Regulations of the pharmaceutical industry, Clinical Trials in Turkey
The Pharmaceutical legislation of Turkey
The Code on Pharmaceuticals and Pharmaceutical Preparations No. 1262 (Pharmaceutical Code) is the fundamental piece of legislation that is applied through secondary legislation such as regulations, communiqués, and recommendations to further govern all aspects of the pharmaceutical sector. Even though Turkey is not a member of the European Union, its pharmaceutical legislation is frequently influenced by EU practice, and the majority of secondary legislation and soft law materials are derived from relevant EU directives. Furthermore, sector-specific legislation may have an impact on pharmaceuticals, even while it applies to a variety of other industries that overlap with pharmaceuticals but are not regulated under the Pharmaceutical Code.
National Health Care system of Turkey
The Code on Fundamental Health Services No. 3359 empowers the Ministry of Health to make healthcare laws and create an equal healthcare system that is accessible to all Turkey.
The Ministry of Health is responsible for the establishment of hospitals and public health facilities that provide medical services to the general public. These services are paid for out of the state's healthcare budget. Reimbursement of health services given by health institutions, including physical examinations, operations, and medical testing, is usually covered by general health insurance, which is funded by patient contributions. Pharmaceuticals prescribed to patients are repaid by the Ministry of Health's reimbursement plan, which is supported by direct personal payments or deductions from public officials' income.
Due to the widespread coverage of public health insurance, the Turkish state is the largest customer in the pharmaceutical sector. With the implementation of the General Health Insurance legislation, it is projected that everyone residing in Turkey will be covered by state health insurance. The Ministry of Health is the primary regulating body. Its organization, the Pharmaceutical Products and Medical Device Institution, are in charge of overseeing the pharmaceutical industry (Institution). All aspects of pharmaceuticals are regulated by the Institution, including marketing authorization, production, pricing, import/export, and clinical trials.
The Ministry of Health and the Institution are both national governmental agencies with jurisdiction over the entire country. Inspections of public and private businesses in the medical and pharmaceutical sectors, on the other hand, are carried out by the Ministry of Health's provincial directorates.
The Institution has the authority to control the pharmaceutical industry's advertising efforts. Furthermore, under the Turkish Commercial Code, firms involved in the pharmaceutical and medical sectors are subject to advertising laws (for example, unfair trade practice regulations). As a result, the entities in the pharmaceutical sector are also scrutinized by the Advertisement Board for any violations of such restrictions.
Funding of the medicinal product by the government
The Social Security Institution (SSI) is in charge of pharmaceutical reimbursement. The SSI acquires most pharmaceutical products produced in Turkey through the reimbursement system because the general coverage of public health insurance in Turkey is relatively large. Pharmaceuticals must be registered with the SSI's reimbursement list to be reimbursed by the public health system. This means that extra discounts of up to 41% are applied to product prices, depending on the price specified by the March 2013 Health Implementation Communiqué (as amended periodically). Furthermore, the SSI established an alternative reimbursement system that may result in further discounts being applied to product pricing, depending on case-by-case agreements negotiated and signed between pharmaceutical companies and the SSI.
The Code on Pharmacists and Pharmacies governs pharmacies, which sell pharmaceutical products obtained from pharmaceutical warehouses. In circumstances when the patient's pharmaceutical product requires a prescription, the pharmacist should request one and submit it to the SSI's MEDULA online system. The pharmacy does not collect any money from the patient if the prescription includes products on the reimbursement list (or only collects the portion exceeding the reimbursement percentage). The patient is usually responsible for pharmaceutical items and treatments that are not on the SSI reimbursement list.
Patients, on the other hand, are free to use private insurance policies. Private insurance policies typically cover pharmaceutical items and treatments that are not covered by the SSI's reimbursement list more comprehensively (i.e., they either cover a product or treatment that is completely excluded from the SSI's reimbursement list or provide a larger percentage of payment). It is also common for private insurance policies to allow patients to receive treatment not only in public hospitals but also in private hospitals.
