has set forth following two other grounds for suspension, which provides that the purpose of the Regulation is increasing availability on the market:
- Provided that it is deemed appropriate by the Agency, failure to place on the market at least one commercial batch of a human medicinal product within the first 30 months as of the MA grant date excluding the following circumstances that; the product is not produced for the market of a single country due to the size of the commercial batch or the product is not placed on market in Turkey.
- Determining that the authorized human medicinal products that are within the scope of the QR code application which have been manufactured and placed on the market in Turkey before and at least one commercial batch of the product has not been placed on the domestic or foreign markets for an uninterrupted 30 months; as for the products imported into our country, that they have not been placed on the domestic market for an uninterrupted 30 months; or that the official documents presenting human medicinal product has been placed on the market are not submitted to the Agency, for the products that are not within the scope of the QR code application.
The Regulation has foreseen an undertaking mechanism for the MA holders in case the authorizations are suspended for the abovementioned reasons. According to the mechanism, if the product that the authorization is suspended of, would like to be placed on the market again than an application for removal of suspension can be made to the Agency by undertaking to supply the product to the market in 6 months at latest, in accordance with the procedures determined by the Agency. The suspension will be removed if deemed appropriate by the Agency; however, if the products are not supplied to the market in the term undertaken then the decision will be made according to the provisions on withdrawal of the MA.
Besides, for the sustainability of accessing medicines and for human medicinal products which are important for public health; it has been regulated that the MA will be suspended if these products are not placed on the market by the MA holder despite the Agency’s request, within 6 months as of the request date. However, the Regulation does not contain any provisions specifying the criteria for determining the human medicinal products that are important for public health and the sustainability of accessing medicines.
Lastly, per the amendment made to the responsibilities of the MA holder; if a product available on the market cannot be provided for any reason, the market authorization holder is obliged to notify the Agency at least 30 days before this condition arises, otherwise the MA holder will be subject to suspension of the MA.
The Obligation to Submit Samples for Authorization of Sale is over
Pursuant to the previous Regulation; when obtaining a sales permission for human medicinal products, a sample of the final product produced with the information based on the MA was requested to be submitted to the Agency. The obligation to submit samples has been removed in the Regulation after determining that the difficulties in supplying sample for sales permission causes delays in launching the product on the market and reimbursement processes.
In this context, unlike the previous Regulation, another sales permission is not required to be obtained for the transactions that cause changes in the package information, quality and product information leaflet according to the Regulation. However, a sales permission shall be obtained upon application to the Agency with the documents specified under the article for the following: transfer of workplace from Turkey to abroad or from abroad to Turkey, change in package size, after the MA transfer and before supplying the products to the market for which the suspension is removed pursuant to Article 22 paragraph 5.
Conditional MA and MA under Exceptional Circumstances
Provisions establishing principles on conditional (emergency use authorization) and exceptional MA have entered into force. In this context, applications for conditional and exceptional MA will be examined by Priority Evaluation Committee and both MA types will be issued for a year.
Emergency use authorization (“EUA”), which was entered in our lives in order to provide fast supply of vaccines that will be used against COVID – 19 pandemics, was regulated by a provision that is added to the previous Regulation and a guideline was published just afterward which only covered EUA for vaccines.
With the Regulation, EUA is named as conditional MA and has become applicable for all human medicinal products. In the Regulation, the general criteria of conditional MA are regulated, and it is stated that the EUA Guideline will be applied in terms of evaluating applications. In this context, an amendment must be made in the mentioned EUA Guideline because EUA Guideline only regulates the process of EUA for the vaccines. On the other hand, even though the main reason for the new Regulation is compliance with the EU legislation; UEA and conditional MA, which are regulated as different types of applications in the EU, are considered as equivalent terms.
Pursuant to the Regulation, a periodic benefit/risk evaluation report must be submitted to the Agency upon the Agency’s request or once in every 6 months minimum. The Agency will determine specific requirements for the products with conditional MA to complete the ongoing studies or conduct new studies to ensure that the MA holder fulfills the requirements determined in the Regulation and confirms that the benefit/risk balance is positive. Later, the specific requirements of the conditionally authorized product and the schedule required to complete the requirements will be announced by the Agency on its official website and when all the requirements are fulfilled, the Agency will issue an MA that is not subject to specific requirements.
Exceptional MA was also an existing practice; however, the application criteria, the Agency department which the application will be submitted to, and the validity term of the exceptional MA have been regulated more precisely in the Regulation.
Comment
Taking into consideration that the vaccines were given conditional MA by EU Commission during the COVID-19 Pandemic and the EU Commission stated in a briefing that the conditional MA and EUA are two different processes; it has not been clarified how the conditional MA provisions in Turkey will be implemented before the Agency yet.