Regulations of Clinical trials
Clinical trials are governed by Article 10 of the Fundamental Health Services Act No. 3359. The Regulation on Clinical Trials of Medicinal Products for Human Use and Biological outlines the regulatory requirements for clinical trials. The relevant EU directives on appropriate clinical practices, as well as the Ministry of Health's Good Clinical Practice Guideline, are factored in this legislation. The Pharmaceutical Product and Medical Device Institution Clinical trial Dept has the jurisdiction to adjudicate on clinical trial-related matters, including applications.
Clinical trials can only be performed with the Institution's permission, according to Article 10 of the Code on Fundamental Health Services No. 3359. Sponsors of clinical trials must apply for such approval. Although it is permissible to apply for Institutional authorization and ethics committee approval at the same time, the ethics committee permission must be included in the application file. University hospitals, teaching and research hospitals, and public hospital associations all have local ethical committees.
In multi-centre trials, the permission of one local ethics committee (of the co-ordinating clinical centre) is required
- The procedure and documentation used to inform trial subjects must be approved by the local ethics commission.
- Trial participants' consent.
- Concerns about the rights, safety, and well-being of trial participants.
Sponsors have the right to apply for and run trials through contract research organizations (CROs) based in Turkey under the Clinical Trials Regulation, but they are obligated to do so if they do not have a representative in Turkey. Clinical studies can also be transferred between sponsors under the Clinical Trials Regulation. In circumstances where the sponsor wishes to transfer the clinical trial to another sponsor, the sponsor must notify the Institution and the ethics committee, according to Article 21 of the Regulation on Clinical Trials. If the transfer is approved, the Institution notifies the sponsor that it is possible to effectuate the transfer.
Under the Regulation on Clinical Trials, clinical trial subjects or their legal representatives must be informed about the trial via an informed consent form, which must include, among other things, information such as the trial's objective, methodology, expected benefits, foreseeable risks, difficulties, and properties of the trial that may be unfavourable to the subject—conditions for conducting the study, as well as the subject's ability to withdraw from it. The informed consent form should be written in an easy-to-understand manner and contain enough information. The Ministry of Health publishes the minimum content criteria for these forms regularly, and the forms are updated as needed to meet these standards.
Manufacturing and distribution of Medicinal Products in Turkey
The Pharmaceutical Product and Medical Device Institution must receive applications for manufacturing and distributing medical products in Turkey (Institution). Before beginning operations, not only the producers but also the marketers, importers, and distributors of pharmaceutical products should get authorization. Under Turkish legislation, there are no blanket authorizations. Thus, each product must apply for authorization separately.
The Manufacturing Regulation lays out the requirements for obtaining authorization to manufacture medicinal items, which includes
- Hiring a production manager, a quality assurance manager, a quality control manager, and enough staff with the requisite knowledge and experience with pharmaceutical products, which are held accountable for the manufacturing process by the manufacturer and the Institution.
- Forming a quality assurance group.
- Obtaining a Good Manufacturing Practices (GMP) certificate and ensuring that the manufacturing facility follows the criteria of good manufacturing practices for medical products (global standards in regards to good manufacturing practices are followed in Turkey).
- Outlining the workplace’s opening and operating permits, as well as production flow diagrams.
- Outlining the environmental impact assessment report.
Monitoring compliance and Imposing Penalties
Before or after giving the authorization, the Institution has the right to inspect and examine the manufacturing site. An inspection is not required to be announced in advance by the Institution. The Institution will prepare a report on the manufacturing site's compliance with legal standards after an inspection. Inspectors may collect the product and active substance samples, as well as papers and records from manufacturing sites, if necessary. The Institution has a wide range of inspection and collecting authorities.
Administrative fines range from TRY 17,094 to TRY 854,804 can be issued under Article 18 of the Pharmaceutical Code for manufacturing, selling, and/or delivering pharmaceutical items that do not conform with the law. Repeated offences result in doubled penalties. The fine can be appealed to the administrative courts by the person who received the sentence.
According to Article 5 of the Licensing Regulation, pharmaceutical products cannot be launched on the market before obtaining a license to be granted by the Ministry of Health. To obtain a license, real persons or legal entities resident in Turkey shall apply to the Ministry of Health by submitting the documents listed under the Licensing Regulation, published in the Official Gazette dated January 19, 2005, and numbered 25705.
Pharmaceutical items cannot be released on the market without first acquiring a license from the Ministry of Health, according to Article 5 of the Licensing Regulation. Real persons or legal entities residing in Turkey must apply to the Ministry of Health for a license by providing the documentation stipulated in the Licensing Regulation, which was published in the Official Gazette on January 19, 2005, and numbered 25705.
The application documents include, among other things,
- a description of the manufacturer's control methods;
- toxicological and pharmacological tests and clinical trials; and
- a certificate (and a Turkish translation thereof) issued by the licensor where a pharmaceutical product is manufactured under a license (granted by a third-party owner of intellectual property) or will be imported. Or, if applicable, a certificate indicating that a real person or legal organization other than the only authorized representative in Turkey has been authorized for co-marketing, as well as the written consents of the real people or legal organizations who will be involved in co-marketing activities.
Marketing of Medicinal Products
The Pharmaceutical Product and Medical Device Institution must be contacted to obtain a marketing authorization for pharmaceutical items (Institution). The documents required in the Licensing Regulation should be included in the application. The list of required documents includes, among other things, the applicant's trade registry records, the applicant's information, details about the manufacturer, the product's indications and adverse effects, all relevant information about the product (e.g., dosage, pharmaceutical form, shelf life, etc.), GMP certificate, and documents demonstrating the product's compliance with other jurisdictions. The following items can be marketed without a marketing authorization, according to Article 2 of the Licencing Regulation:
- Pharmaceuticals made for a specific patient using a magistral formula,
- Products manufactured by pharmacies using pharmacopoeia formulas, which are well-known for their formulations;
- Pharmaceuticals that are used in research and development studies
- Semi-products destined for use by the manufacturer at a later stage
- Radionuclide sources that are sealed
- Human whole blood, plasma, and blood fractions
- Implementation of allergens for allergy diagnosis using personalized allergens and skin testing.
The Institution must consider the following criteria when deciding whether to give a marketing authorization for a Human Medical Product, according to Article 16 of the Licensing Regulation:
- Whether it is effective in the conditions for which it was designed.
- Whether the safety of the pharmaceutical product has been established.
- Whether the pharmaceutical product has the technical and pharmaceutical properties that are required.
According to Article 7 of the Licensing Regulation, legal entities seeking marketing authorization must employ at least one individual with a bachelor's degree in pharmacy, medicine, or chemistry who is also qualified to practice one of these professions in Turkey.
If a pharmaceutical product is to be imported into Turkey, Article 8 of the Licensing Regulation stipulates that the applicant must submit a certificate, together with a Turkish translation, stating that the applicant is a representative authorized to import, authorize, and sell the medicinal product in Turkey.
A human medicinal product's marketing authorization is valid for five years. Three months before the marketing authorization's expiration date, information on the medical product's quality, safety, and efficacy, as well as pharmacovigilance data, must be submitted to renew the marketing authorization. Failure to renew the marketing authorization within five years does not mean that the license will automatically expire. The renewal procedure for pharmaceutical items is not always followed in practice, and certain drugs are now on the market without having their authorizations renewed.
Apart from acquiring an import license in line with the Licensing Regulation, a certificate of control must be obtained from the Ministry of Health for the import of pharmaceutical items, according to the Communiqué on Import of Certain Products that are Audited by the Ministry of Health (and active substances). This certificate of control must be obtained before the importation of the relevant pharmaceutical product by submitting specified documents, including a pro forma or standard invoice, a certificate of analysis, and an approved health certificate provided by the responsible authority in the country of origin.
Except for certificates of control issued for pharmaceutical substances subject to the Communiqué on Standardization of Foreign Trade concerning Import of Certain Substances Requiring a Special Permit to be obtained from the Ministry of Health (Communiqué No: 2011/4), which are valid for a term of 6 months, all certificates of control are valid for 12 months.
Market exclusivity and generic pharmaceuticals
Market exclusivity is designated in European Union regulations as a two-year term during which a novel medicine is shielded from direct competition from generics. Please be aware that there is no express provision for market exclusivity in Turkish law.
However, it would not be inaccurate to say that the Ministry of Health's interpretation of data exclusivity protection equates to simply market exclusivity. We've found that the Ministry of Health's data exclusivity policy is to allow shorter license applications referring to an original product that is still protected by data exclusivity but withholds sales approval until the original product's data exclusivity period expires.
Restrictions on dealings with health care professionals
The Regulation on Promotional Activities of Medicinal Drugs for Human Use and the Regulation on Sales, Marketing, and Promotion of Medical Devices both provide restrictions and limits on how human medicinal products and medical devices are marketed. The following are examples of these:
- Human medicinal products and medical devices that are only intended for use by healthcare professionals or are on the reimbursement list of the Social Security Institution cannot be advertised to the general public.
- The value of promotional materials/gifts cannot exceed 2.5 per cent of the Turkish monthly gross minimum wage (currently around TRY74).
- Offering any rewards or incentives to healthcare practitioners is forbidden to encourage the prescription, usage, and referral of medicinal items and medical devices.
- The promotion of human medicinal products and medical devices (for which public marketing is prohibited) is only allowed if it is done through brochures, symposiums, meetings, or personal contact.
Symposiums or conferences attended by healthcare professionals that are sponsored by marketing authorization or sales (for medical devices) permit holders are also controlled and strictly supervised by the Institution in terms of the amount of sponsorship, the location of the symposium or meeting, the types of costs reimbursed, and so on. The holders of marketing authorizations must notify the Institution of any symposiums or conferences that they are sponsoring. Donations are also subject to restrictions.
Furthermore, public officials are prohibited from receiving or requesting gifts or favours under Article 29 of the Public Officials Code and Article 15 of the Regulation on the Principles of Ethical Conduct of Public Officials. Article 252 of the Criminal Code makes receiving or providing a bribe with a criminal offence. Apart from the punishments imposed on both the briber and the bribe recipient, extra measures may be imposed on a legal organization that profits from a bribe, according to the Criminal Code seizures of financial assets, such as property and earnings and cancellation of official licenses, such as a marketing authorization.
Certain pharmaceutical items must be sold solely in pharmacies, according to Article 28 of the Code on Pharmacists and Pharmacies. Human medicinal items, traditional herbal items, dietary food, and infant formulae are examples of these. In Turkey, there is no such thing as a "drugstore," hence every product that can be sold, whether it is over-the-counter or just by prescription, must be sold exclusively at a pharmacy. The sale of pharmaceutical products via the internet or any other electronic platform is prohibited by Article 24 of the Code on Pharmacists and Pharmacies. As a result, in Turkey, the selling of pharmaceutical products via the internet, e-mail, or mail order is prohibited.
Restrictions to the advertising and promotion of Medicinal Products
Advertising of medicinal products is governed by the Pharmaceutical Code and the Regulation of Promotional Activities of Medicinal Products for Human Use, as well as associated legislation. Human pharmaceutical product advertising to the general public is strictly prohibited in Turkey. The Pharmaceutical Code bans ads directed at healthcare professionals from overstating and exaggerating the therapeutic effects of pharmaceutical medicines. Furthermore, advertisements for prescription medicines can only be published in medical journals and media aimed at healthcare professionals. Before publishing such an advertisement, the Institution's prior consent must be acquired before publishing such advertisements.
Without the Institution's prior consent, healthcare practitioners and institutions are unable to participate in pharmaceutical product advertising. Authorization holders who violate the advertising limitations face heavy administrative fines up to five times the total sales value of the product in the previous year.
In terms of promotional restrictions, there is no difference between over-the-counter and prescription-only drugs; both groups are barred from advertising and marketing. In Turkey, internet advertising of pharmaceutical products is severely prohibited. The same is true for social media platforms.
Packaging, labelling, and tracking of medicinal products
The principal legislation regulating the packaging and labelling of medicinal items is the Regulation on Packaging Information, Inserts, and Tracking of Medicinal Products for Human Use (Regulation on Packaging). The Pharmaceutical Product and Medical Device Institution (Institution) continues to be the governing body.
Certain information must be included on the packaging, which can be summarized as follows:
- The medicinal product's name, strength, and pharmaceutical form. The name on the Institution-approved license or permit should be written if necessary, stating whether it is meant for babies, children, or adults.
- The active compounds' unit amount, route of administration, and weight or volume.
- The number of units in the package (tablets, ampoules, or bottles), as well as the volume, weight, or dosage number of active substances in pharmaceutical form.
- Colorants, preservatives, antioxidants, flavouring compounds, and alcohol are examples of excipients.
- A list of excipients with known side effects.
- Instructions and manner of application (if necessary).
- A particular warning noting that the medicinal product should be kept out of the reach of children and in its original packaging, as well as additional special warnings (as necessary).
- The medical product's storage conditions.
- A special warning about how to dispose of unused or discarded products, as well as the proper collection system if necessary.
- The package type's recyclable symbol, number, and abbreviation.
- The name and address of the manufacturer and the holder of the authorization/permit.
- The authorization or permit number for the medicinal substance.
- The batch number and expiration date of the medicinal substance.
- The expiration date of the medicinal product.
- If necessary, user instruction.
- Appropriate cautionary statements.
- Whether or not the pharmaceutical product requires a prescription;
- There is a barcode.
- Pricing information.
Each pharmaceutical product sold in Turkey should be labelled with a barcode and registered with the Drug Tracking System. The Drug Tracking System is a database created by the Ministry of Health under the Packaging Regulation that allows users to monitor a pharmaceutical product's route from production or importation to the end-user. To allow full monitoring of the product, each player in the pharmaceutical business should comply with their part of the notification obligations. For example, once a product is produced/imported, the producers/importers should assign a barcode to it and notify the Drug Tracking System.
Article 5 of the Packaging Regulation lays out the requirements for the packaging of pharmaceutical items. According to the article, the product package should include, among other things, the following:
- The product's name and the demographics to which it caters.
- The pharmaceutical product's shape, weight, volume, and dosage, as well as the mode of application.
- Information on the holder of the market authorization.
- A warning that the product should be kept out of the reach of minors.
Product safety, quality, and liability
The Code on Product Safety and Technical Regulations No. 7223 (Products Code) sets out the general framework for market monitoring and audits to be performed on any product put on the market in Turkey and can be regarded as the main legislation regarding product safety. Article 5 of the Recall Regulation provides the Institution with the power to do the following after it detects a defective medicinal product on the market.
The Code on Product Safety and Technical Regulations No. 7223 (Products Code) establishes the general framework for market monitoring and audits on any product placed on the Turkish market and can be considered the most important piece of product safety law. After discovering a defective pharmaceutical product on the market, the Institution has the authority under Article 5 of the Recall Regulation to perform the following:
- Compel the relevant company to provide information or an explanation.
- Assess the responsible company's explanations and determine the recall's class and severity.
- Keep track of the recall's progress.
- If necessary, halt production or import of the faulty pharmaceutical product.
- Complete the responsible company's recall process and manage the processes for closing the recall file.
- If the responsible company is found to be inept during the recall procedure, take the required steps.
- If the problem has been fixed, it will allow the pharmaceutical product to be released onto the market.
- If necessary, issue a second recall.
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